Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Gillespie SH, Crook AM, McHugh TD, et al. Four-month moxifloxacin-based regimens for drugsensitive tuberculosis. N Engl J Med 2014;371: DOI: /NEJMoa

2 REMox TB: A Phase 3 Trial of Two Four-Month Moxifloxacin-based Regimens for Drug-Sensitive Tuberculosis This supplement contains the following items: 1. Original protocol, final protocol, summary of changes 2. Original statistical analysis plan, final statistical analysis plan, summary of changes

3 Grace Hansen Editorial Assistant New England Journal of Medicine 10 Shattuck Street Boston, MA Dear Ms. Hansen Protocol 1.3 dated 05 Feb 2007 was the first version of the protocol globally implemented. Version 6.1 was the last protocol amendment to be implemented. Significant changes between V1.3 and V6.1 are listed below: Addition of pyridine, 10 mg, to be given to all subjects, addition of patients found to be HIV positive will be given co-trimoxazole prophylaxis according to the local National HIV/AIDS program guidelines, and additional that will be assessed for musculoskeletal toxicity at each appointment, and ethambutol associated ocular toxicity at baseline and week 8. Clarification of the study endpoints and that both comparisons (regimen 1 versus regimen 2, and regimen 1 versus regimen 3) were performed for all study endpoints. Clarification that the primary efficacy endpoint was defined by culture using solid media. Clarification of secondary study endpoints, including the addition of combined failure of bacteriological cure and relapse within one year of completion of therapy as defined by culture using liquid media. Increase in Sample size from 500 participants per treatment arm to 800 based on experiences from other trials and a submission made to the FDA for licensing of rifapentine an approach whereby all losses to follow-up after completion of treatment were classified as having an unfavorable response would mean that the true bacteriological failure/relapse rate, which was expected to be no more than 5% in the control regimen, would have been completely dominated by subjects classified in this way. In view of this it was proposed that in the primary analysis losses to follow-up after treatment were classified as being assessable unless there was any evidence the patient had active TB. This change also had implications for the section which defined primary outcome status. The original power calculations table was expanded to address a wider variety of scenarios and the number of subjects to be enrolled was increased to allow for expected losses during followup and to ensure 90% power was maintained. Inferiority margin (delta) increased from 5% to 6% in the unfavourable response rate and one sided significance level changed from0.05 to Losses to follow-up after completion of treatment classified as being unassessable (unless there was any evidence of active TB) versus unfavourable.

4 Clarification of the definition of outcome status, definition of relapse, and definition of primary outcome status, including: o Clarification of outcome status: At month 18, a subject is considered have negative sputum if he or she has two negative sputum samples in a row from either the same or different visits and has not had two (or more) positive cultures in a row post-treatment end. Additionally, if the subject had a single positive sputum culture any time posttreatment end, he or she must not have been re-treated. At month 18, if a subject s sputum sample culture is contaminated on solid medium, but the MGIT culture result is negative, the sputum sample will be considered to be negative. At month 18, a subject is considered to be positive if he or she has one or more positive, non- contaminated sputum cultures(s) from samples taken at the 18-month visit. o Clarification that a positive at 6 months could be re-infection or relapse, based on strain typing, because in the blinded study subjects on 6 month treatment regimen cannot be distinguished from those on a 4 month regimen o Additional definition of the primary outcome status including: The only exception to this will be for contaminated LJ samples, when no further sample can be obtained, then these subjects will be classified according to their MGIT result. Subjects who at 18 months or later who are clinically asymptomatic and unable to produce sputum who had not already been classified as having an unfavorable outcome. The power to demonstrate non-inferiority was changed from 90% to 85%, and the sample size was changed from 731 subjects in each regimen to 633 subjects in each regimen. Change in sponsor from UCL to TB Alliance Please feel free to contact me if you require further information. Sincerely Dr. Stephen H Gillespie MD DSc FRCP FRCPath Sir James Black Professor of Medicine Attachments: Protocol V1.3 dated 05Feb07 Protocol V6.1 dated 18Aug11 Statistical Analysis Plan V1.0 dated 09June11 Statistical Analysis Plan V2.2 plus addendum to 2.2 Changes made to SAP version 1.0 to Version 2.2 Final Integrated SAP Statistical Analysis Plan dated 07Jun13

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35 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Project Title: A randomised placebo controlled double blind trial comparing two treatment shortening regimens with the standard regimen (two months ethambutol, isoniazid, rifampicin and pyrazinamide followed by four months isoniazid and rifampicin) namely 1) two months moxifloxacin, isoniazid, rifampicin and pyrazinamide followed by two months moxifloxacin, isoniazid and rifampicin and 2) two months ethambutol, moxifloxacin, rifampicin and pyrazinamide followed by two months moxifloxacin and rifampicin for the treatment of adults with pulmonary tuberculosis Short Project Title: Controlled comparison of two moxifloxacin containing treatment shortening regimens with the standard regimen in pulmonary tuberculosis. Chief Investigator: Professor Stephen H. Gillespie, Centre for Clinical Microbiology, University College Medical School, London, UK. Principal Investigators: Principal investigators and sites are listed in Appendix 4. Sponsor Global Alliance for TB Drug Development, New York, USA Funding: European and Developing Countries Clinical Trials Partnership (EDCTP), The Hague, The Netherlands. Global Alliance for TB Drug Development, New York, USA. 1

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37 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Table of Contents 1. Study Clinician contact information Summary Lay summary Summary of trial design Study hypotheses Disease/patients studied Trial interventions research and control Study endpoints Primary study endpoints Secondary study endpoints Duration of patient participation Data recording Ancillary studies/sub studies Background Fluoroquinolones Moxifloxacin Relevant studies/trials Risks and benefits Study objectives Sites Investigational plan Study design Population Inclusion/exclusion criteria Patient inclusion criteria Patient exclusion criteria Screening procedures and pre-randomisation investigations Enrolment Treatments to be administered Trial regimens Dosage adjustments Supervision of dosage and adherence Identity of investigational products Randomisation Randomisation schedule Blinding Unblinding of the randomisation Assessments and procedures Enrolment Post-enrolment Biostorage of specimens for subsequent biomarker studies Management of Unscheduled Visit Management of Early/Late Visit Procedures for assessing efficacy Summary of Bacteriological methods Procedures for assessing safety

38 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Defining outcome status Definition of treatment failure Definition of relapse Removal of subjects from the study (including removal from study treatment) Discontinuation of study treatment Withdrawal from the study Lost to follow-up Premature termination of study or closure of a study site Data quality Data monitoring Clinical site monitoring Direct access to data Quality assurance and quality control of data Laboratory quality assurance Documentation Ethical considerations National and local ethics committees Ethical conduct of the study Regulatory authority approvals Subject information and Informed Consent Insurance Confidentiality Statistical considerations Analysis population Determination of sample size Statistical and analytical plan Definition of primary outcome status Primary efficacy endpoint Primary safety endpoint Secondary endpoints Sub-group analyses Surrogacy Method comparison Additional secondary analyses Interim monitoring and analyses Safety reporting Definitions Adverse event Serious adverse event Life-threatening Hospitalisation Disability Important medical event Unexpected adverse event Relationship of adverse event to investigational product Severity of the adverse event

39 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Recording and reporting of Adverse Event Management of adverse events Criteria for discontinuation of study drugs Criteria for temporary discontinuation of study therapy Criteria for permanent discontinuation of study therapy Trial Committees Trial Steering Committee (TSC) Independent Data Monitoring Committee (IDMC) Publications and Sharing Study Results & Information with Investigators References Appendices Signatures Sponsor s Representative Investigator(s) Glossary of abbreviations

40 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Study Clinician contact information Reporting of serious adverse events Any serious adverse events, including death due to any cause, which occurs to any patient entered into treatment in this study or within 14 days of the final study visit, whether or not related to the investigational product, must be reported within 24 hours using the following contact details. All patients with serious adverse events must be followed up for outcome. Alert study clinician on call by phone or Tel: _44 (0) remox@instant .t-mobile.co.uk AND remoxtb_trial@ctu.mrc.ac.uk Forward form by fax OR scan and Fax: +27 (0) remoxsafety@tballiance.org AND remoxtb_trial@ctu.mrc.ac.uk See Protocol Section for definition of serious and other adverse events 6

41 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Summary 2.1 Lay summary The current recommended treatments for tuberculosis (TB) require a patient to take multiple drugs for six to eight months. Because the course of therapy is long, many patients do not adhere to treatment and as a consequence they have a poor outcome. In these cases either the sputum is not cleared of the bacteria causing tuberculosis, or the disease returns again (called relapse). Response to medication can be monitored during treatment by collecting regular sputum samples and examining these samples by culture, for the organisms that cause tuberculosis. The commonly used drugs to treat tuberculosis are rifampicin, isoniazid, ethambutol and pyrazinamide. Previous studies in animals and in humans suggest that a new drug called moxifloxacin may also be an effective treatment in tuberculosis. Moreover, promising laboratory studies on mice suggest that moxifloxacin may enable the total duration of chemotherapy to be reduced to four months, which would be a significant improvement for patients taking medication for tuberculosis. This study will involve comparisons that are designed to assess whether substituting moxifloxacin for individual drugs in existing treatment combinations will enable tuberculosis treatment to be shortened. Patients selected for the study will be allocated to one of three treatment groups. The first group will be given six months standard treatment. A second group will receive moxifloxacin substituted for ethambutol, as part of a four month regimen, to see whether the shorter treatment is as effective as the standard six month treatment. The third group will receive moxifloxacin substituted for isoniazid, as part of a four month regimen, to see whether the shorter treatment is as effective as the standard six month treatment. 7

42 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 At selected sites, additional blood, urine, and sputum specimens will be collected for biostorage for biomarker studies. These samples will be stored at a central bio-repository for the discovery and validation of TB drug effect biomarkers. No human genetic testing on these samples will be performed. The Biostorage substudy is further described in the Biostorage Protocol Addendum which will be implemented only at participating sites. 2.2 Summary of trial design Study hypotheses 1) In treatment-naïve adults with active pulmonary TB treated with eight weeks of moxifloxacin (M), isoniazid (H), rifampicin (R) and pyrazinamide (Z) (i.e. a standard regimen where moxifloxacin is substituted for ethambutol (E)), followed by nine weeks of moxifloxacin, isoniazid and rifampicin, followed by nine weeks of placebo, the proportion of patients who experience treatment failure or disease relapse in the twelve months following treatment completion will not be inferior to that observed in patients who are treated with a standard regimen (eight weeks of ethambutol, isoniazid, rifampicin and pyrazinamide followed by eighteen weeks of isoniazid plus rifampicin) (Comparison 1). See Fig. 1 REMox Trial Design. 2) In treatment-naïve adults with active pulmonary TB treated with eight weeks of ethambutol, moxifloxacin, rifampicin and pyrazinamide (i.e. a standard regimen where moxifloxacin is substituted for isoniazid), followed by nine weeks of moxifloxacin and rifampicin followed by nine weeks of placebo, the proportion of patients who experience treatment failure or disease relapse in the twelve months following treatment completion will not be inferior to that observed in patients who are treated with a standard regimen (eight weeks of ethambutol, isoniazid, rifampicin and pyrazinamide followed by eighteen weeks of isoniazid plus rifampicin) (Comparison 2). See Fig. 1 REMox Trial Design. 8

43 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Disease/patients studied Patients with newly diagnosed previously untreated sputum smear positive pulmonary tuberculosis Trial interventions research and control Patients will be randomised to receive, at appropriate dose for weight, one of three regimens: 1. 2EHRZ/4HR (Regimen 1 - the control regimen) - Eight weeks of chemotherapy with ethambutol, isoniazid, rifampicin and pyrazinamide plus the moxifloxacin placebo, followed by - Nine weeks of isoniazid and rifampicin plus the moxifloxacin placebo, followed by 9

44 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Nine weeks of isoniazid and rifampicin only. 2. 2MHRZ/2MHR (Regimen 2) - Eight weeks of chemotherapy with moxifloxacin, isoniazid, rifampicin and pyrazinamide plus the ethambutol placebo, followed by - Nine weeks of moxifloxacin, isoniazid and rifampicin, followed by - Nine weeks of the isoniazid placebo and the rifampicin placebo. 3. 2EMRZ/2MR (Regimen 3) - Eight weeks of chemotherapy with ethambutol, moxifloxacin, rifampicin and pyrazinamide plus the isoniazid placebo, followed by - Nine weeks of moxifloxacin and rifampicin plus the isoniazid placebo, followed by - Nine weeks of the isoniazid placebo and the rifampicin placebo. 2.3 Study endpoints The study consists of two comparisons: Comparison 1 (regimen 1 versus regimen 2) and Comparison 2 (regimen 1 versus regimen 3) (Figure 1). Both comparisons will be performed for all study endpoints Primary study endpoints 1. Efficacy: Combined failure of bacteriological cure and relapse within one year of completion of therapy as defined by culture using solid media. 2. Safety: Both comparisons: Proportion of patients with grade 3 or 4 adverse events Secondary study endpoints Efficacy: 1. Combined failure of bacteriological cure and relapse within one year of completion of therapy as defined by culture using liquid media 10

45 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 The following endpoints will be measured separately using both solid and liquid media: 2. Sensitivity analyses assuming all losses to follow-up and non-tuberculous deaths have an unfavourable outcome. 3. Sensitivity analyses assuming all losses to follow-up and non-tuberculous deaths have a favourable outcome. 4. Proportion of patients who are culture negative at eight weeks. 5. Time to first culture negative sputum sample. 6. Speed of decline of sputum viable count. 2.4 Duration of patient participation All patients will be followed for 18 months (6 months treatment and 12 months follow-up). 2.5 Data recording Data collected will be maintained in a clinical database. Data will be recorded on paper or in electronic case report forms. 2.6 Ancillary studies/sub studies 1. A pharmacokinetic study will be performed on a sub-set of patients. 2. Studies to monitor the bacteriological load and immune response and the way in which these data can be used to predict the treatment outcome will also be performed. 3. A Biostorage substudy will be performed at selected sites to collect and store blood, plasma, urine, and sputum from enrolled patients for the discovery and validation of TB drug effect biomarkers. 11

46 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Background The treatment of tuberculosis depends on patients adhering to a regimen of antituberculosis drugs over an extended period of time. A series of clinical trials has resulted in a reduction in the length of therapy from 24 months to six months(1;2). Under trial conditions the cure rates of the 2EHRZ/4HR regimen are approximately 95%(3) but under programme conditions cure rates can be much lower(4). Directly observed therapy short-course (DOTS) was proposed as the solution to poor adherence but reports suggest that in some DOTS programmes less than 70% of patients achieve a cure(4). Since patients feel better long before it is safe for them to discontinue antibiotic therapy, adherence to treatment is difficult to maintain in tuberculosis. Improved adherence might be achieved if the length of therapy could be reduced significantly. Moreover, many patients may not require more than 4 months treatment (5). To date there are no effective 4 month regimens although several have been trialled(6). The closest comparator to 2EHRZ/2HR is 2SHRZ/2HR and 2SHRZ/2HRZ but these had an unacceptably high combined relapse rate in patients with fully sensitive organisms of 13%, i.e. 28 of 208 patients assessed (6). Similar results were obtained in a study in Singapore using the same regimens (6). 3.1 Fluoroquinolones Fluoroquinolones have considerable activity against mycobacteria in vitro and in animal models(7;8). They are bactericidal and penetrate well into pulmonary tissue. They are taken up by macrophages and therefore are ideally suited as an anti-tuberculosis drug. Earlier compounds were mainly active against Gramnegative pathogens, but the fluoroquinolones such as ciprofloxacin had an increased potency against Gram-negative pathogens and a wider spectrum that included staphylococci and mycobacteria. Ciprofloxacin has been shown to have useful activity(9) and a controlled clinical trial indicated that for HIV seronegative individuals a regimen of isoniazid, rifampicin and ciprofloxacin was well tolerated and effective(10). It is for this reason that quinolones have found an important 12

47 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 role in therapy when the standard regimen cannot be prescribed because of toxicity or antibiotic resistance(11;12) Moxifloxacin Moxifloxacin is an 8-methoxyquinolone that has been introduced into clinical practice especially for the treatment of respiratory tract infections. It has enhanced activity against Gram-positive pathogens, and anaerobes while retaining useful activity against Gram-negative organisms. It has been shown to inhibit the growth of the main species of mycobacteria infecting humans(13;14). Studies of the activity of moxifloxacin in mouse models also suggest that it has important bactericidal activity(14-17). We have previously evaluated the bactericidal activity of moxifloxacin in African patients with smear positive pulmonary tuberculosis. In this study patients were given moxifloxacin alone for five days and the effect of the drug compared with that of isoniazid and rifampicin. Moxifloxacin proved to be highly bactericidal with activity slightly less than isoniazid but similar to rifampicin(18). The next stage in the process of identifying the value of moxifloxacin in therapy of tuberculosis is to trial combinations of drugs. Data on the long-term use of moxifloxacin show that it has an excellent safety profile(19). Previous studies have added new agents to standard regimens, but this approach has many drawbacks. Under trial conditions any ethically approved control regimen will have greater than 95% efficacy making it very difficult to show any further benefit from the addition of a new drug. This is illustrated by the trial of levofloxacin in which the quinolone was added to standard therapy without significant benefit(20). It is important therefore to design a trial that does not obscure any activity of the new agent. Clinical trials in tuberculosis in which relapse is the primary endpoint require longterm follow-up. Current chemotherapeutic regimens provide relapse rates of 5% or less and, therefore, very large numbers of patients are required to 13

48 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 demonstrate superiority of a new regimen. We have previously shown that the risk of relapse can be predicted from culture negativity at two months although this in part is dependent on the continuation regimen(6,21). We argue, therefore, that if treatment is to be shortened significantly the new regimen would need to produce a more rapid sputum conversion than the currently recommended four drug regimen. The validity of this approach is demonstrated by the MRC/East Africa study that showed that both the proportion of patients with positive cultures at two months and relapse rates were lower when pyrazinamide was added to a rifampicin-containing regimen(22). Additionally, by using time to culture negativity as a secondary endpoint it may be possible to demonstrate improved bactericidal activity. For both comparisons data on two month positivity and combined failure of bacteriological cure and relapse within one year of completion of therapy will be measured. This will allow us to confirm the relationship between two-month culture negativity and relapse, and to explore the relationship between the time to first negative sputum culture and relapse. 3.2 Relevant studies/trials In a study at the Tuberculosis Research Site, Chennai, India, a regimen of three months of ofloxacin, isoniazid, rifampicin and pyrazinamide (OHRZ) followed by only one month of twice weekly isoniazid and rifampicin resulted in sputum conversion in 95% of patients at two months and a 3% relapse rate after treatment (23). This suggests that quinolone containing regimens may shorten therapy. It is notable that earlier five month studies with other drug combinations starting with two months of streptomycin, isoniazid, rifampicin and pyrazinamide (SHRZ) had a sputum conversion of 91% and a relapse rate of 4% (6). In a review of all available short-course regimens, a mean relapse rate of 3% was found after regimens lasting months and 12% after regimens lasting four months (6,22) similar to that in the Chennai ofloxacin study. If fluoroquinolones are to reduce the duration of therapy significantly a more bactericidal agent such as moxifloxacin would be necessary. 14

