TB Updates for the Physician Rochester, Minnesota June 19, 2009

Transcription

1 TB Updates for the Physician Rochester, Minnesota June 19, 2009 Recent Findings & Activities of the Tuberculosis Trials Consortium (TBTC) Bill Burman Denver TBTC Unit & Denver Public Health Recent findings and Activities of the Tuberculosis Trials Consortium (TBTC) Bill Burman Denver TBTC unit and Denver Public Health 1

2 Tuberculosis Trials Consortium - overview Multicenter clinical trials group funded by the Division of TB Elimination at CDC Mission To conduct programmatically-relevant studies to improve the treatment of latent and active TB History 1993 constituted to conduct one trial 1997 re-organized as a clinical trials group 1999 sites re-competed for 10-year contract 2009 sites re-competing again Current TBTC sites stay tuned for changes! 28 clinical sites worldwide CDC Administrative, Statistical, and Data Management Center 2

3 TBTC current capabilities Trials of treatment of active TB Enrollment of 400 patients per year Pilot studies of MDR-TB treatment enrollment of 50 patients per year Latent TB Enrollment of 1350 patients per year Enrollment of children (> 2 years) Other TBTC activities Data and coordination center - CDC Central microbiology lab - CDC confirmatory drug-susceptibility testing genotypic resistance testing DNA fingerprinting CRO for training and site-monitoring (Westat) Working groups on Pharmacokinetics, Biomarkers, Drug-Resistant TB, and Hepatotoxicity 3

4 Our current collaborations HIV-focused clinical trials groups ACTG, IMPAACT Leverage funding Access to special populations and expertise (e.g., HIV co-infected subjects, expertise in pediatric PK) Other TB trials groups on secondary analyses, cross-protocol analyses Growing number of basic science labs: UCSF genotyping lab, CSU Mycobacteriology Research Labs, UCSD, Emory, Yale, Albany Medical College, Boston University, Nelson Mandela School of Medicine Major TBTC studies Study 22 once-weekly rifapentine during continuation phase of TB treatment Study 23 rifabutin-based regimen for HIV-TB Study 24 treatment of INH-resistant TB Study 25 higher doses of weekly rifapentine Study 26 phase 3 trial of weekly INH/RPT x 12 doses vs. 9 mos of INH for latent TB Studies 27, 28 role of moxifloxacin in intensive phase Study 29 rifapentine vs. rifampin in intensive phase Study 30 pilot study of linezolid for MDR-TB 4

5 Problems in TB treatment: latent TB infection Shorter regimens that increase treatment completion and therefore, overall effectiveness Treatment for patients exposed to drug-resistant TB Treatment regimens that are effective for evolving TB (in transition from initial infection to active disease) Close contacts who are young children HIV-infected patients Choosing the study regimen Weekly RPT + INH active in an animal model of latent TB treatment 3 months (12 doses) as active as INH for 6-9 months Directly observed preventive therapy (DOPT) may work well, if it involves few doses DOPT is ideal for children 900 mg dose of RPT (15 mg/kg) well-tolerated in an initial study (TBTC Study 25) 5

6 TBTC Study 26 Latent TB high risk for progression Close contact, new + TST, HIV-positive, Class 4 x-ray Age > 2 years N = 4000 N = 4000 INH for 9 mos RPT (900) + INH weekly x 12 Follow for 33 months Modeling from Phase 1 study - dose in children predicted to achieve RPT AUC comparable to 15 mg/kg dose in adults Pediatr Infect Dis J 2006; 25:

7 Median RPT C24 was significantly greater in children vs. adults, though variance was also greater n Dose median (IQR) mg/kg RPT C24 median (IQR) g/ml Children ( ) 12.4 ( ) Adults ( ) 8.3 ( ) P-value * <.0001 <.0001 Ratio medians * P-value by Mann-Whitney Weiner M, 2008 IUATLD conference Progress of Study 26 Patient 8000 enrolled in February 2008 Follow-up will end in November 2010 Enrollment continuing to establish tolerability in key subgroups (n = 644 for each) Young children (2-12 years) HIV-infected persons Per the DSMB No safety concerns Pooled event rate is low 7

8 Limitations of the Study 26 regimen Have not assessed tolerability, adherence, and activity if self-administered TBTC may undertake a follow-up study to compare DOPT vs. self-administered Drug interactions of RPT much like those of rifampin Activity in HIV-co-infected patients may not be optimal May not be active for evolving TB Problems in TB treatment: drug-susceptible disease Shorter regimens to improve treatment completion Safer therapy we shouldn t tolerate 3-5% risk of hepatoxicity Regimens without serious interactions with so many other drugs, particularly antiretroviral drugs Regimens that are reliably active for high-risk patients (duration, intermittent dosing) Extensive pulmonary TB Advanced HIV co-infection 8