49 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 The IUATLD study A showed that ethambutol plus isoniazid in a six month continuation phase was inferior to a four month continuation of isoniazid plus rifampicin. A reanalysis of Jindani s original early bactericidal study suggested that ethambutol may reduce the bactericidal activity of isoniazid and rifampicin (24;25). Several groups are currently evaluating moxifloxacin as a substitute for ethambutol. Evidence from a recent mouse study showed that there was a significant improvement in the response with moxifloxacin, rifampicin and pyrazinamide (MRZ) compared to moxifloxacin, isoniazid, rifampicin and pyrazinamide (MHRZ) suggesting the possibility that rifampicin and isoniazid may be antagonistic(16). Such an antagonism is plausible and has been demonstrated between antibiotics that inhibit protein synthesis and those that interfere with cell wall metabolism(26). In a second murine study, MRZ proved to be the optimum regimen tested (none of them contained ethambutol) (27). This provides compelling evidence why the various substitution regimens should now be tested in humans. The recent Tuberculosis Clinical Trials Consortium (TBTC) Study 27 showed that an increased proportion of patients treated with an ethambutol substitution regimen were culture negative after four and six weeks indicating that this regimen provides more rapid bacterial killing than the control arm, although at eight weeks the culture conversion rates for the two arms were identical (28). A phase IIb study of the moxifloxacin for isoniazid substitution (TBTC Study 28) has been reported and showed in a small but statistically non-significant increase in week-8 culture negativity indicating it was appropriate to continue to a phase III trial. There is a possibility that either or both of the four month regimens may be demonstrated to be non-inferior when compared to the control regimen providing a substantial advantage in patient adherence and treatment completion rates. 15

50 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Risks and benefits The major problem with chemotherapy for tuberculosis is that successful regimens are too long. As a result, adherence to treatment and consequently outcomes are frequently poor. The development of shorter regimens would provide a major benefit for public health by ensuring a higher completion rate, and reducing the risk of emergence of multiple drug resistance. For individuals participating in this trial there is a possibility that either or both of the study regimens may prove superior to the standard regimen: the ethambutol substitution by removing the potential antagonism between isoniazid and ethambutol and substituting a more bactericidal drug, and the isoniazid substitution by removing the potential rifampicin isoniazid antagonism. It is generally accepted that ethambutol, a drug with no apparent sterilizing activity, contributes little to the intensive phase of short course regimens in patients with fully sensitive organisms; it carries a risk of optic neuritis at a dose level of 25 mg/kg or higher. On the other hand it is possible that either or both of these regimens could prove inferior. As it has been shown previously that the bactericidal activity of moxifloxacin is similar to isoniazid, the degree of inferiority, if any, is likely to be slight. TBTC Study 27 results suggest that an ethambutol substitution is unlikely to be inferior. Additionally, further sterilising activity is being added by the use of moxifloxacin in the continuation phase. Although relapse rates could be higher in the shortened four month regimen based on data from earlier studies of four month regimens, relapsing patients will almost certainly be re-treatable with drugs in the existing regimens. In addition to this, the results of study 28 have provided additional support for this study. There is a possibility that the moxifloxacin regimens might prove more toxic than the standard arm. This is unlikely as the toxicity profile for moxifloxacin is well known (Investigator s Brochure) and there is sufficient toxicity data collected to indicate that two month moxifloxacin containing regimens are safe. Moxifloxacin 16

51 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 is now being used regularly in the treatment of patients with tuberculosis who are not able to tolerate the standard therapy. Patients in this trial will be closely monitored for adverse events and for this reason we have chosen to use a double blind approach to examine this objectively. An Independent Data Monitoring Committee (IDMC) will review safety and efficacy data regularly. All patients who enrol in the study will benefit indirectly as it is well established that the outcome for patients enrolled in tuberculosis trials is better than patients in routine care. 3.4 Study objectives The purpose of this study is to evaluate the efficacy, safety and acceptability of two moxifloxacin-containing regimens to determine whether substitution for ethambutol or isoniazid makes it possible to reduce the duration of chemotherapy. This will be achieved: a) by testing a four month regimen which replaces ethambutol with moxifloxacin to determine whether it is not inferior to the current standard six month regimen. b) by testing a four month regimen which replaces isoniazid with moxifloxacin to determine whether it is not inferior to the current standard six month regimen. 4. Sites Sites with a caseload of newly diagnosed patients with tuberculosis have been selected to participate in the study. In order to complete the study in a shorter period of time additional sites with a caseload of newly diagnosed patients with tuberculosis may be recruited. 17

52 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Investigational plan 5.1 Study design A randomised placebo controlled double blind trial involving 1) a treatment shortening regimen comparing two months moxifloxacin, isoniazid, rifampicin and pyrazinamide followed by two months moxifloxacin, isoniazid and rifampicin with the standard regimen (two months ethambutol, isoniazid, rifampicin and pyrazinamide followed by four months isoniazid and rifampicin) and 2) a treatment shortening regimen comparing two months ethambutol, moxifloxacin, rifampicin and pyrazinamide followed by two months moxifloxacin and rifampicin with the standard regimen, for the treatment of adults with pulmonary tuberculosis. 5.2 Population This will be a multi-site, international study. Newly diagnosed, previously untreated, male and female patients who are sputum smear-positive for tubercle bacilli will be entered into the study from these sites. A total of 1900 patients will be recruited into the study. 5.3 Inclusion/exclusion criteria In order to be randomised all patients must meet all the inclusion criteria and none of the exclusion criteria Patient inclusion criteria A. Signed written consent or witnessed oral consent in the case of illiteracy, before undertaking any trial related activity. B. Two sputum specimens positive for tubercle bacilli on smear microscopy at least one of which must be processed and positive at the study laboratory. C. Aged 18 years or over. 18

53 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 D. No previous anti-tuberculosis chemotherapy. E. A firm home address that is readily accessible for visiting and willingness to inform the study team of any change of address during the treatment and follow-up period. F. Agreement to participate in the study and to give a sample of blood for HIV testing (see appendices 1 & 2). G. Pre-menopausal women must be using a barrier form of contraception or be surgically sterilised or have an IUCD in place. H. Laboratory parameters performed up to 14 days before enrolment. Serum aspartate transaminase (AST) and alanine transaminase (ALT) activity less than 3 times the upper limit of normal Serum total bilirubin level less than 2.5 times upper limit of normal Creatinine clearance (CrCl) level greater than 30 mls/min Haemoglobin level of at least 7.0 g/dl Platelet count of at least 50x10 9 cells/l Serum potassium greater than 3.5 mmol/l I. Negative pregnancy test (women of childbearing potential) Patient exclusion criteria A. Unable to take oral medication. B. Previously enrolled in this study. C. Received any investigational drug in the past 3 months. D. Received an antibiotic active against M. tuberculosis in the last 14 days (fluoroquinolones, macrolides, standard anti-tuberculosis drugs). E. Any condition that may prove fatal during the first two months of the study period. F. TB meningitis or other forms of severe tuberculosis with high risk of a poor outcome G. Pre-existing non-tuberculosis disease e.g. diabetes, liver or kidney disease, blood disorders, peripheral neuritis, chronic diarrhoeal disease in which the 19

54 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 current clinical condition of the patient is likely to prejudice the response to, or assessment of treatment. H. Pregnant or breast feeding. I. Suffering from a condition likely to lead to uncooperative behaviour e.g. psychiatric illness or alcoholism. J. Contraindications to any medications in the study regimens. K. Known to have congenital or sporadic syndromes of QTc prolongation or receiving concomitant medication reported to increase the QTc interval (e.g. amiodarone, sotalol, disopyramide, quinidine, procainamide, terfenadine). L. Known allergy to any fluoroquinolone antibiotic or history of tendinopathy associated with quinolones. M. Patients already receiving anti-retroviral therapy. N. Patients whose initial isolate is shown to be multiple drug resistant (i.e. resistant to rifampicin and isoniazid) or monoresistant to rifampicin, or resistant to any fluoroquinolone). (See Section 5.9.2) O. Weight less than 35kg P. HIV infection with CD4 count less than 250 cells/µl. Q. End stage liver failure (class Child-Pugh C). 5.4 Screening procedures and pre-randomisation investigations Patients documented to be sputum smear microscopy positive for tubercle bacilli will be invited to participate in the trial. They will be given a patient information sheet (Appendix 1) about the trial and will be explained the benefits and the risks associated with all the protocol procedures. Screening or any other study specific procedure will be initiated after the patient has signed the Informed Consent form. Patients will be told that screening includes collecting a sputum sample for smear and culture and blood samples for safety assessments (as per the Summary Chart of Assessments and Procedures in Section 5.8.2). A urine sample will be collected for pregnancy testing if applicable. Blood analysis will include testing for HIV by an agreed algorithm. The patient will be encouraged to receive their HIV result, but may choose not to be informed of the result (see 20

55 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Appendix 5 for procedure). HIV seropositive individuals, who agree, will be referred to the local HIV services. Patients will be told that participation in the trial will require that they attend weekly for sputum culture, physical exam and vital sign assessments for the first eight weeks and monthly thereafter until completion of treatment (for details see Summary Chart on page 31). Subsequent follow-up visits will be scheduled on a 3 monthly basis until the end of the follow up phase at 12 months post treatment completion. Patients will also be informed that any information collected that is entered into the database for the trial, or sent to the laboratory will be identified by a unique patient number and their initials but not by name. They will be told that they will be free to withdraw from the study at any time and if they do so this will not jeopardise their future care. If the site staff are satisfied that the patient understands the information contained in the Patient Information Sheet about the study procedures, and is willing to continue, the patient will be asked to consent to participate in the study either by signature or by thumbprint (if the volunteer is illiterate) on the Informed Consent form (Appendix 2). Illiterate volunteers will be required to have a witness present (friend, family or another member of staff independent of the study team) to witness the discussion and thumbprint consent. Participants will be given a copy of the signed/thumb-printed consent form and an information sheet to take away if they wish. A list of unique screening numbers will be provided to each site by the Sponsor. Once a participant has signed the Informed Consent Form, their details will be recorded on a screening register. For those found to be ineligible during the screening process, the reason for non-inclusion should be recorded on the screening register. 21

56 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Enrolment Patients who following the screening assessments remain eligible for the trial and are willing to participate, will be randomised into the study and assigned a Randomization Number. The Randomization Number combined with the Country Code and the Site Number will form the Patient Number. The Patient Number will serve as a unique identifier for the duration of the study. All patients participating in the study will be required to attend weekly for sputum culture assessments for eight weeks and then for subsequent follow-up. They will be informed that any information collected that is entered into the database for the trial, or sent to the laboratory, will be identified by a number and their initials but not by name. They will be told that they will be free to withdraw from the study at any time and if they do so this will not jeopardise their future care. Contact details of participants will be collected, but are confidential and will remain at the clinic. At selected sites, enrolled patients will also have the option of participating in the Biostorage substudy. Refer to the Biostorage substudy Addendum for full details. All patients providing their consent to participate in the study may be asked to provide their consent for the biostorage of additional specimens for biomarker tests. Those providing their consent for biostorage of their specimens will be requested to give blood, urine, and sputum samples at baseline, at weeks 2, 4, 8 17, and 26, and at month 12 of the study and at any visit at which a recurrence of TB is suspected. No human genetic testing on these samples will be performed. 22

57 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Treatments to be administered Trial regimens Patients will be randomised to receive, at appropriate dose for weight, one of three regimens: 1 2EHRZ/4HR (Regimen 1 - the control regimen) - Eight weeks of chemotherapy with ethambutol, isoniazid, rifampicin and pyrazinamide plus the moxifloxacin placebo, followed by - Nine weeks of isoniazid and rifampicin plus the moxifloxacin placebo, followed by - Nine weeks of isoniazid and rifampicin. 2 2MHRZ/2MHR (Regimen 2) - Eight weeks of chemotherapy with moxifloxacin, isoniazid, rifampicin and pyrazinamide plus the ethambutol placebo, followed by - Nine weeks of moxifloxacin, isoniazid and rifampicin, followed by - Nine weeks of the isoniazid placebo and the rifampicin placebo. 3 2EMRZ/2MR (Regimen 3) - Eight weeks of chemotherapy with ethambutol, moxifloxacin, rifampicin and pyrazinamide plus the isoniazid placebo, followed by - Nine weeks of moxifloxacin and rifampicin plus the isoniazid placebo, followed by - Nine weeks of the isoniazid placebo and the rifampicin placebo. All therapy will be taken orally, seven days a week. All patients will receive pyridoxine. 23

58 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Dosage adjustments Doses of study medications during the intensive phase will be determined by body weight as follows: Drug Dose for daily therapy Moxifloxacin 400 mg Rifampicin < 45 kg 450 mg > 45 kg 600 mg Isoniazid 300 mg Pyrazinamide < 40 kg 25 mg/kg rounded to nearest 500 mg* kg 1000 mg > 55 kg 75 kg 1500 mg > 75 kg 2000 mg Ethambutol < 40 kg 15 mg/kg rounded to nearest 100 mg kg 800 mg > 55 kg 75 kg 1200 mg > 75 kg 1600 mg * for pyrazinamide dosing in patients < 40 kg, 1000 mg used instead of 500 mg Patients who during the course of the trial require anti-retroviral therapy, will be given a regimen that substitutes nevirapine with efavirenz. All patients will be given pyridoxine 10mg daily as prophylaxis against peripheral neuropathy. Patients found to be HIV positive may be given co-trimoxazole prophylaxis according to the HIV/AIDS guidelines implemented locally. The prescription of cotrimoxazole will be recorded in the patient s CRF. 24

59 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Patients who have malaria at screening will be excluded (see exclusion criteria E and J). However if a patient develops malaria during the course of the study, the investigator is advised to consult the guidance document regarding the interaction between Moxifloxacin and anti-malarial drugs distributed as part of the training material for the trial (Training Update Memo # 28). Investigators may also contact Study Clinician for further guidance Supervision of dosage and adherence Chemotherapy will be administered on a supervised basis; the mechanism for doing this may vary according to local circumstances. Each Investigator Site will provide a local procedure to indicate how patients have treatment supervised at their local setting. The importance of adherence should be reinforced at each visit. Patients missing 7 or more doses of study drug may extend the duration of treatment period in order to complete the prescribed number of doses (Section 7.3.2). Nonadherence should prompt the clinician to identify and address the cause(s) (e.g. side effects) and contact the study clinician on call. If for any reason (including non adherence) the managing clinician thinks the patient needs to restart TB therapy, this should be discussed with the study clinician on call. Adherence will be recorded at each study visit. This information will be used to define the per protocol analysis population (see Section 7) Identity of investigational products Chemotherapeutic agents will be labelled according to the local regulatory requirements. The package inserts, investigator brochure, Certificate of Analysis and pharmacy manual will be provided to investigators. 25

60 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Randomisation Eligible patients will be randomised by entering their name on the next available line of the study register. This will assign a Randomisation Number to the patient, corresponding to a treatment regimen on the randomisation schedule. The Randomisation Number combined with the Country Code and the Site Number will form the Patient Number. The Patient Number will serve as a unique identifier and be used on all documentation relating to the study and should never be given to any other patient Randomisation schedule The randomisation schedule will be produced centrally by the Sponsor, using randomised blocks of variable size. Randomisation will be stratified by five weight bands. The study pharmacist or delegate will randomise eligible patients by allocating them to the next randomisation number from the appropriate weight range on the study register. This number corresponds to the treatment pack to be given to that patient. Each patient will be randomised to receive either the 2EHRZ/4HR, 2MHRZ/2MHR or 2EMRZ/2MR regimen, with equal probability of being allocated to any one regimen Blinding This will be a blinded study with matching placebo for each of the study medicines except for pyrazinamide Unblinding of the randomisation Unblinding is discouraged except on safety grounds. Prior to unblinding there should be consultation with, and authorisation from the Chief Investigator or a clinical member of the sponsor team. The study clinician on call (can be contacted by telephone on +44 (0) or at remox@instant .t-mobile.co.uk). All instances of unblinding should be 26

61 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 recorded together with the reason for unblinding. IMPORTANT unblinding of the randomization should be kept confidential and restricted to the managing clinician(s) responsible for the case. 5.8 Assessments and procedures Enrolment Patients will undergo a baseline clinical examination including a PA chest X-ray unless one was taken as a part of the clinical investigation of their TB. A digital image of the chest X-ray will be sent electronically to the study clinician (see Appendix 6 for procedure). At baseline two sputum specimens (from those collected at screening and baseline) will be processed for culture. A physical examination/vital signs assessment, visual tests (Isihara and Snellen) will be carried out. A urine sample for urinalysis will be collected at baseline as part of the clinical evaluation of the subject (data will not be recorded in the Case Report Form). After review of all inclusion and exclusion criteria and eligibility is confirmed, patients will be enrolled in the trial and will receive study medication. Patients at selected sites may also have the option of participating in the Biostorage substudy (refer to the Biostorage Protocol Addendum for full details) Post-enrolment The scheduled dates for study visits will all be individually calculated from the date of the baseline visit. Study visits for weeks 1 to 7 may occur from 3 days before to 3 days after the scheduled day, for week 8 the visit may be from 3 days before to 1 week after, for weeks 12 to 22 from 2 weeks before to 2 weeks after and for week 26 from 2 weeks before to 6 weeks after the scheduled day. For visits at month 9 (week 39), month 12 (week 52), month 15 (week 65) and month 18 (week 78) the visit may occur from 6 weeks before to 6 weeks after the scheduled day. 27

62 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 During the first eight weeks post-enrolment patients will be required to attend the clinic every week to undergo a physical examination/vital signs assessment, to provide a sputum specimen (preferably early morning the first sputum of the day) for smear, culture, and to be assessed for possible adverse events. For the remainder of the 6 months on trial drugs patients will be seen at the clinic monthly (weeks 12, 17, 22 and 26) where they will have a physical examination/vital signs assessment, will be questioned about possible adverse effects of treatment and asked to provide a sputum specimen (preferably early morning) for smear and culture. At some visits (weeks 2, 4, 8, 12 and 17) patients will also undergo blood testing as outlined in the Summary Chart of Assessment and Procedures. The treatment phase will end at month 6 (week 26) (unless treatment phase needs to be extended) and thereafter the patients will attend the clinic at months 9 (week 39), 12 (week 52), 15 (week 65) and 18 (week 78). After treatment has begun to be effective, it is possible that patients will no longer be able to produce sputum. If this is confirmed by study staff, the patient s inability to produce sputum should be noted in the source. Saliva should not be collected in the place of a sputum sample. Should the laboratory report that the 18 month sputum sample is contaminated on both solid and liquid (MGIT) culture, the patient should be requested to return to the clinic (repeatedly if necessary until at the latest, 6 weeks after the 18 month visit of the Last Patient In), to provide a repeat sputum specimen (preferably one early morning sample first of the day - and an additional spot sample) until either an uncontaminated sputum specimen is cultured and reported or the subject is documented to be clinically asymptomatic and unable to produce sputum. If the patient is unable to produce sputum, this should be documented in the source. Saliva should not be collected in place of sputum. Additionally, the presence or absence of any clinical symptoms related to TB should be noted. The treatment period may be extended to allow the patient to complete the course of treatment due to missed doses (refer to Section 7.3.2). In this case 28