9 Percentage of patients not completing treatment for active TB Hlabisa, South Africa Percent not completing TB treatment '92 '93 '94 '95 '96 Int J Tuberc Lung Dis 1999;3: Side effects of directly-observed therapy with INH, RIF, PZA, EMB Side effects Non-alcoholics (n = 249) Alcoholics (n = 118) Any toxicity 79 (32%) 68 (58%) Hepatitis 16 (7%) 25 (21%) Nausea / vomiting 33 (13%) 15 (13%) Fevers 0 12 (11%) Unpublished data Denver Public Health 9

10 Effect of rifampin on plasma concentrations (AUC) of HIV-1 protease inhibitors Percentage of normal concentrations With 100 mg RTV * * SQV RTV IDV NLV AMP LPV ATV Clin Infect Dis 1999; 28: Antimicrob Agents Chemother : Antimicrob Agents Chemother 2006; 50: Other drug classes having significant interactions with rifampin Antimicrobial drugs: antibiotics (doxycycline) azole antifungals antiparasitics (atovaquone) Hormonal agents LT4, estrogens Narcotics - methadone Anticoagulants - warfarin Cardiovascular drugs: beta-blockers calcium-channel antagonists ACE inhibitors and ARBs digoxin (with renal insufficiency) anti-arrythmics Theophylline Immunosuppressives glucocorticoids cyclosporine, tacrolimus Sulfonylureas Hypolipidemics Psychotropic drugs benzodiazepines tricylic antidepressants neuroleptics 10

11 Dosing frequency and risk of relapse after 6 month regimens results of a meta-analysis Relapse (%) Daily Daily, then TIW Daily, then BIW 6.5 TIW 14.5 Non-cavitary Cavitary Cavitary, 2 mo. + Am J Respir Crit Care Med 2006; 174: Opportunities for clinical trials Fluoroquinolones Shorten therapy for drug-susceptible TB Enhanced-dose rifamycins Shorten therapy for drug-susceptible TB New drug classes: TMC207, OPC67683, PA824, SQ109, PNU Improve treatment outcomes for MDR-TB, allow effective treatment of latent MDR-TB Shorten therapy for drug-susceptible TB, shorten therapy for latent TB, 11

12 Activity of moxifloxacin in combination therapy in a mouse model of TB 10 Log CFU in entire lung logs Untreated 2RHZ+4RH 2RHZM+4RHM 2RMZ+4RM Duration of treatment (mos.) Am J Respir Crit Care Med 2004; 164:421-6 % culture-negative at 2 months Activity of moxifloxacin in Phase 2B clinical trials PZA 13% difference at 2 months Moxi EMB Moxi EMB Moxi EMB Moxi INH TBTC 27 JHU Brazil Oflotub TBTC 28 Am J Respir Crit Care Med 2006; 174:331-8, Lancet, in pres Int J Tuberc Lung Dis 2008; 12: , Am J Respir Crit Care Med, epub

13 TBTC Study 27 - symptoms reported at study visits, by treatment arm Symptom Moxifloxacin Ethambutol P-value Fever Nausea Vomiting Dizziness Insomnia Joint pain 18% 21% 12% 14% 12% 36% 13% 9% 9% 10% 9% 26% Am J Respir Crit Care Med 2006; 174:331-8 Recommendations for use of fluoroquinolones in drug-susceptible TB Current data do not support treatmentshortening; need to wait for the results of Phase 3 trials Best of the current 2 nd -line drugs Replacement for other drugs (INH, RIF) if there is resistance Useful in management of cases of hepatotoxicity 13

14 USPHS Study 19 Randomized trial of rifampin doses (with INH and EMB) Rifampin dose % culture positive 12 weeks 20 weeks 450 mg 600 mg 750 mg Am Rev Respir Dis 1979;119: Dose-response curve for rifampin in mice area under the concentration-time curve (AUC) / MIC RIF 10/mg/kg If tolerated, higher dose rifampin or rifapentine are highly likely to allow treatment shortening Antimicrob Agents Chemother 2003; 47:

15 Activity of enhanced-dose rifapentine in the mouse model R 10 HZ (5/7) R 10 MZ (5/7) P 10 HZ (5/7) PLoS Medicine 2007: 4: e344 Relapse after ultra-short therapy: the mouse model % relapse RIFR10HZ 10 RPT P7.5HZ 7.5 HZ RPT P10HZ 10 HZ 10 wk 12 wk Am J Respir Crit Care Med 2008; 178:

16 Pharmacodynamic simulations (free drug/mic) of RPT vs. RIF in the mouse model Rifapentine (10 mg/kg/day) Rifampin (10 mg/kg/day) PLoS Medicine 2007: 4: e344 The effect of rifampin dose on early bactericidal activity Antimicrob Agents Chemother 2007; 51:

17 Mouse and man rifapentine (RPT) Mouse PK - daily RPT (10 mg/kg) AUC (week) 2157 Cmax 24 PLoS Medicine 2007: 4: e344 Human Phase 1 data daily RPT was welltolerated, up to 600 mg Human PK data daily RPT 600 mg AUC (week) 1645 Cmax 19 Int J Tuberc Lung Dis 1999; 3: TBTC Study 29 Schema Sputum smear+ PTB suspect randomization RPT (600 mg) INH+PZA+EMB Daily for 8 weeks RIF (600 mg) INH+PZA+EMB Daily for 8 weeks assess for primary endpoints ATS/CDC/IDSA-recommended continuation phase regimen 17

18 TBTC Study 29 - Evaluation of a rifapentinecontaining regimen for intensive phase treatment of pulmonary tuberculosis Key inclusion criteria Non-pregnant adult with suspected TB with positive AFB smear Less than 6 days of TB treatment Informed consent Primary endpoints 2-month culture status Completion of assigned study therapy Progress on Study 29: RPT vs. RIF ~ 170 patients enrolled (of 438) ~30 patients enrolled in an intensive PK substudy (of 60) Two reviews by DSMB no safety concerns Completion of enrollment in late 2009 or early 2010 Final results by mid

19 Initial considerations Phase 3 trial of enhanced rifamycins Regimens Optimal RPT regimen: 2HPZE 5 / 1HP Optimal high-dose RIF regimen: 2HR high ZE 5 / 2HR Control regimen: 2HR standard ZE 5 / 4HR Questions Duration of experimental regimens (3-4 months) Whether (and how) to extend therapy for highrisk patients Dosing frequency after 2 months Enhanced rifamycins: summary Daily RPT is likely to be much more potent than daily RIF (~4-fold in mouse model) Likely to support treatment-shortening to 3 or 4 months Tolerability will be the key parameter Should be applicable to children, women of child-bearing potential, pregnant women Unlikely to decrease drug interactions: RPT has similar effects as RIF 19

20 Drug resistance in Donetsk Oblast, Ukraine (2005-6) Per cent resistant Any INH RIF MDR New Previous treatment Int J Tuberc Lung Dis 2008;12: Outcomes of treatment of MDR-TB, Western Cape, South Africa, Success Death Default Failure Transfer Limited follow-up posttreatment: 7% had recurrent TB within 2 years Int J Tuberc Lung Dis 2008; 12:

21 Update on causes of XDR-TB in Tugela Ferry, South Africa Superinfection was a common cause of XDR-TB among HIVpositive patients J Infect Dis 2008;198: New drugs for MDR-TB TMC207 an inhibitor of mycobacterial ATPsynthase OPC67683 inhibitor of cell wall synthesis PA824 inhibitor of cell wall synthesis SQ109 congener of ethambutol, active against ethambutol-resistant strains Oxazolidinones Linezolid PNU

22 Time to culture conversion (MGIT) on ITT population (n=44) 9% p= % (a) p-value from Cox proportional model adjusting for strata Diacon A, 2008 ICAAC Current status of TMC207 Highly potent in mouse and man; not active for common bacterial pathogens Evaluation for MDR may allow early licensure Well-tolerated in initial, small short-term human trials Unusual PK terminal half-life of 5 months Drug-drug interaction profile may be problematic 50% decrease with rifampin Moderate increase with ketoconazole 22

23 Linezolid for TB Moderate in vitro activity against M. tuberculosis MIC ug/ml No cross-resistance resistance with other drug classes Apparent activity in case series 4 series, total of 27 MDR patients 2 month culture conversion - 70% Toxicities cytopenias,, peripheral neuropathy, optic neuropathy Linezolid for Multidrug-Resistant Tuberculosis (LiMiT( LiMiT) ) Study Linezolid 600 mg daily for 16 weeks or placebo added to Optimized Background Therapy (OBT) for MDR- TB or XDR TB OBT: > 4 drugs with activity against tuberculosis to which the patient s s isolate is believed to be sensitive by history or DST Sample size 32 patients per arm Enrollment King George Hospital, Durban 23

24 LiMiT study progress Pfizer providing the drug and placebo, paying for pharmacokinetic substudy Approvals obtained Enrollment started in May, expected to be completed in late 2009 Valuable experience with a new drug class Valuable experience in the challenges on a trial for MDR-TB treatment TBTC addresses key problems in TB treatment Poor completion of treatment of latent TB infection 3-month (12 dose) regimen Marginal completion of treatment of active TB evaluation of daily RPT Frequency of dosing required not being addressed by current studies Common bothersome side effects, unusual serious side effects hepatitis substudies of current trials, collaboration with Drug-Induced Liver Injury Network 24

25 TBTC addresses key problems in TB treatment, continued MDR-TB treatment that is toxic, relatively ineffective and requires months LiMiT protocol, MDR Working Group Challenges of co-treatment of TB and HIV collaborations with ACTG, IMPAACT Lack of data on treatment of TB in children Study 26, collaboration with IMPAACT and other groups 25