63 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 assessments and procedures should be conducted as per the corresponding treatment phase. Thus patients receiving intensive active phase treatment should continue weekly visits until this treatment phase is complete. Additional unscheduled visits may be required. It is important that a visit occurs and a sputum sample is collected at the end of each treatment phase. At each followup clinic visit the patient will be asked to provide two sputum specimens (preferably one early morning sample and one additional sample) for smear and culture, a physical examination/vital signs assessment will be performed, the possible occurrence of adverse events will be evaluated. Patients will be assessed for musculoskeletal toxicity (arthrotoxicity, chondrotoxicity or tendon rupture) at each visit during treatment and follow-up phases of the study, until the last follow-up visit. This will be performed by study clinic staff and will involve history taking and physical examination. Ocular toxicity will be assessed using the Snellen and Ishihara tests at baseline and week 8. Guidelines for performing these tests can be found in Appendix 10. The patients will be instructed about symptoms of ocular toxicity at the onset of therapy, and will be asked if they have any symptoms at each assessment visit during the first two months of therapy when they may be receiving ethambutol. Snellen and Ishihara tests should be repeated if any symptoms or change in vision is suspected. One sputum specimen (preferably early morning) will be collected at each weekly and monthly visit during the treatment phase. Two samples will be collected at the three-monthly follow-up assessments (preferably one early morning sample and one additional sample). For unscheduled visits before week 17, one sputum specimen will be collected and tested. Two sputum specimens will be collected and tested for those patients who return for an unscheduled visit after week

64 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 In the event of a positive smear at week 17 the following actions need to be implemented: a. Take a repeat sputum sample to confirm the result b. Report (by fax/ ) the smear positive result within 24 hours of being available on Form EF16 In the event of positive smear after week 17 the following actions need to be implemented: a. Take a repeat sputum sample to confirm the result In the event of a positive culture confirmed as M. tuberculosis at or after week 17 the following actions need to be implemented: a. Take a repeat sputum sample b. Report (by fax/ ) culture positive result within 24 hours of being available on Form EF16 TB treatment change (including restarting treatment) is usually not indicated by a single positive smear or culture. Treatment change is usually not considered unless there is clinical evidence of deterioration or relapse in symptoms or on chest X-ray. If the patient remains well clinically, i.e., there is no clinical or radiological evidence of failure or relapse, the clinician may consider to request additional sputum samples and review the patient s progress in two to four weeks time depending on the clinical condition of the patient. If a treatment change is being considered: a. Take additional samples to ensure that a total of three sputum samples have been collected for smear and culture before any change or restart of treatment occurs. b. Discuss proposed treatment change with study clinician before implementing (alert using EF 16) and schedule next visit as clinically indicated. 30

65 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Biostorage of specimens for subsequent biomarker studies At selected sites, enrolled patients will be given the option to participate in the Biostorage substudy. If the patient has consented to specimens for biostorage being collected then additional blood, urine and sputum specimens will be collected at baseline and weeks 2, 4, 8, 17, and 26, and at month 12 of the study and at any visit at which a recurrence of TB is suspected, for conducting biomarker tests at a later date. No human genetic testing on these samples will be performed. Refer to the Biostorage substudy Protocol Addendum for full details Management of Unscheduled Visit Any visit which is conducted in addition to those required as per the Summary Chart of Assessments and Procedures should be considered unscheduled regardless of the reason for the visit. The assessments which are undertaken as part of an unscheduled visit should be as clinically indicated. At a minimum, a sputum sample must be collected at every unscheduled visit, if the patient is capable of producing sputum. 31

66 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Visit Windows Up to 14 days after screening Summary Chart of Assessments and Procedures +/- 3 days Active Treatment Phase - 3 days +1 week after +/- 2 weeks (except week 26 to +6 weeks after) Follow-Up Phase Week Week Mnth Activity Screen Base- Week Week Week Week Week Week Week Week Week Week Mnth Mnth and week of visit line jk j Visit Number Inclusion/Exclusion X X Demographics X Smoking/Drug History X Randomisation X Study Drug X X X X X X X X X X X X Physical exam/vital signs X X X X X X X X X X X X X X X X X Visual Tests X X Urinalysis X Sputum smear/culture a X b X c X X X X X X X X X X X X X X X X a AST X X X i X i X i X ALT X X X X X X Bilirubin X X X i X i X i X Haemoglobin X X X i X i X Platelet Count X X X i X i X Serum K X X X i X i X Albumin X PT, PTT d X X X i X i X i X Full blood picture d X X X X X Creatinine, Urea, X X X i X i X electrolytes d Pregnancy test e X X Susceptibility testing f X l +/-6 weeks 32 Mnth 18

67 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Visit Windows Up to 14 days after screening +/- 3 days Active Treatment Phase Follow-Up Phase a. One sputum sample will be collected from week 1 up to and including week 26. Two sputum samples will be collected at month 9, 12, 15 and 18 from all patients still producing sputum. If sputum samples given at month 18 are contaminated, subject should return for unscheduled visit(s) to give additional samples (See Section 5.8.2) or to document that the patient is not able to produce sputum. b. Two sputum specimens positive for M.Tb. bacilli on smear microscopy at least one of which must be processed at the study lab. c. At baseline, two sputum specimens (from those collected at screening/baseline) will be processed for culture d. Full blood picture includes all tests prescribed on the chart plus any additional test investigator deems necessary for the clinical evaluation of the subject e. If applicable f. Susceptibility testing, mycobacterial speciation and molecular typing will be performed on all initial strains and any treatment failure or suspected relapse strain g. CD4 count will only be performed on patients who are HIV positive. h. Blood, urine, and sputum will be processed for storage at a bio-repository (Refer to Biostorage substudy Protocol Addendum). Specimens of only those patients will be collected for biostorage who have given their consent for this purpose. i. See Section for Management of Unscheduled Visit j. Post the withdrawal visit, drawing the safety bloods is not required k. Treatment period may be extended to allow the patient to complete the course of treatment due to missed doses. In this case assessments and procedures should be determined by the corresponding treatment phase (see Section 5.8.2) l. At selected sites where MDR rates are greater than 2%, rapid molecular drug susceptibility testing will be carried out on smear positive screening samples. - 3 days +1 week after Week 8 jk +/- 2 weeks (except week 26 to +6 weeks after) Activity and week of visit Screen Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 12 Week 17 j Week 22 Week 26 j Mnth 9 Mnth 12 Mnth 15 Mycobacterial X speciation and typing f Adverse event screen X X X X X X X X X X X X X X X X X X HIV testing X CD4 Count g X Chest X-ray X Specimens for biostorage (if applicable) h X X X X X X X +/-6 weeks Mnth 18 33

68 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Management of Early/Late Visit Any visit for which a patient attends outside of the specified visit window but not in addition to those required as per the summary chart of assessments and procedures should be considered as an early/late visit. The assessments which are undertaken as part of an early/late visit should reflect those for the visit which will be or has been missed. Any additional assessments should be undertaken as clinically indicated Procedures for assessing efficacy Summary of Bacteriological methods 1 All patients will have had two sputum specimens positive for tubercle bacilli on smear microscopy, at least one of which must be processed and positive at the study laboratory. Two sputum samples will be cultured (from those taken at screening or baseline). Culture testing will use the Becton Dickinson Mycobacterial Growth Indicator Tube system (MGIT) and Löwenstein-Jensen (LJ) slope. During the first two months of therapy sputum specimens will be submitted for smear and culture weekly. Smear and culture will also be performed at week 12, 17, 22, 26, 39 (9 months), 52 (12 months), 65 (15 months) and 78 (18 months), including repeat month 18 samples if necessary due to contamination of the original month 18 cultured specimen. Smear examination and culture will be performed additionally on specimens at unscheduled visits. Bacterial load will be determined on all patients by using the time to positivity in the MGIT. Additionally, in a subgroup of patients, the bacterial load will be determined using conventional colony count analysis. M. tuberculosis will be identified by its characteristic appearances on Z-N staining from LJ slope and by molecular testing of all initial isolates (baseline culture, or nearest positive culture if the baseline is contaminated or negative, i.e. screening or week 1). Drug susceptibility testing (DST) will be performed on all initial isolates using the MGIT methodology. In addition, M. tuberculosis DNA will be extracted from all initial isolates for molecular typing. 1 Full details of Bacteriological Methods can be found in the Laboratory Manual. 34

69 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 All positive cultures at or after week 17 should be speciated to confirm the presence of M. tuberculosis. If a patient has a culture positive sputum (confirmed by an additional sample) at or after week 17, drug susceptibility testing will be performed. DNA will also be extracted from this isolate to perform molecular typing in parallel with the corresponding initial isolate to distinguish relapse from re-infection. DNA extraction will be carried out at the study sites and sent to UCL, where MIRU-VNTR and IS6110 typing methodologies will be performed. These are the standard methods for which databases exist and are used by public health organisations internationally (including CDC and the Health Protection Agency UK) for strain typing (30;31). At subsequent visits, it is only necessary to repeat DST and DNA extraction if the patient has a new confirmed positive culture (i.e. was subsequently culture negative and then becomes culture positive again); for patients who are continuously culture positive it is not necessary to repeat DST and DNA extraction at each visit. Speciation, DST and DNA extraction are also required for any other positive culture result that may be used to influence decisions regarding treatment change. All initial M. tuberculosis isolates and isolates from positive cultures at or after week 17 should be stored locally as per the REMoxTB laboratory manual, should typing or further analyses of these isolates be required at a later date. Drug resistant isolates will also be sent to UCL, London for confirmatory testing and further analysis. At selected sites, where the MDR rate in previously untreated patients, is estimated to be greater than 2%, a rapid molecular test (Hain assay) for the identification of resistance to isoniazid and/or rifampicin will be performed directly on smear positive screening sputum samples from all patients to exclude those with MDR TB prior to enrolment. These estimates will be based on any available data & information provided by the site PIs. The MGIT based sensitivity testing must still be performed on all enrolled patients as outlined in the laboratory manual. 35

70 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 All methods to be employed are given in detail in the REMoxTB Laboratory Manual. In addition, some sites may be required to store residual blood and sputum from the samples collected during the study to evaluate new diagnostic tests as they become available in the future. These samples will be stored at study site and transferred to UCL for specific analyses as required. Transferred material will be kept at UCL for no more than 10 years beyond the completion of the study. A Standing Committee will be formed (including at least each site s PI and a Sponsor representative) on completion of the study to ensure governance of the material. To ensure protection of the patient s rights, local ethics will be informed and where necessary, approval sought, for any further analyses of these samples. No human genetic testing will be performed on any sample at any time Procedures for assessing safety At each clinic visit patients will be asked about adverse events that have occurred since their previous visit and physical examination will be performed. Safety laboratory investigations will be performed at screening and weeks 2, 4, 8, 12 and 17 (visits). At screening tests will include: Liver function (AST/ALT), Prothrombin Time (PT), Partial Thromboplastin Time (PTT), Creatinine, Urea, Electrolytes, Bilirubin, Haemoglobin, Platelet count, Serum Potassium (K), Albumin At weeks 2, 8, 12 and 17 the following tests will be performed: Liver function (AST/ALT), Prothrombin Time (PT), Partial Thromboplastin Time (PTT), Creatinine, Urea, Electrolytes, Bilirubin, Haemoglobin, Platelet count, Serum Potassium (K) 36

71 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 At week 4, the following tests will be performed: Liver function (AST/ALT), Prothrombin Time (PT), Partial Thromboplastin Time (PTT), bilirubin. Any additional test that the investigator deems necessary for the clinical evaluation of the subject can be performed. Any adverse events detected will be graded according to a modified version of the toxicity criteria produced by the Division of AIDS (Table for Grading the Severity of Adverse Events (see Appendix 3) and coded using MedDRA. Serious adverse events will be reported to the sponsor, regulatory authorities and research ethics committees, according to their specific requirements as set out in Section Defining outcome status At month 18, a subject is considered to have negative sputum if he or she has two negative sputum samples in a row from either the same or different visits and has not had two (or more) positive cultures in a row post-treatment end. Additionally, if the subject had a single positive sputum culture any time posttreatment end, he or she must not have been re-treated. At month 18, if a subject s sputum sample culture is contaminated on solid medium, but the MGIT culture result is negative, the sputum sample will be considered to be negative. At month 18, a subject is considered to be positive if he or she has one or more positive, non-contaminated sputum culture(s) from samples taken at the 18 month visit and cannot be brought back for further testing to determine if it is an isolated positive. 37

72 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Definition of treatment failure Patients are considered as treatment failures if their sputum sample is culture positive at the end of treatment with a strain that is indistinguishable from the initial isolate and this is confirmed by a second sample. Patients who are on either of the four month regimens may require additional treatment if culture positive at four months. Since only smear results are available at four months all patients will be assessed for their risk of being culture positive. This allows all potential failures on the four month regimens to be identified without unblinding. If a patient presents at four months with a positive smear the case will be referred to the study clinician to decide whether it will be classified as being at risk of failure (or not) based on a review of all the previous culture results. This allows a prediction to be made on the time at which the patients would be expected to become culture negative. Any patient defined as being at risk of failure after 4 months of study treatment will receive active rifampicin and isoniazid blinded to subject and all study staff. Management of patients will be reviewed once culture results are available Definition of relapse In the event of a positive smear or culture after the completion of treatment, the patient will be requested to return to provide a sputum specimen for testing, to confirm treatment failure or recurrence. If the second sample is found to be negative the patient should not be considered to be a failure or recurrence unless requiring treatment on account of clinical deterioration, in which case a further sample should be collected. If the sample confirms the positive culture result, the strain will be typed by international standard methods. Only those patients positive with a strain indistinguishable from their presenting strain will be deemed to have relapsed. Detailed methodology can be found in the laboratory manual. In some instances it may be necessary or more convenient to collect that sample at the patient s home. Patients who present with symptoms of 38

73 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 tuberculosis and whose smear result is positive at 6 months or later should be managed according to the National Tuberculosis Guidelines. If for any reason a patient is restarted on anti-tuberculosis drugs without confirmatory evidence he/she will be classified as a relapse. While the treatment regimen is blinded it may not be possible to distinguish between failure and an early recurrence since a confirmed positive culture at 6 months for patients on the 6 month regimen will be a failure but for patients on either 4 month regimen who were culture negative at 4 months, will be an early recurrence (reinfection or relapse, based on strain typing). 5.9 Removal of subjects from the study (including removal from study treatment) In the case that a subject is withdrawn from the trial, the sponsor will be informed immediately (within 24 hours). A patient withdrawal form must be completed. Withdrawn patients will be referred to the local tuberculosis treatment services Discontinuation of study treatment The study clinician or investigator may discontinue a patient from treatment in the event of a severe or serious adverse event, or at any time he/she thinks it s in the patient s best interest. This however needs to be first discussed with the Sponsor or representative before a decision is made, the only exception being in an emergency situation. If there is a medical reason for withdrawing study treatment, the patient will remain under the supervision of the medical investigator until satisfactory health has returned irrespectively of the reason for discontinuation. The frequency of patient review will be determined by the clinical need to ensure optimal care. For the purposes of the trial, the discontinued patient must be seen at least 3-monthly following the study procedures described in the Follow-up Phase schedule up to and including the month 18 visit. 39

74 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Any patient that falls pregnant whilst taking study treatment should be managed as described in section Withdrawal from the study Patients withdrawn from study due to a protocol violation will be included in the safety database of the study. Protocol Violators (i.e. individuals who are enrolled in the study and have received at least one dose of study drug, but do not meet entry criteria) will be withdrawn from the study treatment as soon as possible after the violation has been discovered. This will be decided by the investigator in consultation with the Sponsor. No follow up will be required past the date of withdrawal for these patients unless they are experiencing an adverse event at the time of withdrawal. In which case, they will require follow up until resolution or stabilisation of the event. Patients withdrawn from study because their initial TB isolate is found to be MDR or mono-resistant to any fluoroquinolone or to rifampicin are classified as late exclusions and will not be followed up further, unless required for patient safety (e.g. an adverse event present, in which case follow-up should occur as clinically indicated). Similarly, patients withdrawn from study because their initial cultures are negative do not need to be followed up further (unless there is an ongoing adverse event). Participation in the study is strictly voluntary. A participant has the right to withdraw from the study at any time for any reason. Patients who withdraw their consent will not have to undergo any follow up procedures Lost to follow-up All efforts should be made to contact patients that do not attend for scheduled study visits. The investigator should attempt to follow up patients that miss scheduled visits according to the study protocol unless the participant withdraws consent. In this event a patient withdrawal form should be completed. 40

75 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 If a patient fails to attend scheduled visits during the first five months, a home visit will be made, or the patient will be contacted by phone (if applicable), to encourage attendance at the earliest opportunity. Patients failing to attend at 6 (week 26), 9 (week 39), 12 (week 52), 15 (week 65) or 18 (week 78) months within two weeks of their specified appointment, will be visited at home. For patients who have died outside hospital as much information as possible on cause of death and details of the final illness will be obtained from relatives or neighbours. If a patient misses their 18 month scheduled visit adequate effort must be made to repeatedly contact the patient following the 18 month scheduled time point (until 6 weeks after the 18 month visit of the Last Patient In, i.e., the last patient enrolled in the study). If these attempts are unsuccessful, the patient should then be considered lost to follow up and reported as such. A comprehensive definition of lost to follow up for data analysis purposes will be provided in the Statistical Analysis Plan Premature termination of study or closure of a study site The study can be terminated by the Trial Steering Committee (TSC) on the advice of the Independent Data Monitoring Committee (IDMC). In addition, the sponsor has the right to close this study, and the sponsor has the right to close a site at any time, although this should occur only after consultation between involved parties. The local and central Ethics Committee/Institutional Review Board (EC/IRB) and Regulatory Authorities must be informed. Should the study/site be closed prematurely, all study materials (except documentation that has to remain stored at site) must be returned to the sponsor. The investigator will retain all other documents until notification given by the sponsor for destruction. Patients currently on treatment will receive an appropriate regimen, to completion of therapy. 41

76 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Data quality Data monitoring This trial involves patients with a serious illness, using a drug (moxifloxacin) that is not licensed for treatment of tuberculosis. It is taking place in different countries in sites experienced in running tuberculosis treatment trials. The data from this trial may be used to extend the license for moxifloxacin. Close monitoring of the data, patient safety and clinical sites will therefore be necessary. The study data will be entered locally and transmitted to a central database. The information system will be programmed to maintain an audit trail, undertake consistency checks and generate reports of missing/ inconsistent data. It will also allow the Sponsor to monitor the timeliness and accuracy of data entry to identify sites or staff not performing to the necessary standard Clinical site monitoring Direct access to data Direct access to data at each site will be required for the purposes of monitoring and audit. This will be made explicit in the patient consent form. Local investigators and their employing institution will provide direct access to source data and documents for trial-related monitoring, audit and regulatory inspections Quality assurance and quality control of data Good Clinical Practice (GCP) training (applicable to personnel not in possession of a valid GCP Training Certificate), and where appropriate Good Laboratory Practice (GLP) training, will be provided for all staff involved in the study as part of the capacity strengthening component. Staff will also be trained and retrained in the study procedures. 42

77 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Each site will be visited prior to the trial opening to ensure that everything is in place for the trial to start, the site file contains all essential documents and staff understands the study procedures and their own roles and responsibilities. Soon after recruitment of the first patient at each site the site will be visited again and all procedures reviewed and data checked. All trial sites will be monitored according to the currently approved version of the monitoring plan. Monitoring visits will be carried out to ensure that: Consent procedures are being followed Only eligible patients are recruited Dispensing of trial medication is according to the protocol Blinding is maintained Treatment and follow-up procedures are followed Accurate completion of CRFs by clinical staff Timely and accurate data entry Identification of missing/inaccurate data Timely resolution of discrepancies Adverse events are recorded accurately, managed and reported appropriately Laboratory quality assurance Details of the arrangements for laboratory quality assurance are found in the Laboratory Quality Manual Documentation ICH-GCP requirements for data documentation will be followed throughout. The study file and all source data should be retained until notification given by the sponsor for destruction. 43

78 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Ethical considerations 6.1 National and local ethics committees The protocol will be submitted to the relevant Ethical Review Committees of all sites participating in the trial. 6.2 Ethical conduct of the study This study will be performed in accordance with the ethical standards set out in the latest version of the Declaration of Helsinki. 6.3 Regulatory authority approvals Because moxifloxacin is not currently licensed for use in tuberculosis, approvals will be required from the regulatory bodies in each of the participating countries. 6.4 Subject Information and Informed Consent Only patients who give Informed Consent will be enrolled in the study. Consent will be based on the Patient Information Sheet (PIS) (Appendix 1). If eligible, the patients will have the conditions of the study explained to them. The information contained in the PIS will be translated into the relevant local languages. Literate patients will be asked to read the form while the illiterate patients will have the contents explained to them by a literate witness. Patients will have the opportunity to discuss the PIS with the site investigator or delegate. They will be assured that their decision to participate in the trial or not should be voluntary and made completely without prejudice to their future treatment. Once this person is satisfied that the patient has understood the PIS and the consent form, the patient will be asked to sign the Informed Consent Form (Appendix 2). The originals will be retained in the investigator site file, and additional copies included in the patient s study folder. If mandated by local regulatory requirements, the patient may be asked to provide Informed Consent at two stages: first for screening and upon being 44

79 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 found to be complying with inclusion-exclusion criteria, for participation in the study. 6.5 Insurance Indemnity for non-negligent harm will be available through a policy provided by the Global Alliance for TB Drug Development. All of the local clinical investigators will be required to have indemnity for clinical negligence arranged through appropriate local medical defence societies. 6.6 Confidentiality All records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. Subject names will not be supplied to the sponsor. All study documents including CRFs will include patient number and patient initials. If the subject name appears on any study document (e.g., pathologist report), it must be obliterated before a copy of the document is supplied to the sponsor. Study findings will be stored on a computer in accordance with local data protection laws. The subjects will be informed in writing that representatives of the sponsor, EC/IRB, or Regulatory Authorities may inspect their medical records to verify the information collected, and that all personal information made available for inspection will be handled in strictest confidence and in accordance with local data protection laws. If the results of the study are published, the subjects identity will remain confidential. The investigator will maintain a list to enable subjects records to be identified. 45

80 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Statistical considerations 7.1 Analysis population It is proposed to analyse participants who default prior to the final study visit at month 18 (losses to follow-up) for whom there is no evidence of failure or relapse in three ways, by classifying them as 1) not assessable (and thereby excluded from the numerator and denominator), 2) having an unfavourable outcome and 3) having a favourable outcome. The primary analysis would consider the losses to follow-up as not assessable since together with the non-tuberculous deaths this group is likely to considerably out-number the bacteriological failures and relapses. If, at the time of default from follow-up a patient has any bacteriological evidence of active tuberculosis that patient would be classified as having an unfavourable outcome. There is a clear precedent for this analytic approach in other TB trials, and these trials also provide examples of why the inclusion of the losses to followup as unfavourable greatly affects the results. Data from the Priftin trial (31) which led to accelerated approval of rifapentine and a trial conducted by the International Union Against TB & Lung Disease (IUATLD) in African and Asian sites (24) illustrate the problems associated with classifying all losses to follow-up and deaths as having an unfavourable outcome. In the Priftin trial bacteriological relapses occurred in 5% of patients on the rifampicin based regimen compared to 11% on the rifapentine based regimen. Approximately one third of patients were lost to follow-up and when this group combined with patients unassessable for other reasons were added to the bacteriological failures, the rates increased to 53% and 57% respectively. The true bacteriological relapses were greatly outnumbered by these other groups. At the time of the licensing submission to the FDA it was recognised that because there were a substantial number of patients likely to be unassessable the main focus should be on the relapse rates. In the final statistical report, the results were first reported excluding those not 46

81 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 assessable and then assuming all losses had an unfavourable outcome and finally assuming all losses had a favourable outcome. In the study conducted by the IUATLD, the published failure/relapse rates 12 months after stopping treatment based on 1044 assessable patients were 4% for the control regimen (using the same control regimen as in the REMox trial) and 10% and 14% in each of the experimental arms. If the 311 not assessable patients were considered to have an unfavourable outcome these rates would increase to 24%, 32% and 35% respectively. The 311 not assessable patients were not evenly distributed across the three trial arms. There were 42 deaths, of which 20 occurred in one of the experimental arms (the stronger of the two regimens) and 11 in the other, a difference which was not considered to be due to the treatment, but due to chance. There were also imbalances among those without a bacteriological assessment (7 in one arm versus 19 and 22 in the other two arms) and in the distribution of losses to follow-up. Every effort will be made in the present trial to recruit patients with a stable address in order to minimise loss to follow-up. Maintaining patients in active follow-up for a year after completion of treatment is however expected to be difficult, especially in resource poor areas when some participants may be forced to move residence or leave the district due to unforeseen circumstances. 7.2 Determination of sample size The REMox study has two primary comparisons. Comparison 1: The effect on the failure/relapse rates of substituting moxifloxacin for ethambutol in the standard regimen and continuing moxifloxacin during the continuation phase of treatment and reducing the total treatment duration to four months. Comparison 2: The effect on the failure/relapse rates of substituting moxifloxacin for isoniazid in the standard regimen and reducing the total treatment duration to four months 47

82 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 The following assumptions have been made in calculating the numbers of participants needed for the primary analysis. 1) The bacteriologically confirmed failure/relapse rate in the control regimen will be 5% (consistent with the finding in many randomised trials, most recently the IUATLD study referred to above conducted in African and Asian sites (24)); 2) Deaths during treatment and participants failing to complete their prescribed treatment who cannot be assessed bacteriologically at 18 months will be classified as having an unfavourable outcome. 3) Participants who default from follow-up after completion of their prescribed treatment who were culture positive when last seen will be classified as having an unfavourable outcome whether or not a second sample has been obtained confirming bacteriological relapse. 4) Losses to follow-up, after completing chemotherapy who were culture negative at the time of default will be considered unassessable on the basis that they would be at no greater risk of an unfavourable outcome than those retained in follow-up. 5) An acceptable inferiority margin (delta) is 6% as discussed in the Appendix of the statistical analysis plan. 6) A one sided significance level of will be used for the confidence interval; this includes a Bonferroni correction to allow for the two primary comparisons. 7) The power to demonstrate non-inferiority is 85%. Numbers needed per group are given in the following table in which both the assumptions about the proportions of patients who fail or relapse and the proportion who are unassessable are varied. 48

83 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Number needed to randomise per group by failure/relapse rates in the control arm Unassessable Failure/relapse rate 5% 6% 7% 8% 9% 10% 11% 12% None % % % Assuming 10% of participants in the control arm are classified as having an unfavourable outcome (as defined in section below) and assuming approximately 15% of participants are un-assessable for any reason (MDR disease, failure to confirm TB on culture or not assessable at 18 months) 633 participants would need to be enrolled in each arm, giving a total sample size of 1900 participants for the trial. 7.3 Statistical and analytical plan Definition of primary outcome status The primary analysis will be conducted using culture results from solid media for purposes of consistency with earlier trials. The only exception to this will be for contaminated LJ samples at the 18 month visit, when no further sample can be obtained, then these patients will be classified according to their MGIT result. Unfavourable outcome 1. Patients requiring an extension of their treatment beyond that permitted by the protocol, a restart or a change of treatment for any reason except reinfection or pregnancy. 2. Patients who had a positive culture when last seen (with the exception of patients found to have been reinfected) whether confirmed by a second sample or not. 3. Patients dying from any cause during treatment. 4. Patients failing to complete treatment and not assessable at 18 months 49

84 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Favourable outcome 1. Patients with a negative culture result at 18 months who had not already been classified as having an unfavourable outcome. 2. Patients who at 18 months or later who are clinically asymptomatic and unable to produce sputum who had not already been classified as having an unfavourable outcome. Not assessable 1. Patients who, having completed active treatment, default from follow-up their last culture result being negative. 2. Women who become pregnant during the treatment phase and stop their allocated treatment, unless their last culture was positive in which case they would be classified as having an unfavourable outcome. 3. Patients who died during the follow-up phase with no evidence of failure or relapse of their TB. 4. Patients reinfected with a new strain different from that with which they were originally infected Primary efficacy endpoint The study consists of two comparisons: Comparison 1(regimen 1 versus regimen 2) and Comparison 2 (regimen 1 versus regimen 3) (Figure 1). In both comparisons non-inferiority will be assessed using the lower bound of the 97.5% confidence interval (one sided 98.75%) for the difference between the proportion of participants who are classified as having an unfavourable outcome on the control regimen and the intervention to the predefined noninferiority margin of 6%. All of these analyses will be conducted both by per protocol and intention to treat. The per protocol population is defined as patients with culture confirmation of drug-sensitive tuberculosis who have received at least 42 doses of their allocated intensive phase treatment within 70 days of starting treatment, at least 42 doses of their continuation phase treatment within 84 days for those allocated to a 4 month regimen and at least 84 of their 50

85 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 continuation phase treatment within 168 days for those allocated to receive the 6 month regimen. Patients included in the per protocol population allocated to a 4 month regimen should have missed no more than a total of 28 doses of treatment and those allocated to the 6 month regimen should have missed no more than a total of 42 doses of treatment. Patients whose treatment was modified or extended for reasons other than an unfavourable response to treatment will not be included in the per protocol population Primary safety endpoint The primary safety endpoint, i.e. the proportion of patients with grade 3 or 4 adverse events as defined in a modified version of the toxicity criteria produced by the Division of AIDS (Table for Grading the Severity of Adverse Events, see Appendix 3) will be presented as a descriptive analysis Secondary endpoints The following endpoints will be applied to comparisons of each of the intervention regimens with the control regimen. Efficacy: 1. The same as the primary analysis but using liquid media to define bacteriological status. 2. Sensitivity analyses assuming all losses to follow-up and nontuberculous deaths have an unfavourable outcome. 3. Sensitivity analyses assuming all losses to follow-up and nontuberculous deaths have a favourable outcome. Non-inferiority will only be considered to have been demonstrated if shown in the per protocol analysis and provided the results of the intention to treat analysis and the sensitivity analyses are consistent with those findings. 4. Proportion of patients who are culture negative at eight weeks. 5. Time to first culture negative sputum sample. 6. Speed of decline of sputum viable count 51

86 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Analyses 2-6 above will be conducted separately using both solid and liquid media. Time to first culture negative sputum and time to relapse will both be analysed using survival analysis techniques, Kaplan Meier plots and Cox proportional hazard regression. Speed of decline of sputum viable counts will be analysed by a variety of exploratory techniques involving polynomial or bi-exponential mixed effects modelling and summary regression estimates Sub-group analyses Primary endpoint analyses will be conducted by site, by drug sensitivity at enrolment and by HIV status Surrogacy The rate of decline in viable colony counts and the increase in time to positivity in liquid culture will be used to explore surrogate endpoints for long term relapse outcomes Method comparison Efficacy analyses (two-month culture result and failure/relapse) will be performed in parallel using liquid culture (MGIT) results; the two methods will be compared on individual sputum specimens. In line with EMEA recommendations the primary analysis will be with solid media since the previous studies were conducted using solid media Additional secondary analyses 1) Status at end of treatment based only on assessable patients, i.e. culture result at end of chemotherapy, 4 or 6 months, using penultimate month culture if culture result at end of chemotherapy is unavailable. 2) Relapse by 18 months in patients with bacteriological cure at the end of chemotherapy. 52

87 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Full details of all statistical analyses are given in the Statistical Analysis Plan. 7.4 Interim monitoring and analyses The Independent Data Monitoring Committee (IDMC) will review safety data regularly and could in exceptional circumstances recommend termination of the study or termination of one of the treatment regimens because of unacceptably high relapse rates or unacceptable levels of drug toxicity. In view of the theoretical risk of increased liver toxicity in the isoniazid substitution arm, the IDMC will review the liver function tests after 50 patients have completed two months in each arm. The IDMC will be asked to give advice on whether the accumulated data from the trial, together with results from other relevant trials, justifies continuing recruitment of further patients. The IDMC will advise the TSC that the trial should be stopped if in their view the randomised comparison has provided proof beyond reasonable doubt that one of the trial interventions is clearly indicated or clearly contra-indicated in terms of a net difference in efficacy or adverse events or, there is proof beyond reasonable doubt from other studies to influence clinic staff in their management of participants that is incompatible with continuing. Such proof would require a difference in failure/relapse rates between two of the study arms significant at the 0.1% level. 8. Safety reporting 8.1 Definitions Adverse event An adverse event is any untoward medical occurrence in a study patient, or clinical investigation subject once Informed Consent obtained. The adverse event does not necessarily have to have a causal relationship with this treatment. 53

88 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Adverse events associated with the use of a drug, whether or not considered drug related, include the following: An adverse event occurring from an overdose whether accidental or intentional. An adverse event occurring from drug abuse. An adverse event occurring from drug withdrawal. An adverse event where there is a reasonable possibility that the event occurred purely as a result of the patient s participation in the study (e.g. adverse event or serious adverse event due to discontinuation of treatment during wash-out phase) must also be reported as an adverse event Serious adverse event A serious adverse event is any untoward medical occurrence which: Results in death. Is life-threatening. Requires in-patient hospitalisation or prolongation of existing hospitalisation. Results in persistent or significant disability or incapacity. Is a congenital anomaly or birth defect. Is an important medical event Life-threatening The term life-threatening in the definition of serious refers to an adverse event in which the patient was at risk of death at the time of the event. It does not refer to an adverse event, which hypothetically might have caused death if it were more severe Hospitalisation Any adverse event leading to hospitalisation or prolongation of hospitalisation will be considered as serious, UNLESS at least one of the following exceptions is met: 54

89 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 a) The admission results in a hospital stay of less than 12 hours OR b) The admission is pre-planned (i.e. elective or scheduled surgery arranged prior to the start of the study) OR c) The admission is not associated with an adverse event (e.g. social hospitalisation for purposes of respite care). However it should be noted that invasive treatment during any hospitalisation may fulfil the criteria of medically important, dependant on clinical judgement. In addition where local regulatory authorities specifically require a more stringent definition, the local regulation takes precedent Disability Disability means a substantial disruption of a person s ability to conduct normal life functions Important medical event Any adverse event may be considered important if it jeopardises the subject and requires intervention to prevent another adverse condition. Such reported events warrant special attention because of their possible association with an underlying disease state and may need more decisive action than reports on other terms Unexpected adverse event An unexpected adverse event is any adverse drug event, the specificity or severity of which is not consistent with the current Investigator Brochure, additional study drug information or the Summary of Product Characteristics. Also, reports which add significant information on specificity or severity of a known, already documented adverse event constitute unexpected adverse reactions. For example, an event more specific or more severe than described in the Investigator Brochure would be considered unexpected. Some 55

90 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 examples would be; (a) acute renal failure as a labelled adverse event with a subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant hepatitis Relationship of adverse event to investigational product The assessment of the relationship of an adverse event to the administration of the study drugs is a clinical decision based on all available information. An assessment of Unlikely or Not Related would include: 1. The existence of a clear alternative explanation e.g. mechanical bleeding at surgical site OR 2. Non-Plausibility e.g. the subject is struck by an automobile when there is no indication that the study drugs caused disorientation that may have caused the event; cancer developing a few days after the first drug administration. An assessment of Yes (possible, probably or definitely) indicates that there is a reasonable suspicion that the adverse event is associated with the use of the investigational drugs Factors to be considered in assessing the relationship of the adverse event to the study drugs include: The temporal sequence from drug administration. The event occurs after the drugs are given. The length of time from drug exposure to event should be evaluated in the clinical context of the event. Recovery on discontinuation (de-challenge), recurrence on reintroduction (re-challenge). Subject s response after drug discontinuation (de-challenge) or subjects response after drug re-introduction (re-challenge) should be considered in the view of the usual clinical course of the event in question. 56

91 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Underlying, concomitant, inter-current diseases: Each report should be evaluated in the context of the natural history and course of the disease being treated and any other disease the subject may have. Concomitant medication or treatment: The other drugs the subject is taking or the treatment the subject receives should be examined to determine whether any of them may be suspected to cause the event in question. The pharmacology and pharmacokinetics of the test drug: The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of the test drug(s), coupled with the individual subject s pharmacodynamics should be considered Severity of the adverse event The severity of adverse events should be graded according to a modified version of the toxicity criteria produced by the Division of AIDS (Table for Grading the Severity of Adverse Events, see Appendix 3) 8.2 Recording and reporting of Adverse Event Throughout this study patients will be closely monitored for signs and symptoms of drug toxicity. In accordance with international regulatory requirements participating investigators are responsible for reviewing all information relevant to the safety of the study drugs. Any untoward medical occurrence in a patient having signed informed consent to participate in this study will be recorded in a timely and accurate manner as an adverse event. Any sign or symptom present at the time of enrolment and which worsens during the study constitutes an adverse event. Laboratory findings will be recorded as an adverse event only if clinically significant. All adverse events will be both assessed for seriousness for expedited reporting and, for the primary safety variable, graded for severity according to modified DAIDS criteria (Appendix 3). It is required that any adverse event which meets the definition of being a suspected unexpected serious adverse reaction (SUSAR) be promptly 57

92 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 reported to International regulatory agencies, the Sponsor, institutional review boards/ethics committees, and all clinical investigators. In order to achieve this, any Serious Adverse Event, including death due to any cause, which occurs to any patient in this study or within 14 days of the last study visit, must be reported to the Sponsor on the Fast Track Adverse Event Report Form within 24 hours of the site's awareness of the event. In addition, the local responsible institutional review board/ethics committee and regulatory authorities should be notified of any serious adverse event in line with local regulatory requirements. Serious adverse events can be of any severity. Any Adverse Event with a severity grade 3 or 4 (according to a modified version of the toxicity criteria produced by the Division of AIDS (Table for Grading the Severity of Adverse Events, see Appendix 3)), whether assessed as serious or not must be reported to the Sponsor on the Fast Track Adverse Event Report Form within 24 hours of the site's awareness of the event. Adverse events leading to the study therapy being temporarily or permanently discontinued and all Grade 3 or 4 severity effects will require thorough investigation with relevant clinical and laboratory tests, as clinically indicated. These should be repeated as needed until final resolution or stabilisation of the event. For the purposes of this study, pregnancy will be reported on a Pregnancy Report Form. Pregnancy will be communicated to the Sponsor within 24 hours of the site s awareness of the event. All pregnant patients will be taken off study therapy and treated according to the National Tuberculosis Programme standard medication. These women will continue to receive scheduled follow-up, not receive additional X-rays unless clinically indicated, and be classified as being on a non-study regimen. The outcome of pregnancies occurring in the first 6 months, or whilst the patient is taking trial treatment will be reported on a Pregnancy Monitoring Form. The study drugs are moxifloxacin, ethambutol, isoniazid, rifampicin, and pyrazinamide. The most common adverse effects known to be associated 58

93 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 with the study drugs are specified in the Investigators Brochure for moxifloxacin and the Summary of Product Characteristics for the standard drugs. The investigators are responsible for reporting all adverse events that are observed or reported during the study, regardless of whether they are thought to be related to the study drugs. 8.3 Management of adverse events For adverse events that in the investigator s judgment may be due to study drugs, the following approach to management should be applied. In general, for grade 1 events the patient will be followed carefully and the study drugs will be continued. For grade 2 events the patient will be followed more closely, with additional laboratory and/or clinic visits as necessary; drugs should be continued unless in the view of the investigator this would be unsafe. Any grade 3 or 4 event should be carefully assessed. The local clinician should rule out other possible causes of the symptoms before discontinuing study medication. When possible, concomitant medications should be withheld first at the discretion of the principal investigator if he/she suspects they are contributing to the event. If after careful assessment and in the principal investigator s judgment the event is due to study drug(s), the causative study drug(s) may be withheld. The patient should be permanently discontinued from study medications if it is in their best interests to do so. Further treatment of the TB will be directed by the local study investigators on an individual basis, based on the local National Tuberculosis Programme. The patient will continue to be followed according to the protocol. Other adverse events of any grade not thought to be due to the study drugs, should be managed at the discretion of the principal investigator; study treatment should be continued, if possible. 59

94 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Criteria for discontinuation of study drugs Certain events or conditions may necessitate temporary or permanent discontinuation of the study medication. Patients who experience such events or conditions, however, will still be considered to be part of the study and will continue to be followed until study completion. Any patient for whom the study medication is temporarily discontinued will be restarted on study medication as soon as possible. Study regimens will be discontinued and non-study regimens used when patients fail to respond to study therapy either clinically and/or bacteriologically, when treatment-emergent drug toxicity warrants it, or if the subject becomes pregnant. If study drugs are permanently discontinued, further anti-tuberculosis therapy may be administered at the clinic staff's discretion according to the National Tuberculosis Programme s guidelines of the respective countries. The patient will continue to be followed according to the guidelines established in the study protocol Criteria for temporary discontinuation of study therapy Development of another medical condition that makes the administration of the study drug inadvisable. The decision to discontinue temporarily the study medication in this situation will be at the investigator's discretion. The period during which the patient is off study medication will be as short as clinically possible Criteria for permanent discontinuation of study therapy The patient refuses further therapy (withdraws consent to be treated). Development of a grade 3 or 4 event that warrants permanent discontinuation of any study drug. It is the investigator's judgment that it is no longer in the best interest of the patient to continue study therapy. Termination of the study/site. 60

95 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 If a patient refuses further therapy or withdraws consent for treatment under the protocol, the patient will be referred to the National Tuberculosis Programme. If the patient withdraws consent to follow-up, all follow-up will stop or if the study is terminated prematurely, patients currently on treatment will be referred to the National Tuberculosis Programme. 9. Trial Committees 9.1 Trial Steering Committee (TSC) A TSC with an independent chairman will have overall responsibility for the conduct of the trial including the ability to close the trial prematurely if necessary. An independent chair will be appointed and additional independent members will be co-opted. A TSC charter will be developed. 9.2 Independent Data Monitoring Committee (IDMC) An Independent Data Monitoring Committee will be appointed to provide advice to the TSC. The primary responsibility of the IDMC will be to oversee the safety of the trial participants. It will have access to unblinded data; it may recommend premature closure of the trial, extension or continuation. The IDMC will convene at approximately six monthly intervals. A charter for the IDMC will be developed to describe their responsibilities and method of operation. 61

96 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Publications and Sharing Study Results & Information with Investigators Publications strategy To manage the publication strategy a publications strategy group (PSG) will be established consisting of the Chief Investigator and all of the Principal Investigators as defined in the protocol and representatives of collaborating organizations. Representatives from funding agencies may be asked to join the PSG. The PSG may decide to co-opt attend additional individuals with specific expertise as necessary for specific tasks. Terms of reference: 1. To agree on general content and use of data in any proposed publication using REMox material. 2. To discuss and prioritize publications/presentations. 3. To define the authorship of publications and to resolve any disagreements about the same 4. To review and authorize final versions of publications Mode of operation The use of any data from the REMox TB trial for the purposes of publication or presentation must be approved in advance by the REMox TB Senior Team (ST) according to the procedure for submission of proposals for sub-studies which is available upon request and that will be posted on the REMox TB study website at Similarly, any proposals for the collection of additional data must be agreed in advance of commencement and reviewed by the same group. To this end the ST will hold meetings throughout the year, depending on the workload, to provide prompt review of all proposals. The PSG will meet at least annually to set/review the publication policy. They will also be responsible for the arrangements for authorship and for the 62

97 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 review of progress towards agreed publications. Relevant members of the REMoxTB consortium may be asked to join by teleconference. This publication policy must be in accord with the terms of the various contracts and funding agreements that support the trial. In case of any conflict, these contracts and agreements take precedence over the policy set by the PSG. With respect to the paper describing the final results (the main paper ), there will be a writing committee chaired by the Chief Investigator and comprising the authors identified by the PSG. Appropriate acknowledgement of all key contributors such as the Site PIs will be determined by the PSG. 63

98 Private & Confidential REMoxTB Version 6.1 Final dated 18 August References 1. Fox W. The current status of short course chemotherapy. Bull.Int.Union Tuberc. 1978;53(4): Combs DL, O'Brien RJ, Geiter LJ. USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness, toxicity, and acceptability. The report of final results. Ann.Intern.Med. 1990;112(6): Kennedy N, Berger L, Curram J, Fox R, Gutmann J, Kisyombe GM et al. Randomised controlled trial of a drug regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis. Clin.Infect.Dis. 1996;22(5): Walley JD, Khan MA, Newell JN, Khan MH. Effectiveness of the direct observation component of DOTS for tuberculosis: a randomised controlled trial in Pakistan. Lancet 2001;357(9257): Fox W. Whither short-course chemotherapy? Br.J.Dis.Chest 1981;75(4): Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Councils Tuberculosis Units, , with relevant subsequent publications. Int.J.Tuberc.Lung Dis. 1999;3(10):S Ji B, Lounis N, Truffot-Pernot C, Grosset J. In vitro and in vivo activities of levofloxacin against Mycobacterium tuberculosis. Antimicrob.Agents Chemother. 1995;39(6): Gillespie SH, Morrissey I, Everett D. A comparison of the bactericidal activity of quinolone antibiotics in a Mycobacterium fortuitum model. J.Med.Microbiol. 2001;50(6): Kennedy N, Fox R, Kisyombe GM, Saruni AO, Uiso LO, Ramsay AR et al. Early bactericidal and sterilizing activities of ciprofloxacin in pulmonary tuberculosis. Am.Rev.Respir.Dis. 1993;148(6 Pt 1): Kennedy N, Fox R, Uiso L, Ngowi FI, Gillespie SH. Safety profile of ciprofloxacin during long-term therapy for pulmonary tuberculosis. J.Antimicrob.Chemother. 1993;32(6): Gillespie SH, Kennedy N. Fluoroquinolones: a new treatment for tuberculosis? Int.J.Tuberc.Lung Dis. 1998;2(4): Yew WW, Chau CH, Wong PC, Lee J, Wong CF, Cheung SW et al. Ciprofloxacin in the management of pulmonary tuberculosis in the face of hepatic dysfunction. Drugs Exp Clin Res. 1995;21(2): Gillespie SH, Billington O. Activity of moxifloxacin against mycobacteria. J.Antimicrob.Chemother. 1999;44(3): Ji B, Lounis N, Maslo C, Truffot-Pernot C, Bonnafous P, Grosset J. In vitro and in vivo activities of moxifloxacin and clinafloxacin against Mycobacterium tuberculosis. Antimicrob.Agents Chemother. 1998;42(8):

99 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Miyazaki E, Miyazaki M, Chen JM, Chaisson RE, Bishai WR. Moxifloxacin (BAY ), a new 8-methoxyquinolone, is active in a mouse model of tuberculosis. Antimicrob.Agents Chemother. 1999;43(1): Nuermberger EL, Yoshimatsu T, Tyagi S, O'Brien RJ, Vernon AN, Chaisson RE et al. Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am.J.Respir.Crit.Care Med. 2003;169: O'Brien RJ. Scientific blueprint for tuberculosis drug development. Tuberculosis 2001;81(S1): Gosling RD, Uiso LO, Sam NE, Bongard E, Kanduma EG, Nyindo M et al. The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis. Am.J. Respir.Crit. Care Med 2003;168(11): Iannini PB, Mandell LA. An updated safety profile of moxifloxacin. J.Chemother. 2002;14 Suppl 2: El Sadr WM, Perlman DC, Matts JP, Nelson ET, Cohn DL, Salomon N et al. Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG). Clin.Infect.Dis. 1998;26(5): Aber VR, Nunn AJ. Short term chemotherapy of tuberculosis. Factors affecting relapse following short term chemotherapy. Bull.Int.Union Tuberc. 1978;53(4): East African/British Medical Research Councils Study. Controlled clinical trial of five short-course (4-month) chemotherapy regimens in pulmonary tuberculosis. Second report of the 4 th study. Am.Rev.Respir.Dis. 1981;123: Tuberculosis Research Site. Shortening short course chemotherapy: a randomised clinical trial for treatment of smear positive pulmonary tuberculosis with regimens using ofloxacin in the intensive phase. Indian.J.Tuberc.Lung Dis. 2002;49: Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multisite randomised trial. Lancet 2004;364: Jindani A, Dore CJ, Mitchison DA. Bactericidal and sterilizing activities of antituberculosis drugs during the first 14 days. Am.J.Respir.Crit. Care Med. 2003;167(10): Ostergaard C, Yieng-Kow RV, Knudsen JD, Frimodt-Moller N, Espersen F. Evaluation of fusidic acid in therapy of experimental Staphylococcus aureus meningitis. J Antimicrob.Chemother. 2003;51(5): Nuermberger EL, Yoshimatsu T, Tyagi S, Williams K, Rosenthal I, O'Brien RJ et al. Moxifloxacin-containing Regimens of Reduced Duration Produce a Stable Cure in Murine Tuberculosis. Am.J.Respir.Crit.Care Med. 2004;170(10):

100 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW et al. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am.J.Respir.Crit.Care Med 2006;174: Supply P, Lesjean S, Savine E, et al. Automated high-throughput genotyping for study of global epidemiology of Mycobacterium tuberculosis based on mycobacterial interspersed repetitive units. J.Clin.Microbiol. 2001;39: Van Embden JDA, Cave MD, Crawford JT, et al. Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardised methodology. J.Clin.Microbiol. 1993;31: (Anon. Package insert rifapentine (Priftin ). Kansas City: Hoechst Marion Roussel, 1998.) 12. Appendices 66

101 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 APPENDIX 1: PATIENT INFORMATION SHEET REMoxTB PATIENT INFORMATION SHEET Version August 2011 Study Title: A randomised placebo controlled double blind trial comparing two treatment shortening regimens with the standard regimen (two months ethambutol, isoniazid, rifampicin and pyrazinamide followed by four months isoniazid and rifampicin) namely 1) two months moxifloxacin, isoniazid, rifampicin and pyrazinamide followed by two months moxifloxacin, isoniazid and rifampicin and 2) two months ethambutol, moxifloxacin, rifampicin and pyrazinamide followed by two months moxifloxacin and rifampicin for the treatment of adults with pulmonary tuberculosis. INFORMATION FOR PATIENTS Study Title: Controlled comparison of two moxifloxacin containing treatment shortening regimens in pulmonary tuberculosis with the standard regimen. Chief Investigator: Prof Stephen Gillespie Address: Medical and Biological Sciences Building University of St. Andrews North Haugh, St. Andrews Fife KY16 9TF, UK Telephone: +44 (0) Principal Investigator at site: Address: Telephone: Regulatory Authority: (Name) Ethics Committee: (Name) Member Secretary: (Name) Ph: (Of designated patient contact person) Instructions: 67

102 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Please read and understand the information given below. 2. If you have any questions or need any clarifications then please feel free to discuss at any time. 3. After you have agreed to participate and signed the document, you will be provided with a copy, the original will be filed by the study doctor, and one copy will remain in your medical records. Dear Sir / Madam, Thank you for taking time to read this information. You are being invited to take part in a research study. Before you decide to participate, it is important that you understand why the research is being done and what it will involve. Please take time to read the following information carefully and discuss it with others if you wish. Feel free to ask us if there is anything that is not clear or if you would like more information. You are completely free to choose whether or not you wish to take part. Please take your time to decide. Q 1. What is the Purpose of the Study? A 1.The purpose of this study is to compare the effect of two new combinations of drugs for tuberculosis (TB) with a standard treatment combination. The new combinations contain three out of the four drugs that are normally used for the treatment of tuberculosis as well as moxifloxacin, which has been shown in other studies to be active against tuberculosis. Moxifloxacin has been in use throughout the world for treatment of other infectious diseases, and there is evidence from several studies that it can be used to treat tuberculosis. Q 2. Who can take part in the Study? A 2.If you are aged 18 years or over suffering from TB of the lungs and have not been treated for TB in the past, you can take part in this study. This is a multi-site, international study which will include up to 1900 patients from participating sites in Africa, Asia and Latin America. More sites may be added later in other regions around the world. Q 3. What will be the expected duration of my participation? A 3. We expect your participation to last for about 18 months (about 78 weeks). Q 4. Is it necessary for me to take part in the study? A 4. Whether or not you take part in the study is entirely up to you. You do not have to give a reason if you don't want to be in it. After reading this information and satisfying yourself about all concerned aspects - if you decide to take part in the study - you will be asked to sign an Informed Consent form. At this stage - you will receive a copy of your signed consent form also. If you decide not to take part, there will be no penalty or loss of benefit and you will receive standard TB treatment. If you decide to take part in the study, 68

103 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 but change your mind later, you will be free to withdraw from the study at anytime, without giving a reason. If you withdraw from the study it will not affect your medical care; you will be given standard TB treatment. Q 5. What does the study involve? A 5. The study is in three parts: 1. The screening phase; 2.The treatment phase, and 3. The follow-up phase. Part 1: The screening phase The first part is called screening phase when we will evaluate your suitability for the study. The evaluation will include your medical history, your medical examination, a chest X-Ray if required. You will be asked to produce a sputum specimen (material that you will cough up) which will be for TB. Examination will include blood tests to see that there are no abnormalities (problems) in your results that would prevent you from entering the study. A test will be conducted to check if the common TB medicines are likely to be effective against the bacteria causing your TB. Examination will also include an HIV test with pre- and post-test counseling (discussion with you to guide about HIV-AIDS and related test procedures) If your HIV test is positive, you will have another blood test to measure your CD4 cell level (these are blood cells involved in fighting infections).the level of CD4 cells will help to decide when you should have HIV treatment. If you may need HIV treatment at the same time as TB treatment you will be referred to specialist doctors and you will not be eligible (suitable) for this study. The blood tests at this stage will require approximately 3 or 4 teaspoons of blood, depending on whether you need a CD4 count. If you are a woman of childbearing age a urine pregnancy test will be conducted. If there are no major abnormalities (problems) and you are willing to proceed further, you can join the study. We will give you a sputum pot and ask you to produce some sputum first thing in the morning to bring as early as possible on the day of your next visit. Part 2 & 3: The treatment phase & follow-up phase At this stage - all patients participating in the study are divided into 3 groups and each group is given a different treatment; one of the three treatments is a standard TB treatment. The results of the study shall be compared to see if one treatment is better than the others. The best way of fairly dividing people into groups is to use what is called random allocation. The process is equivalent to flipping a coin or rolling a dice. In this study we use a computer generated random number to determine which of the three treatments an individual is allocated to. Neither you nor your doctor will be able to choose which treatment you will receive. You will have an equal chance of receiving any one of the three treatments; 69

104 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 A general clinical examination will be conducted on you, which will include a vision test, blood pressure, pulse and temperature measurements. You will also have a urine test to check for any indication of diabetes and kidney diseases. You will be given the TB treatment to which you have been allocated and will be seen regularly during treatment and for a year after finishing treatment to see that the TB is cured. You will be asked to come to the clinic weekly for the first 8 weeks (approximately 2 months) of treatment and then every 4 weeks until the end of treatment (approximately month 6). We will check your clinical condition by performing a clinical examination and also that the treatment is working. Any side effects will be monitored during your visits to the clinic. After the end of treatment period (26 weeks), you will be asked to come to the clinic every 12 weeks for another 1 year. During these visits - we will check your clinical condition by performing a clinical examination and will see if you have any signs of the TB coming back. If you are not cured after taking the study treatment or if you develop TB again during follow-up period, you will be given the treatment your doctor thinks will be best for you. Samples of your sputum will be taken weekly during the first 8 weeks of the study, monthly to the end of treatment, and then at 3 months (week 12), 6 months (week 26), 9 months (week 39) and 12 months (week 52) after finishing the treatment. Should you be required to visit the study doctor for an unscheduled visit before week 17, one sputum sample will be collected and tested. Should your study doctor consider changing your treatment in the absence of a positive culture at or after your week 17 visit, a third sample will be taken. These specimens will be tested in the laboratory to see if they contain TB bacteria. We will give you a sputum pot at each visit and ask you to produce some sputum first thing in the morning to bring with you in your next visit to the clinic as early as possible. Samples of your blood will be taken before you start treatment, and at weeks 2, 4 and 8 and at month 3 (week 12) and month 4 (week 17) to check that the treatment is not having any bad effects. Approximately 3 teaspoons of blood will be collected on each occasion. Urine specimens of female patients (of child bearing age) will be collected at beginning of the study and at the end of sixth month (week 26), to test for pregnancy. Additionally urine specimen will also be collected prior to beginning your treatment for other tests. Q 6. What are the treatments that are being tested? 70

105 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 A 6. There are three different treatments being compared in this study: the standard treatment and two new treatment combinations. The active components of each treatment group are as follows: Treatment A: The standard treatment comprising 2 months (approximately 8 weeks) of four anti-tuberculosis drugs rifampicin, pyrazinamide, isoniazid and ethambutol followed by 4 months (approximately 17 weeks) of rifampicin and isoniazid. This is currently the standard treatment combination for TB. Treatment B: A new treatment that includes moxifloxacin together with three of the standard drugs, rifampicin, pyrazinamide and isoniazid for 2 months (approximately 8 weeks), followed by 2 months (approximately 8 weeks) of treatment with moxifloxacin, rifampicin and isoniazid. Treatment C: A new treatment that includes moxifloxacin together with three of the standard drugs, rifampicin, pyrazinamide and ethambutol for 2 months (approximately 8 weeks) followed by 2 months (approximately 8 weeks) of moxifloxacin and rifampicin. To compare the treatments fairly, it is important that so far as possible - you or the medical staff working on the study do not know which of the treatments you are on. This avoids influencing of the care they provide you or their judgment of how effective the treatment is. However, if your doctor needs to know what treatment you are on for your medical care, they will be able to find out from the study organisers. Because each of the treatments is made up of different drugs, each treatment group will also include 'placebo' tablets, to make the regimens appear as similar as possible. Placebo is a drug that is similar in appearance to the real treatment but does not contain any active drugs. Every day you will take five different types of drugs (the number of tablets will vary from 9 to13 depending upon your weight) by mouth for the first 8 weeks, three drugs (5 tablets/day) for the next 9 weeks and two drugs (4 tablets/day) for the last 9 weeks. As explained above - some of the tablets in the combination you take shall be placebos. Q 7. What do I have to do? A 7. If you decide to take part, you will agree to take the medication as instructed and to attend the clinic for the follow-up visits. This means attending all 17 scheduled visits (after screening visit) over the next 18 months (approximately 78 weeks), according to the following schedule: For first 8 weeks (approximately 2 months): Once a week For next 18 weeks (approximately 4 months): Once a month For next 52 weeks (approximately 12 months): Once every 3 months 71

106 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Your final visit will be at the end of 18th month (approximately 78 weeks) from now. You may need to attend the clinic for additional follow-up visit(s) after your final visit if the results are not clear from the sputum sample(s) you gave at your final visit. At this visit, you will be asked to try to give another sputum sample and inform your doctor of how you are feeling and if any of your symptoms of TB have returned. Screening visit will take approximately 1 to 2 hours. At each subsequent study visit - you will be expected to spend approximately 30 minutes at the clinic. This time is in addition to any waiting time at the clinic. At the time of your enrolment in the study - a member of the study team may call and/or visit your home, so that they know where you live. If for some reason you do not attend one of the follow-up clinics, someone from our team will then be able to visit you in your home, to see that you are well, and to arrange further visits. You will also be asked to provide contact details of someone from your neighbour or a relative, who may need to be contacted in case you can not be reached. If any bad side effects appear during the study, your doctor will prescribe appropriate treatment for them. You are advised not to take any other drugs (including vitamins, herbal medicines and over the counter treatments) except those prescribed to you by the study doctor, as they may lead to harmful reactions or may interfere with the treatment. If you need any other treatment, you should immediately inform the doctor at the clinic. Please inform if you are currently involved in any other drug study or have been involved in one anytime during the previous 3 months. Q 8. Are there any special concerns for women participating in the study? A 8. Pregnant and nursing women cannot be included in this study because the effects of the study treatment on babies that are still in the womb and are breast fed are not completely known. It is possible that it could be dangerous to an unborn child and breast fed babies. Women of childbearing age must have a pregnancy test before they can be included in the study and they must be using an effective method of barrier contraception, such as a condom or be surgically sterilised or have an IUCD in place. If you become pregnant while participating in the study - you must inform the study doctor immediately. In that case you will be withdrawn from the study treatment and given standard TB therapy. Even after withdrawing from the study due to pregnancy - you will be followed up until childbirth. Q 9. What are the possible disadvantages and risks of taking part in the study? 72

107 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 A 9. All TB treatment may be associated with side effects. You may or may not suffer from some of these effects. Common side effects of the current TB treatments are as follows: nausea, vomiting, diarrhoea, skin rashes, flu like illness, drowsiness, headache, confusion, inflammation (swelling/ tenderness/ redness/ pain) and damage to the liver, inflammation (swelling/ tenderness/ redness/ pain) of the kidneys, orange discolouration of the urine and tears, joint pains, signs of nerve disturbances, such as pins and needles or vision disturbances such as blurred vision. We will give you an extra vitamin tablet that should prevent the nerve disturbances. You will also have eye tests at the beginning of treatment and after 8 weeks to check your vision. You should let the study team know if you notice any change in your eyesight. Moxifloxacin, the new drug, is generally well tolerated and has been used widely in Europe, North America, South Africa as well as India. The most common side effects that can occur include nausea, diarrhoea, pain in the belly, headache and dizziness. You will be asked if you experience any of these at each appointment. Moxifloxacin may also have an influence on your ability to drive or operate machinery and these activities should be undertaken with caution. In some people, moxifloxacin may cause changes to the heart beat (a test to measure your heart function may show abnormal results). These changes are noted more frequently in women and elderly patients, but they have not proven to be significant. Mild increases in liver enzymes (naturally occurring liver chemicals) may also occur. There are other unlikely but serious side effects that can occur: inflammation (swelling/ tenderness/redness/pain) of the gut (intestine/digestive tract), allergic reactions, loss of smell and mental/mood changes (including behaviour that may result in self-harm). There are also some very unlikely but very serious side effects that can occur: irregular heartbeat, fits, severe allergic reaction, tendon (fibrous connective tissue that connects muscle to bone) inflammation (swelling/ tenderness/ redness/ pain and rupture (breaking/tearing), arthritis,kidney failure and make your myasthenia gravis (weakness of eye and other muscles), worse. Very rarely a severe skin rash with blistering (a local swelling of the skin that contains watery fluid) and peeling (loss of outer skin) has been found to be associated with use of moxifloxacin and this may be lifethreatening. Liver inflammation (swelling/ tenderness/ redness/ pain) leading to liver failure which may be life threatening is a recognised uncommon complication of standard TB treatment. It has also been recognised to very rarely occur with moxifloxacin. Yellowing of the skin or urine, nausea/vomiting, itching and easy bruising or bleeding can all be signs of liver inflammation (swelling/ tenderness/ redness/ pain). Medication used for heartburn and/or gastric (stomach) burning, anti-retroviral medication and medication containing magnesium, aluminum or zinc should be taken at least 4 hour before or 2 hours after taking the study medication. The risks associated with taking blood are very small but could include bleeding, pain, infection, bruising and inflammation. 73

108 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 In the event that you experience any of these or other bad reactions to the study drugs during the course of this study, you should immediately contact the doctor in charge of the study so that you can be tested for them. Current standard TB treatment is for 6 months (approximately 26 weeks) and if the full course of treatment is completed, it is rare for TB to return. It is not known whether this will also be true for a 4 month (17 weeks) course of treatment. It is possible that patients receiving the shorter treatment combinations (only 4 months / 17 weeks) of active drugs may be slightly less likely to be cured of the TB or to have TB again later. You will be followed for a year after the end of treatment to look for this, and will receive a further course of standard treatment if the TB returns. Q 10. What are the possible benefits of taking part? A 10. Apart from the free treatment and medical care (which may also be available from the government clinics) - there will be no direct benefits to you from this study, but the information that will be obtained from this study will help future TB patients by showing us how to treat patients with your disease in a better way. Q 11. What if new information becomes available? A 11. Sometimes during the course of a research project, new information becomes available about the drug that is being studied. If this happens, your study doctor/clinical officer/nurse will tell you or your legally acceptable representative about it and will discuss with you whether you want to continue in the study. If you decide to withdraw, your study doctor will refer you to National TB programme. If you decide to continue in the study you may be asked to sign an updated Informed Consent form. New information may also lead your study doctor to withdraw you from the study. He/she will explain the reasons and refer you to National TB programme. Q 12. What if something goes wrong? A 12. In the event that something goes wrong and you are harmed as a result of participating in the study, you would be suitably compensated. Treatment for bad effects of study treatments will be provided free of charge. If you are harmed due to someone's negligence then you may have grounds for a legal action for compensation against that person. Q 13. Can the study doctor withdraw me from the study treatment without my consent/opinion? A 13. In case it is considered medically important to ensure your safety the study doctor may withdraw you from the study. Q 14. What are the anticipated circumstances under which my participation in the study may be terminated? 74

109 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 A 14. Here are few examples of situations under which your participation in the study may be terminated: i) Your doctor is of the opinion that your TB treatment is going to fail (Treatment failure). ii) Your TB is re-emerging (Relapse). iii) Review of your health suggests that further participation in the study may cause you more harm than benefit. iv) You are grossly non-compliant and are not taking study drug as per the directions and this may result in more harm than benefit. There may be other similar circumstances as well. The study may be suspended in following cases: i) Reports of severe and significant side effects. ii) Reports suggest that the experimental regimen under trial is not good enough to treat TB. Q 15. Will my information be kept confidential? A 15. All personal and medical information collected for this study will be treated as strictly confidential. If you consent to take part in the study, the staff working on the study (the site study team), the staff who ensure that the study is conducted in a proper manner (monitors/auditors), the regulatory authorities and members of concerned ethics committee would be able to see your medical records during or after the trial. This is necessary to ensure that the study is being carried out correctly and your rights, safety and well-being are well protected. Details about you will be identified by a number and your initials, but will not include your name. The information might also be inspected by members of your study centre s Institutional Review Board (IRB)/Independent Ethics Committee (IEC), the Regulatory Authority in your country, other foreign regulatory agencies as well as your personal doctor. Therefore, you hereby authorise your study doctor to release your medical records if requested - to the sponsor, its employees or agents, your local as well as foreign Regulatory Authorities and the study centre s Ethics Committee. These records will be utilised by them only in connection with carrying out their obligations relating to this clinical study. Q 16. Will any specimens I give be stored? A 16. In addition, we would like to have your permission to store your sputum and blood samples taken as part of the study and the TB bacteria isolated from the sputum to undertake new tests in the future to try and improve TB treatment. Genetic tests may be performed on the TB bacterium isolated from your sputum. However, no genetic tests related to you will be performed on your samples. Q 17. What will happen to the results of the research study? 75

110 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 A 17. The results of this study will be made available to national and international drug regulatory agencies to help them determine whether the new treatments are useful for tuberculosis. In addition, the results will be published in international medical journals so that doctors and other health workers can learn from this work. Q 18. Who is organising and funding this study? A.18. The study is sponsored and funded by Global Alliance for Tuberculosis Drug Development, a not-for-profit organization based in New York. Some of the drugs used in this study are provided free of charge by Bayer AG (moxifloxacin), and by Sanofi-Aventis (rifampicin), both are international pharmaceutical companies. The investigator has no conflict of interest in the inclusion of you as a participant in the study. Q 19. Who has reviewed this study? A 19. This study has been reviewed and approved by the Ethics Committee of insert hospital name, the insert national Ethics body name as well as the insert regulatory authority name. The study has also been reviewed and approved by the ethics committees and regulatory authorities at various other participating sites. Q 20. Who can I contact for further information? A 20. For questions about the study, call the study doctor [ Insert Name ] at [ Insert telephone number ] If you have a study related injury, call [ Insert Name ] at [ Insert telephone number ] For questions about your rights as a study participant, call [Insert Name_( Concerned Ethics Committee Chairperson)] at telephone number ] [ Insert Q 21. Will I receive any payment for participating in the clinical study? 76

111 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 A 21. You will not receive any payment for your participation in the study. But it will be made sure that your involvement in the study will not cost you any additional money. You will be reimbursed for reasonable travelling expenses up to per study visit. There is no cost to you, your private medical insurance (if any), or the public health insurance plan for the study procedures. Study treatments will be provided free of charge for the duration of the study. Thank you very much for having considered participating in this study. 77

112 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 APPENDIX 2: INFORMED CONSENT FORM Short Study Title: Controlled comparison of two moxifloxacin containing treatment shortening regimens in pulmonary tuberculosis with the standard regimen. Chief Investigator: Prof Stephen Gillespie Principal Investigator: I confirm that I have read and understood the information sheet, dated (version ) for the above study. I have had the opportunity to consider the information, ask questions and have had these answered satisfactorily. Thumb Impression or Initials of Patient Initials of Literate Witness (if used) I understand that my participation in the study is voluntary and that I am free to withdraw at any time, without giving any reason, without my medical care or legal rights being affected. Thumb Impression or Initials of Patient Initials of Literate Witness (if used) I understand that my participation in this study will require me to have an HIV test, the result of this will be kept confidential and will not be given to me without my permission. I have been given a chance to think it over and to ask questions. Thumb Impression or Initials of Patient Initials of Literate Witness (if used) I understand that the Sponsor of the clinical study, others working on the Sponsor's behalf, the Ethics Committee and the regulatory authorities will not need my permission to look at my health records both in respect of the current study and any further research that may be conducted in relation to it, even if I withdraw from the study. I agree to this access. However, I understand that my identity will not be revealed in any information released to third parties or published. Thumb Impression or Initials of Patient Initials of Literate Witness (if used) 78

113 Private & Confidential REMoxTB Version 6.1 Final dated 18 August I agree not to restrict the use of any data or results that arise from this study provided such a use is only for scientific purpose(s). Thumb Impression or Initials of Patient Initials of Literate Witness (if used) I agree to take part in the above study. Thumb Impression or Initials of Patient Initials of Literate Witness (if used) D D M M M 2 0 Y Y Signature/thumb impression Date Patient's Full Name of the patient D D M M M 2 0 Y Y Signature of the Witness Date Full Name of Witness (if patient is Illiterate) D D M M M 2 0 Y Y Signature of person conducting Date Full Name of person Informed Consent process conducting informed consent process D D M M M 2 0 Y Y Signature of the Investigator Date Study Investigator's Full Name Time at which consent obtained (24 hours format) H H : M M 79

114 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Appendix 3: Modified DIVISION OF AIDS (DAIDS) TABLE FOR GRADING SEVERITY OF ADULT ADVERSE EVENTS ABBREVIATIONS: Abbreviations utilised in the Table: ULN = Upper Limit of Normal R x = Therapy/ treatment Mod = Moderate ADL = Activities of Daily Living LLN = Lower Limit of Normal Req = Required IV = Intravenous Dec = Decreased ESTIMATING SEVERITY GRADE For abnormalities NOT found elsewhere on this Toxicity Table, use the scale below to estimate grade of severity: GRADE 1 GRADE 2 GRADE 3 GRADE 4 Transient or mild discomfort (< 48 hours); no medical intervention/therapy required Mild to moderate limitation in activity some assistance may be needed; no or minimal medical intervention/therapy required Marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalisations possible Extreme limitation in activity, significant assistance required; significant medical intervention/therapy required, hospitalisation or hospice care probable Determining Severity Grade If the severity of an AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for the AE. PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 ESTIMATING SEVERITY GRADE Clinical adverse event Symptoms causing no Symptoms causing Symptoms causing Symptoms causing NOT identified or minimal greater than minimal inability to perform usual inability to perform basic elsewhere in this interference with interference with usual social & functional self-care functions OR DAIDS AE grading usual social & social & functional activities Medical or operative table functional activities activities intervention indicated to prevent permanent impairment, persistent disability, or death 80

115 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 SYSTEMIC Acute systemic Localised urticaria Localised urticaria with Generalised urticaria Acute anaphylaxis OR allergic reaction (wheals) with no medical intervention OR Angioedema with Life-threatening medical intervention indicated OR Mild medical intervention bronchospasm OR Chills indicated angioedema with no indicated OR laryngeal edema Symptoms causing no or minimal interference with usual social & functional activities medical intervention indicated Symptoms causing greater than minimal interference with usual social & functional activities Symptomatic mild bronchospasm Symptoms causing inability to perform usual social & functional activities Fatigue Symptoms causing no Symptoms causing Symptoms causing Incapacitating fatigue/ Malaise or minimal interference with usual social & functional activities greater than minimal interference with usual social & functional activities inability to perform usual social & functional activities malaise symptoms causing inability to perform basic self-care functions Fever (nonaxillary) C C C > 40.5 C Pain (indicate body Pain causing no or Pain causing greater Pain causing inability to Disabling pain causing site) minimal interference than minimal perform usual social & inability to perform basic DO NOT use for pain due to injection (See Injection Site Reactions: Injection with usual social & functional activities interference with usual social & functional activities functional activities self-care functions OR Hospitalization (other than emergency room visit) indicated site pain) See also Headache, Arthralgia, and Myalgia NA Unintentional weight NA 5 9% loss in body 10 19% loss in body 20% loss in body loss weight from baseline weight from baseline weight from baseline OR Aggressive intervention indicated [e.g., tube feeding or total parenteral nutrition (TPN)] 81

116 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 INFECTION Infection (any other Localised, no Systemic antimicrobial Systemic antimicrobial Life-threatening than HIV infection) systemic antimicrobial treatment indicated treatment indicated consequences (e.g., treatment indicated OR Symptoms AND Symptoms causing septic shock) AND Symptoms causing greater than inability to perform usual causing no or minimal minimal interference social & functional interference with with usual social & activities OR Operative usual social & functional activities intervention (other than functional activities simple incision and drainage) indicated INJECTION SITE REACTIONS Injection site pain Pain/tenderness Pain/tenderness Pain/tenderness Pain/tenderness causing (pain without touching) causing no or minimal limiting use of limb OR causing inability to inability to perform basic Or limitation of use of Pain/tenderness perform usual social & self-care function OR limb causing greater than functional activities Hospitalization (other Tenderness (pain minimal interference than emergency room when area is touched) Injection site reaction (localised) Adult > 15 years Erythema OR Induration of 5x5 cm 9x9 cm (or 25 cm2 81cm2) Pruritis associated with Itching localised to injection See also injection site AND Skin: Pruritis (itching - Relieved no skin lesions) spontaneously or with < 48 hours treatment Alopecia Cutaneous reaction rash Thinning detectable by study participant (or by caregiver for young children and disabled adults) Localised macular rash with usual social & functional activities Erythema OR Induration OR Edema > 9 cm any diameter (or > 81 cm2) Itching beyond the injection site but not generalised OR Itching localised to injection site requiring 48 hours treatment Ulceration OR Secondary infection OR Phlebitis OR Sterile abscess OR Drainage Generalised itching causing inability to perform usual social & functional activities SKIN DERMATOLOGICAL Thinning or patchy Complete hair loss hair loss detectable by health care provider Diffuse macular, maculopapular, or morbilliform rash OR Target lesions Diffuse macular, maculopapular, or morbilliform rash with vesicles or limited number of bullae OR Superficial ulcerations of mucous membrane limited to one site Hyperpigmentation Slight or localised Marked or generalised NA NA Hypopigmentation Slight or localised Marked or generalised NA NA visit) indicated for management of pain/tenderness Necrosis (involving dermis and deeper tissue) NA NA Extensive or generalised bullous lesions OR Stevens- Johnson syndrome OR Ulceration of mucous membrane involving two or more distinct mucosal sites OR Toxic epidermal necrolysis (TEN) 82

117 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 Hyperpigmentation Slight or localised Marked or generalised NA NA Hypopigmentation Slight or localised Marked or generalised NA NA Pruritis (itching no Itching causing no or Itching causing greater Itching causing inability NA skin lesions) (See also Injection Site Reactions: Pruritis associated with injection) minimal interference with usual social & functional activities than minimal interference with usual social & functional activities to perform usual social & functional activities CARDIOVASCULAR Cardiac arrhythmia (general) (By ECG or physical exam) Cardiac - ischemia/infarction Asymptomatic AND No intervention indicated Asymptomatic AND Non-urgent medical intervention indicated Symptomatic, non-life threatening AND Nonurgent medical intervention indicated NA NA Symptomatic ischemia (stable angina) OR Testing consistent with ischemia Life-threatening arrhythmia OR Urgent intervention indicated Unstable angina OR Acute myocardial infarction Hemorrhage NA Symptomatic AND No Symptomatic AND Life-threatening (significant acute transfusion indicated Transfusion of 2 units hypotension OR blood loss) Hypertension Adult > 17 years (with repeat testing at same visit) > mmhg systolic OR > mmhg diastolic > mmhg systolic OR > mmhg diastolic Hypotension NA Symptomatic, corrected with oral fluid replacement Pericardial effusion Asymptomatic, small effusion requiring no intervention Prolonged PR interval Adult > 16 years PR interval sec Asymptomatic, moderate or larger effusion requiring no intervention PR interval > 0.25 sec packed RBCs (for children 10 cc/kg) indicated > 180 mmhg systolic OR > 110 mmhg diastolic Symptomatic, IV fluids indicated Effusion with non-life threatening physiologic consequences OR Effusion with non-urgent intervention indicated Type II 2nd degree AV block OR Ventricular pause > 3.0 sec Transfusion of > 2 units packed RBCs (for children > 10 cc/kg) indicated Life-threatening consequences (e.g., malignant hypertension) OR Hospitalization indicated (other than emergency room visit) Shock requiring use of vasopressors or mechanical assistance to maintain blood pressure Life-threatening consequences (e.g., tamponade) OR Urgent intervention indicated Complete AV block 83

118 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 Prolonged QTc Adult > 16 years Asymptomatic, QTc interval sec OR Increase interval < 0.03 sec above baseline Asymptomatic, QTc interval sec OR Increase in interval sec above baseline Thrombosis/embolism NA Deep vein thrombosis AND No intervention indicated (e.g., anticoagulation, lysis filter, invasive procedure) Vasovagal episode (associated with a procedure of any kind) Present without loss of consciousness Present with transient loss of consciousness Asymptomatic, QTc interval 0.50 sec OR Increase in interval 0.06 sec above baseline Deep vein thrombosis AND Intervention indicated (e.g., anticoagulation, lysis filter, invasive procedure) NA Life-threatening consequences, e.g. Torsade de pointes or other associated serious ventricular dysrhythmia Embolic event (e.g., pulmonary embolism, life-threatening thrombus) Ventricular NA Asymptomatic New onset with Life-threatening dysfunction diagnostic finding AND symptoms OR congestive heart failure (congestive heart intervention indicated Worsening symptomatic failure) congestive heart failure Anorexia Loss of appetite without decreased oral intake Ascites Asymptomatic Symptomatic AND Intervention indicated (e.g., diuretics or therapeutic paracentesis) Cholecystitis NA Symptomatic AND Medical intervention indicated Constipation NA Persistent constipation requiring regular use of dietary modifications, laxatives, or enemas Diarrhea GASTROINTESTINAL Loss of appetite Loss of appetite associated with associated with decreased oral intake significant weight loss without significant weight loss Symptomatic despite intervention Radiologic, endoscopic, or operative intervention indicated Obstipation with manual evacuation indicated NA Life-threatening consequences OR Aggressive intervention indicated [e.g., tube feeding or total parenteral nutrition (TPN)] Life-threatening consequences Life-threatening consequences (e.g., sepsis or perforation) Life-threatening consequences (e.g., obstruction) Adult and Transient or Persistent episodes of Bloody diarrhea OR Life-threatening Pediatric 1 year intermittent episodes unformed to watery Increase of 7 stools consequences (e.g., of unformed stools stools OR Increase of per 24-hour period OR hypotensive shock) OR Increase of stools over IV fluid replacement stools over baseline baseline per 24-hour indicated period period 84

119 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 Dysphagia- Symptomatic but able Symptoms causing Symptoms causing Life-threatening Odynophagia to eat usual diet altered dietary intake without medical intervention indicated severely altered dietary intake with medical intervention indicated reduction in oral intake Mucositis/stomatitis (clinical exam) Indicate site (e.g., larynx, oral) See Genitourinary for Vulvovaginitis See also Dysphagia- Odynophagia and Proctitis Nausea Erythema of the mucosa Transient (< 24 hours) or intermittent nausea with no or minimal interference with oral intake Patchy pseudomembranes or ulcerations Persistent nausea resulting in decreased oral intake for hours Pancreatitis NA Symptomatic AND Hospitalization not indicated (other than emergency room visit) Proctitis (functional symptomatic) Also see Mucositis/stomatitis for clinical exam Vomiting Rectal discomfort AND No intervention indicated Transient or intermittent vomiting with no or minimal interference with oral intake Symptoms causing greater than minimal interference with usual social & functional activities OR Medical intervention indicated Frequent episodes of vomiting with no or mild dehydration Confluent pseudomembranes or ulcerations OR Mucosal bleeding with minor trauma Persistent nausea resulting in minimal oral intake for > 48 hours OR Aggressive rehydration indicated (e.g., IV fluids) Symptomatic AND Hospitalization indicated (other than emergency room visit) Symptoms causing inability to perform usual social & functional activities OR Operative intervention indicated Persistent vomiting resulting in orthostatic hypotension OR Aggressive rehydration indicated (e.g., IV fluids) Tissue necrosis OR Diffuse spontaneous mucosal bleeding OR Life-threatening consequences (e.g., aspiration, choking) Life-threatening consequences (e.g., hypotensive shock) Life-threatening consequences (e.g., circulatory failure, hemorrhage, sepsis) Life-threatening consequences (e.g., perforation) Life-threatening consequences (e.g., hypotensive shock) NEUROLOGIC Alteration in Alteration causing no Alteration causing Alteration causing Behavior potentially personality-behavior or minimal greater than minimal inability to perform usual harmful to self or others or in mood (e.g., interference with interference with usual social & functional (e.g., suicidal and agitation, anxiety, usual social & social & functional activities homicidal ideation or depression, mania, functional activities activities attempt, acute psychosis) psychosis) OR Causing inability to perform basic self-care functions Altered Mental Status Changes causing no Mild lethargy or Confusion, memory Delirium OR For Dementia, see or minimal somnolence causing impairment, lethargy, or obtundation, OR coma Cognitive and behavioral/attentional disturbance (including dementia and interference with usual social & functional activities greater than minimal interference with usual social & functional activities somnolence causing inability to perform usual social & functional activities attention deficit disorder) Ataxia Asymptomatic ataxia detectable on exam OR Minimal ataxia causing no or minimal interference with usual social & functional activities Symptomatic ataxia causing greater than minimal interference with usual social & functional activities Symptomatic ataxia causing inability to perform usual social & functional activities Disabling ataxia causing inability to perform basic self-care functions 85

120 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 Cognitive and behavioral/attentional disturbance (including dementia and attention deficit disorder) Disability causing no or minimal interference with usual social & functional activities OR Specialised resources not indicated Disability causing greater than minimal interference with usual social & functional activities OR Specialised resources on part-time basis indicated Disability causing inability to perform usual social & functional activities OR Specialised resources on a full-time basis indicated CNS ischemia (acute) NA NA Transient ischemic attack Headache Symptoms causing no or minimal interference with usual social & functional activities Symptoms causing greater than minimal interference with usual social & functional activities Insomnia NA Difficulty sleeping causing greater than minimal interference with usual social & functional activities Neuromuscular weakness (including myopathy & neuropathy) Asymptomatic with decreased strength on exam OR Minimal muscle weakness causing no or minimal interference with usual social & functional activities Muscle weakness causing greater than minimal interference with usual social & functional activities Symptoms causing inability to perform usual social & functional activities Difficulty sleeping causing inability to perform usual social & functional activities Muscle weakness causing inability to perform usual social & functional activities Disability causing inability to perform basic self-care functions OR Institutionalization indicated Cerebral vascular accident (CVA, stroke) with neurological deficit Symptoms causing inability to perform basic self-care functions OR Hospitalization indicated (other than emergency room visit) OR Headache with significant impairment of alertness or other neurologic function Disabling insomnia causing inability to perform basic self-care functions Disabling muscle weakness causing inability to perform basic self-care functions OR Respiratory muscle weakness impairing ventilation 86

121 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 Seizure: (known preexisting seizure disorder) Adult 18 years For worsening of existing epilepsy the grades should be based on an increase from previous level of control to any of these levels. Syncope (not associated with a procedure) Vertigo Bronchospasm (acute) NA Increased frequency of pre-existing seizures (non-repetitive) without change in seizure character OR Infrequent breakthrough seizures while on stable medication in a previously controlled seizure disorder Change in seizure character from baseline either in duration or quality (e.g., severity or focality) NA Present NA NA Vertigo causing no or minimal interference with usual social & functional activities FEV1 or peak flow reduced to 70 80% Dyspnea or respiratory distress Adult 14 years Dyspnea on exertion with no or minimal interference with usual social & functional activities Arthralgia See also Arthritis Arthritis See also Arthralgia Joint pain causing no or minimal interference with usual social & functional activities Stiffness or joint swelling causing no or minimal interference with usual social & functional activities Bone Mineral Loss Adult 21 years BMD t-score -2.5 to Adult < 21 years BMD z-score -2.5 to Vertigo causing greater than minimal interference with usual social & functional activities RESPIRATORY FEV1 or peak flow 50 69% Vertigo causing inability to perform usual social & functional activities FEV1 or peak flow 25 49% Dyspnea on exertion Dyspnea at rest causing greater than causing inability to minimal interference perform usual social & with usual social & functional activities functional activities MUSCULOSKELETAL Joint pain causing greater than minimal interference with usual social & functional activities Stiffness or joint swelling causing greater than minimal interference with usual social & functional activities BMD t-score < -2.5 BMD z-score < -2.5 Joint pain causing inability to perform usual social & functional activities Stiffness or joint swelling causing inability to perform usual social & functional activities Pathological fracture (including loss of vertebral height) Pathological fracture (including loss of vertebral height) Seizures of any kind which are prolonged, repetitive (e.g., status epilepticus), or difficult to control (e.g., refractory epilepsy) Disabling vertigo causing inability to perform basic self-care functions Cyanosis OR FEV1 or peak flow < 25% OR Intubation Respiratory failure with ventilatory support indicated Disabling joint pain causing inability to perform basic self-care functions Disabling joint stiffness or swelling causing inability to perform basic self-care functions Pathologic fracture causing life-threatening consequences Pathologic fracture causing life-threatening consequences 87

122 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 Myalgia Muscle pain causing Muscle pain causing Muscle pain causing Disabling muscle pain (non-injection site) no or minimal greater than minimal inability to perform usual causing inability to interference with interference with usual social & functional perform basic self-care usual social & social & functional activities functions functional activities activities Osteonecrosis NA Asymptomatic with radiographic findings AND No operative intervention indicated Symptomatic bone pain with radiographic findings OR Operative intervention indicated Disabling bone pain with radiographic findings causing inability to perform basic self-care functions GENITOURINARY Cervicitis Symptoms causing no Symptoms causing Symptoms causing Symptoms causing (symptoms) or minimal greater than minimal inability to perform usual inability to perform basic (For use in studies evaluating topical study agents) For other cervicitis see Infection: Infection (any other than HIV infection) interference with usual social & functional activities interference with usual social & functional activities social & functional activities self-care functions Cervicitis Minimal cervical Moderate cervical Severe cervical Epithelial disruption (clinical exam) abnormalities on abnormalities on abnormalities on > 75% total surface examination examination examination (erythema, (For use in studies (erythema, (erythema, mucopurulent evaluating topical mucopurulent mucopurulent discharge, or friability) study agents) discharge, or friability) discharge, or friability) OR Epithelial disruption For other cervicitis see OR Epithelial OR Epithelial 50 75% total surface Infection: Infection disruption disruption of 25 49% (any other than HIV < 25% of total surface total surface infection) Inter-menstrual Spotting observed by Inter-menstrual Inter-menstrual bleeding Hemorrhage with lifebleeding (IMB) participant OR bleeding not greater in greater in duration or threatening hypotension Minimal blood duration or amount amount than usual OR Operative observed during than usual menstrual menstrual cycle intervention indicated clinical or colposcopic examination cycle Urinary tract NA Signs or symptoms of Signs or symptoms of Obstruction causing lifeobstruction (e.g., urinary tract urinary tract obstruction threatening stone) obstruction without hydronephrosis or renal dysfunction with hydronephrosis or renal dysfunction consequences 88

123 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 Vulvovaginitis Symptoms causing no Symptoms causing Symptoms causing Symptoms causing (symptoms) or minimal greater than minimal inability to perform usual inability to perform basic (Use in studies interference with interference with usual social & functional self-care functions evaluating topical study agents) usual social & functional activities social & functional activities activities For other vulvovaginitis see Infection: Infection (any other than HIV infection) Vulvovaginitis Minimal vaginal Moderate vaginal Severe vaginal Vaginal perforation OR (clinical exam) abnormalities on abnormalities on abnormalities on Epithelial disruption (Use in studies examination OR examination OR examination OR > 75% total surface evaluating topical study agents) Epithelial disruption < 25% of total surface Epithelial disruption of 25-49% total surface Epithelial disruption 50-75% total surface For other vulvovaginitis see Infection: Infection (any other than HIV infection) OCULAR/VISUAL Uveitis Asymptomatic but detectable on exam Symptomatic anterior uveitis OR Medical Posterior or pan-uveitis OR Operative Disabling visual loss in affected eye(s) intervention indicated intervention indicated Visual changes (from Visual changes Visual changes Visual changes causing Disabling visual loss in baseline) causing no or minimal causing greater than inability to perform usual affected eye(s) interference with minimal interference social & functional usual social & with usual social & activities functional activities functional activities ENDOCRINE/METABOLIC Abnormal fat Detectable by study Detectable on physical Disfiguring OR Obvious NA accumulation participant (or by exam by health care changes on casual (e.g., back of neck, caregiver for young provider visual inspection breasts, abdomen) children and disabled adults) Diabetes mellitus NA New onset without need to initiate medication OR Modification of current medications to regain glucose control New onset with initiation of medication indicated OR Diabetes uncontrolled despite treatment modification Gynecomastia Detectable by study participant or caregiver (for young children and disabled adults) Detectable on physical exam by health care provider Disfiguring OR Obvious on casual visual inspection Life-threatening consequences (e.g., ketoacidosis, hyperosmolar non-- kenotic coma) NA 89

124 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 Hyperthyroidism Asymptomatic Symptomatic causing greater than minimal interference with usual social & functional activities OR Thyroid suppression therapy indicated Hypothyroidism Asymptomatic Symptomatic causing greater than minimal interference with usual social & functional activities OR Thyroid replacement therapy indicated Lipoatrophy (e.g., fat loss from the face, extremities, buttocks) Absolute CD4+ count Adult and Pediatric > 13 years (HIV NEGATIVE ONLY) Absolute lymphocyte count Adult and Pediatric > 13 years (HIV NEGATIVE ONLY) Symptoms causing inability to perform usual social & functional activities OR Uncontrolled despite treatment modification Symptoms causing inability to perform usual social & functional activities OR Uncontrolled despite treatment modification Detectable by study participant (or by caregiver for young children and disabled adults) Detectable on physical exam by health care provider Disfiguring OR Obvious on casual visual inspection HEMATOLOGY Standard International Units are listed in italics /mm /µL /mm x x 109/L Absolute neutrophil count (ANC) Adult and Pediatric, 1,000 1,300/mm3 > 7 days x x 109/L Fibrinogen, decreased mg/dl g/l OR x LLN Hemoglobin (Hgb) Adult and Pediatric 57 days (HIV POSITIVE ONLY) Adult and Pediatric 57 days (HIV NEGATIVE ONLY) g/dl mmol/l g/dl mmol/l OR Any decrease g/dl mmol/l /mm /µL /mm x x 109/L /mm x x 109/L mg/dl g/l OR x LLN g/dl mmol/l g/dl mmol/l OR Any decrease g/dl mmol/l /mm /µL /mm x x 109/L /mm x x 109/L mg/dl g/l OR x LLN g/dl mmol/l g/dl mmol/l OR Any decrease 4.5 g/dl 0.69 mmol/l Life-threatening consequences (e.g., thyroid storm) Life-threatening consequences (e.g., myxedema coma) NA < 100/mm3 < 100/µL < 350/mm3 < x 109/L < 500/mm3 < x 109/L < 50 mg/dl < 0.50 g/l OR < 0.25 x LLN OR Associated with gross bleeding < 6.5 g/dl < 1.01 mmol/l < 7.0 g/dl < 1.09 mmol/l 90

125 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 International Normalised x ULN x ULN x ULN > 3.0 x ULN Ratio of prothrombin time (INR) Methemoglobin % % % > 20.0% Prothrombin Time (PT) x ULN x ULN x ULN > 3.00 x ULN Partial Thromboplastin Time (PTT) x ULN x ULN x ULN > 3.00 x ULN Platelets, decreased 100, ,999/mm x x 109/L WBC, decreased 2,000 2,500/mm x x 109/L 50,000 99,999/mm x x 109/L 1,500 1,999/mm x x 109/L 25,000 49,999/mm x x 109/L 1,000 1,499/mm x x 109/L CHEMISTRIES Standard International Units are listed in italics Acidosis NA ph < normal, but 7.3 ph < 7.3 without lifethreatening consequences Albumin, serum, low 3.0 g/dl < LLN g/dl g/l < LLN g/l < 2.0 g/dl < 20 g/l < 25,000/mm3 < x 109/L < 1,000/mm3 < x 109/L ph < 7.3 with lifethreatening consequences NA Alkaline Phosphatase x ULN x ULN x ULN > 10.0 x ULN Alkalosis NA ph > normal, but 7.5 ph > 7.5 without lifethreatening consequences ph > 7.5 with lifethreatening consequences ALT (SGPT) x ULN x ULN x ULN > 10.0 x ULN AST (SGOT) x ULN x ULN x ULN > 10.0 x ULN Bicarbonate, serum, low Bilirubin (Total) Adult and Pediatric > 14 days 16.0 meq/l < LLN 16.0 mmol/l < LLN meq/l mmol/l meq/l mmol/l < 8.0 meq/l < 8.0 mmol/l x ULN x ULN x ULN > 5.0 x ULN Calcium, serum, high (corrected for albumin) Adult and Pediatric 7 days mg/dl mmol/l mg/dl mmol/l mg/dl mmol/l > 13.5 mg/dl > 3.38 mmol/l Cardiac troponin I (ctni) NA NA NA Levels consistent with myocardial infarction or unstable angina as defined by the manufacturer Cardiac troponin T (ctnt) NA NA NA 0.20 ng/ml OR Levels consistent with myocardial infarction or unstable angina as defined by the manufacturer Cholesterol (fasting) Adult 18 years mg/dl mmol/l mg/dl mmol/l > 300 mg/dl > 7.77 mmol/l NA 91

126 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 Creatinine x ULN x ULN x ULN 3.5 x ULN Glucose, serum, high Nonfasting mg/dl mmol/l Fasting mg/dl mmol/l mg/dl mmol/l mg/dl mmol/l mg/dl mmol/l mg/dl mmol/l > 500 mg/dl > mmol/l > 500 mg/dl > mmol/l Glucose, serum, low Adult and Pediatric 1 month Lactate mg/dl mmol/l < 2.0 x ULN without acidosis LDL cholesterol (fasting) Adult 18 years mg/dl mmol/l mg/dl mmol/l 2.0 x ULN without acidosis mg/dl mmol/l mg/dl mmol/l Increased lactate with ph < 7.3 without lifethreatening consequences 190 mg/dl 4.91 mmol/l < 30 mg/dl < 1.67 mmol/l Increased lactate with ph < 7.3 with lifethreatening consequences Lipase x ULN x ULN x ULN > 5.0 x ULN Magnesium, serum, low meq/l mmol/l meq/l mmol/l meq/l mmol/l < 0.60 meq/l < 0.30 mmol/l Pancreatic amylase x ULN x ULN x ULN > 5.0 x ULN Phosphate, serum, low Adult and Pediatric > 14 years 2.5 mg/dl < LLN 0.81 mmol/l < LLN mg/dl mmol/l mg/dl mmol/l Potassium, serum, high meq/l mmol/l meq/l mmol/l meq/l mmol/l Potassium, serum, low meq/l meq/l meq/l mmol/l 2.9 mmol/l 2.4 mmol/l Sodium, serum, high meq/l meq/l meq/l mmol/l 154 mmol/l 159 mmol/l Sodium, serum, low meq/l meq/l meq/l mmol/l 129 mmol/l 124 mmol/l Triglycerides (fasting) NA mg/dl ,200 mg/dl 8.48 mmol/l mmol/l Uric acid mg/dl mg/dl mg/dl 0.59 mmol/l mmol/l mmol/l URINALYSIS Standard International Units are listed in italics NA < 1.00 mg/dl < 0.32 mmol/l > 7.0 meq/l > 7.0 mmol/l < 2.0 meq/l < 2.0 mmol/l 160 meq/l 160 mmol/l 120 meq/l 120 mmol/l > 1,200 mg/dl > mmol/l > 15.0 mg/dl > 0.89 mmol/l Hematuria (microscopic) 6 10 RBC/HPF > 10 RBC/HPF Gross, with or without Transfusion indicated clots OR with RBC casts Proteinuria, random collection NA Proteinuria, 24 hour collection Adult and Pediatric 10 years mg/24 h g/d 1,000 1,999 mg/24 h g/d 2,000 3,500 mg/24 h g/d > 3,500 mg/24 h > g/d 92

127 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 APPENDIX 4: PRINCIPAL INVESTIGATORS AND TRIAL SITES Principal Investigators - Angela Crook (Blinded Biostatistician), Medical Research Council Clinical Trials Unit (MRC CTU), London, UK. - Professor Andrew Nunn (Senior Biostatistician for IDMC Support and CSR), Medical Research Council Clinical Trials Unit (MRC CTU), London, UK. - Dr Timothy McHugh, Centre for Clinical Microbiology, Royal Free and University College Medical School, London, UK. - Dr Sarah Meredith, Medical Research Council Clinical Trials Unit (MRC CTU) London, UK. - Professor Ali Zumla, Centre for International Health, Royal Free and University College Medical School, London, UK. - Dr Michael Brown, London School of Hygiene and Tropical Medicine, London, UK Trial Sites - Dr. Narendar Aggarawal, Aggarwal Nursing Home, Sector 23 Market, N.I.T. Faridabad, India - Dr. Gerardo Amaya-Tapia, Hospital General de Occidente de la Secretaría de Salud del Estado de Jalisco, Guadalajara, Mexico - Dr Evans Amukoye, Centre for Respiratory Diseases Research (CRDR), KEMRI, Nairobi, Kenya. - Dr. Shalini Arya, Arya Chest Clinic, 245, Lane no. 5, Thapar Nagar, Meerut, India - Dr. Anjula Bhargava, Rajul Nursing Home, Sasni Gate, Agra Road, Aligarh, Uttar Pradesh, India - Assoc. Prof. Watchara Boonsawat, Srinagarind Hospital, Division of Pulmonary Medicine, Department of Medicine, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Rd., Mueang, Khon Kaen 40200, Thailand - Dr. D. K. Chauhan, 4718/21 A Dayanand Road, Daryaganj, New Delhi, India - Dr. Charoen Chuchottaworn, Chest Disease Institute (CDI), Ministry of Public Health, Tiwanon Rd., Mueang, Nonthaburi 11000, Thailand - Professor Gavin J Churchyard, Aurum Institute for Health Research, Klerksdorp, South Africa - Dr Rod Dawson, University of Cape Town Lung Institute, Cape Town, South Africa. - Professor Andreas Diacon, Task Applied Sciences and University of Stellenbosch, Cape Town, South Africa. - Professor Martin Grobusch and Professor Ian Sanne, Clinical HIV Research Unit (CHRU), Helen Joseph Hospital, Themba Lethu Clinic, Westdene, South Africa - Dr. R.K. Garg, III B-16, Nehru Nagar, Ghaziabad, Uttar Pradesh, India - Dr. Eduardo Gotuzzo Herencia, Instituto de Medicina Tropical Alexander Von Humbolt Lima, Peru - Dr. Mohi Anwar Habib, Near Gali Number 29, Main Jagdamba Road, Tughlakabad Extension, New Delhi, India - Dr. Anil Kumar Jain, Diligent Hospital, , Devli, East Sainik Farms, New Delhi, India 93

128 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Dr. Mahesh Kapoor, A-One Hospital, A- 1/7, Paschim Vihar, Main Rohtak Road, Delhi, India - Dr. Vinod Kumar Karhana, Smt. Prakashi Devi Memorial Medical Centre, Nehru Vihar, Karawal Nagar Road, Delhi, India - Dr. Lesego Khantsi, Aurum Tembisa Hospital, Tembisa, South Africa - Dr. Pairaj Kateruttanakul, Rajavithi Hospital, Division of Pulmonary, Department of Medicine, 2, Rajavithi Rd., Phayathai, Bangkok 10400, Thailand - Dr. Narendra Khippal, Bungalow No. - 2, In front of Krishna Kripa 1, Subhash Nagar Shopping Centre, Jaipur, India - Dr. Vijay Khurana, Ram Tej Hospital, 18/6 C, Vibhav Nagar Road (Near Amar Hospital), Agra, Uttar Pradesh, India - Dr. Rakesh Lal, Centre for Advanced Lung and Sleep Disorders, 2A, Lal Quarters, Shiv Mandir Road, Punjabi Bagh (W), New Delhi, India - Prof. Umesh Ganagaram Lalloo, Durban International Clinical Trial Unit, Durban, South Africa - Dr. Chi Chiu Leung, Wanchai Chest Clinic, Wanchai, Hong Kong - Dr. Shanglun Li TB Institute, Heping District, Tianjin, China - Dr Cheryl Louw, Madibeng Centre for Research (MCR), 40 Pienaar Street, Brits, South Africa - Dr Leonard Maboko, Mbeya Medical Research Programme, Mbeya Referral Hospital Hill, Mbeya, Tanzania - Dtin Dr. Aziah Ahmad Mahayiddin, Institute of Respiratory Medicine (IPR) Jalan Pahang, Kuala Lumpur, WP Kuala Lumpur, Malaysia - Dr. Mahesh Mishra, Mahatma Gandhi Medical College and Hospital, RIICO Institutional Area, Sitapura, Tonk Road, Jaipur, India - Dr. Rakesh Mittal, Dr. Mittal's Clinic, Balaji Medical Store, Delhi Gate, Main Bazaar, Najafgarh, New Delhi, India - Dr Peter Mwaba, University Teaching Hospital, Lusaka, Zambia. - Dr. R.S. Nagar, Dr. Nagar Medical Centre, Gali No. 2, Shopping Complex, Shakti Vihar, Molarband School Road, Meethapur, Badarpur, New Delhi, India - Dr Alexander Pym, Unit for Clinical and Biomedical TB Research, MRC Durban, Durban, South Africa. - Dr. Mahip Saluja, Subharti Medical College, Haridwar Delhi Bye Pass Road, Meerut, India - Professor Noel E. Sam, Kilimanjaro Christian Medical Centre (KCMC), Tumaini University, Moshi, Tanzania. - Associate Professor Tae Sun Shim, ASAN Medical Centre (AMC), Division of Pulmonary and Critical Care Medicine, Seoul, Korea - Dr. Suraj Prakash Sondhi, Dr. S. P. Sondhi s Clinic, Eve s Crossing, Hapur Road, Meerut, India - Dr. Sheng Jie Tang, Shanghai Pulmonary Hospital, Shanghai, China - Dr. Pawan Varshney, K. K. Hospital, Ramghat Road, Aligarh, Uttar Pradesh, India - Professor Chong-Jen Yu National Taiwan University Hospital Department of Internal Medicine, Taipei, Taiwan - Lizheng Zhu, MD, Beijing Tuberculosis and Thoracic Tumor Research Institute, Tongzhou District, Beijing, China 94

129 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 APPENDIX 5: HIV REPORTING AND COUNSELING All patients enrolled in the REMoxTB trial will undergo HIV testing regardless of their previous history of HIV testing, as co-infection with HIV and TB are common. Patients have the right to know the result of their HIV test and they should be encouraged to receive the result. Those patients who do not wish to know their result must be aware that they cannot be referred to HIV specialty doctors if they do not know the result of their HIV test. Patients who test positive for HIV will be able to be included in the trial as long as they are not on antiretroviral medications and their CD4+ count is equal or greater than 250 cells/µl. As HIV is a serious medical condition, patients should be properly prepared for the possibility of a positive result and what a positive result may mean to both themselves and those around them. Patients having the test should be encouraged to be told their result in order that those patients found to be HIV positive can be referred to the local programmes for management. All patients should be advised about the risk of contracting HIV and how to reduce the risks of transmission. Procedure PREPARATION AND HIV COUNSELLING 1. Direct the patient to a quiet and private area designated for counselling. 2. Ask the patient which language they prefer to communicate in and use this language to continue counselling. 3. Ascertain the patient s level of literacy, which has been recorded in the screening source document. 4..If the patient is illiterate advise them to have a literate witness present. The witness must be acceptable to the patient and not allocated by the study staff. The witness may be a family member or friend of the patient, or they may be unknown to the patient. They should not be participating in the trial or a member of the study team. 95

130 Private & Confidential REMoxTB Version 6.1 Final dated 18 August Ensure the individual understands the test result will be kept confidential. 6. It is essential that the patient undergo HIV testing for the REMoxTB study. They will give consent to this by signing and dating the Informed Consent Form. If the patient declines HIV testing this makes them ineligible for the trial and they must be referred to the local TB program for further management. 7. The patient should be encouraged to receive the results of the HIV test. If they are found to be HIV positive they will be referred to local HIV services. If they do not want to know their HIV result, they must not be told. However, they cannot be referred for HIV treatment if they do not know their HIV result. This should be clearly explained to the patient. 8. Explain that for this study, patients who are found to be HIV positive will need to have another blood test to check the CD4 count. Explain that these cells fight infections and because they decrease in HIV, are used as a guide when to begin HIV treatment. If the level is below 250 cells/µl or the patient requires treatment for HIV to start straight away, they will not be eligible for the study. These patients will be referred to the local service for treatment of HIV and TB. 9. All patients should then receive pre-test counselling as defined by the local National AIDS Control Programme. HIV TESTING should be performed to an algorithm that is agreed with the Sponsor. GIVING THE PATIENT THEIR RESULTS The results of the two tests (and ELISA if necessary) should be interpreted according to the local algorithm for test interpretation (refer to local guidelines). All patients should be encouraged to receive their results and post-test counselling as defined by the local National AIDS Control Programme. 96

131 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 The patient must not be told the result of their HIV test if they do not wish to know. This will not affect their eligibility for enrolment to the REMox study. PATIENT IS INELIGIBLE FOR THE STUDY 1. If the patient is ineligible for the study on the basis of their HIV test result, they should be referred back to the local TB service and will begin standard TB therapy according to the site National TB Programme. They should also be referred the local HIV specialist for further management of their HIV disease. No further samples should be collected as part of the REMox study and any samples received as part of the study and not yet processed, or in process, will be destroyed. The reason for screening failure should be recorded in the source documentation in the patient s medical notes. 2. Appropriate sections of Clinical Screening CRF should be completed If the patient is ineligible at screening, place all the screening dockets together with their Patient s Contact Details and Informed Consent Form in the Screen Failures Folder. PATIENT IS ELIGIBLE FOR THE STUDY Complete the Clinical Screening CRF 97

132 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 APPENDIX 6: DIGITAL PHOTOGRAPHY OF X-RAY Digital photography permits rapid collection and improved storage and transportation of the CXRs, which can be easily ed to the study clinician in the United Kingdom. This will allow all study CXRs, from all sites, to be reviewed centrally by the same radiologist to reduce subjective bias in reporting. Given the varying technical facilities at the various study sites, a site specific procedure may be required to describe the process at your site to record chest x-ray images if this differs from the processes described in this appendix. The site specific procedure must be signed off by the study clinician prior to implementation to ensure it meets study requirements Equipment Light box Digital camera Connector Battery charger Small tripod Data/memory card for viewing x-rays for uploading from the camera to the computer for camera The radiograph This document covers the technique to digitally capture the radiograph. This cannot undo quality issues that might arise with the radiograph itself. As a reminder, the main quality criteria regarding chest radiographs are mentioned here: a. Exposure quality or penetration the vertebral bodies should be just visible (through the heart shadow) b. Rotation of the patient Check for symmetry of the clavicles (the medial ends of the clavicle should be the same distance from the spinous processes on each side) c. Inspiratory effort can you see enough of the lung field? Count the number of visible anterior or posterior ribs (6 anterior and/or 10 posterior are 98

133 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 adequate) The Procedure 1. Setting up the radiograph a. Correct patient?, Left and R sides labelled correctly? b. The CXR should be placed on the light box and the light switched on. c. Outside light entering the room should be minimised by drawing the curtain or switching off the overhead lightening. (Note the room does not need to be completely dark) d. Complete a card with the: i. patient s study number ii. initials iii. date that the CXR was performed. e. Verify that the details match the CXR f. Place this card below the CXR so as not to obscure any part of the CXR. g. Cover the patient s identifying details where they are printed on the CXR using a card or paper. h. Ensure that the labelling or cover does not cover the radiograph at all. 2. The camera a. Switch the camera on and ensure it contains a memory card. b. Check the settings ii. Mode iii. Picture resolution c. Turn off the flash function. d. Attach the camera firmly to the tripod 3. Positioning the camera a. Place the tripod and camera approximately 1 meter from the radiograph b. The camera should be lined up with the centre of the CXR from left to right and from top to bottom. You might need to place the tripod on a book or box for this. 99

134 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 c. Use the zoom function so the image is central and occupies the most space possible in the viewfinder without any of the CXR or label being cutoff. d. Make sure you can see the patient study ID label and the entire radiograph. e. Make sure all identifying labels are covered (e.g. patient name) Figure 1: Set up 4. Capture the image by pushing the shutter down fully. 5. Check the quality of the image on the viewfinder and or after uploading it onto computer. Check that: a. The image is centered b. The image is in focus c. That you can see the full radiograph If you are not happy with the quality of the image or not sure about it you should re-take the picture. Pictures may be ed to the study 100

135 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 clinician to check for quality and also if you have questions. 6. Uploading the image into the REMox TB database can be done with the camera s own memory and cable or card reader, or with any other digital medium such as a memory stick or a CD. a. The images will be stored on the database for the REMoxTB study. b. Plug the camera into the database computer with the REMoxTB database, and upload the data. Check the clarity of the captured images. 7. The filename will be a combination of study number-initials-date of radiographs follows e.g. 1234D-ABC-03-Apr-2007.jpg (Do not use the patients name as the file name.) NOTE: The site will be asked to repeat any images in the database that are of insufficient quality. 101

136 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 EXAMPLES: PROBLEMS WITH X-RAY Film is on an angle Subject details are showing 102

137 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 X Ray is too small Film is under-exposed 103

138 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 APPENDIX 7 - LIVER TOXICITY MANAGEMENT Standard anti-tb chemotherapy is known to cause derangement of liver function tests in a significant number of patients. In many cases this will be asymptomatic and self limiting. In some cases severe hepatitis and even fulminant liver failure and death can occur. Liver function will be monitored regularly with clinical assessment and blood tests in study participants. The following procedure describes the management of deranged liver function tests in study participants. Procedure Blood tests for liver function will be taken routinely at screening and at weeks 2, 4, 8, 12 and 17 (Visits 2, 4, 8, 9, 10). If at any other visit the clinician suspects derangement of liver function, e.g. the patient describes nausea and vomiting or is jaundiced, blood should be taken for liver function tests and the patient comprehensively assessed for evidence of hepatitis or hepatic impairment and any potentially contributing causes. The laboratory source (print-out of any results) should be stored alongside or transcribed into the clinical source document. Each abnormal value should be marked as clinically significant (CS) or non clinically significant (NCS); the assessment of significance is at the discretion of the clinician. All clinically significant abnormal results must be recorded on the Adverse Event Tracking Sheet (Form PT4 or PT5) and graded clinically as per Modified DAIDS grading. In addition transcribe all laboratory results in appropriate visit docket and grade the abnormal values as per Modified DAIDS grading. If liver function tests are Grade 2 (DAIDS grading) Liver function tests may be repeated at the next scheduled appointment, even if it is a visit when the patient would not normally have blood collected. If any clinical symptoms or signs of liver function abnormalities are present then tests should be repeated immediately. 104

139 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 Assess the clinical significance the patient should be asked about symptoms of hepatic dysfunction. These may include (but are not limited to) malaise, nausea, vomiting, jaundice and fever. Examine the patient for any evidence of hepatitis, impairment, decompensation of chronic liver disease or liver failure (e.g. vital signs, RUQ tenderness, jaundice, bruising/bleeding, fetor, flap). Assess carefully for any contributing factors. The following are important to consider alcohol, other medications/substances taken, intravenous drug use, travel, unwell contacts The patient must be informed about signs that might indicate worsening abnormalities or evidence of drug reaction (e.g. loss of appetite, fever, nausea, vomiting, rash, jaundice) and know to present emergently should any of these be noticed. Reinforce the need to avoid any substances that may worsen or cause liver function abnormalities including alcohol and other medications. Ensure the patient is able to contact staff with any questions or concerns. If liver function tests are Grade 3 or 4 (DAIDS grading) Contact the patient and recall them as soon as possible. Assess the patient for other signs and symptoms of more specific hepatic events including hepatic impairment and or hepatitis. If you are concerned you should consider organising for the patient to present to a medical facility (e.g. emergency department) immediately for assessment. Assess the clinical significance Consider hospitalisation if the ALT is more than 10 times the ULN and/or the patient has jaundice, a coagulation disorder or signs of hepatic encephalopathy. All study drugs should be withheld pending assessment/improvement. Assess possible contributing factors This should include (but is not limited to) alcohol, intra-venous and other drug use, travel, unwell contacts, other medications (including herbal meds), previous or known hepatitis infection. Although anti-tb chemotherapy is known to cause 105

140 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 liver function test derangement, the patient should always be assessed for other possible causes or contributing factors. The patient should also be advised to stop taking any other medications/ substances that may be contributing to or causing derangement of liver function tests. Repeat the liver function tests immediately to confirm the results and to check for severity and for any progression. Useful tests may include AST/ALT, clotting, albumin and glucose. Tests may also help to determine the cause of abnormal liver function tests including tests for causes of viral hepatitis (e.g. hepatitis A and B). If tests for viral hepatitis are not available or not done it may still be helpful to collect an additional 10ml sample for serum for freezing (5ml yellow/sst tube x2) which may be tested later. The patient s consent must be obtained for this. Should the only finding be elevated liver enzymes of clinical significance reported as adverse event this should usually be recorded as elevated liver enzymes. Where the term "hepatitis" is used, the Safety Data Manager will question the site for additional evidence to support the diagnosis, such as clinical signs and serological or biopsy data. While a liver biopsy is not required to make a diagnosis of hepatitis, the term "hepatitis" should be reserved in most instances for cases where there is supportive evidence beyond a liver enzyme abnormality. However, if the investigator will confirm the diagnosis of hepatitis just on the basis of clinical signs and laboratory values the diagnosis will be accepted. Should other symptoms or signs be present, these should also be recorded as adverse events. Further Management Further management should be as clinically indicated and will need to be individualised depending on the circumstances for each patient. 106

141 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 General principles The patient should be contacted regularly. Initially this should be daily and subsequently depends on clinical course/individual circumstances. Staff must ensure that all patients know to seek medical attention urgently if they experience any evidence of worsening liver disease. Symptoms may include (but are not limited to) malaise, fever, nausea, vomiting, loss of appetite, dark urine, yellowing of the eyes or skin (jaundice). Liver function tests should be repeated e.g. Monitor ALT/AST every 3 days for the first week then once a week until they return to normal. Manage the patient symptomatically as required using medications that are not potentially hepatotoxic Infection control issues must be carefully managed whilst TB medications are being withheld, especially if the patient is still smear positive for acid fast bacilli. Restarting medication Once the liver function is normal (or AST/ALT falls to less than 2 times the upper limit of normal and symptoms have significantly improved) a decision must be made about further TB management. This will be dependent on the clinical context and a decision should be made in discussion with the medical deputy and study clinician on call. In all cases treatment should be recommenced under close supervision for any evidence of recurrent liver function abnormalities. All patients should be followed according to the trial protocol unless they withdraw consent to follow up. If there is a further reaction of clinical concern, study drugs should be withdrawn permanently. Patients who stop taking study drug should still be followed up according to the trial protocol. Patients who are withdrawn from study medication should be managed as clinically indicated according to local National TB Programme guidelines. The study clinician on call can provide advice and examples of suitable treatment regimens to use if required. 107

142 Private & Confidential REMoxTB Version 6.1 Final dated 18 August 2011 APPENDIX 8 - CHILD PUGH CLASSIFICATION APPENDIX 9 - CREATININE CLEARANCE CALCULATION 1. Ensure that the creatinine is expressed in μmol/l i. If your lab reports the creatinine in mg/dl : multiply by 88.4 ii. If your lab reports the creatinine value in μmol/l : use this value 2. Calculate the creatinine clearance using the Cockcroft-Gault formula Where Constant is 1.23 for men and 1.04 for women 108