Supplementary appendix

Transcription

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet 2015; published online Dec 9. S (15)

2 Appendix Contents Table S1: Definitions of mitt population and mitt population by FDA galactomannan criteria... 2 Table S2: Description of the study population: inclusion and exclusion criteria... 3 Table S3: DRC-Assessment definitions of clinical, mycological and radiological response... 5 Table S4: Summary of trough plasma concentrations of isavuconazole (pharmacokinetic analysis set)... 7 Table S5: Most common TEAEs ( 5% of patients in either treatment group)... 8 Table S6: Efficacy summary for mitt population by FDA galactomannan criteria Table S7: All-cause mortality in the per protocol ITT and mitt populations Table S8: Outcome in patients with culture positive results at baseline Table S9: All cause mortality for the mitt patients plus patients with baseline BAL GM Table S10: DRC assessed overall response at days 42 and 84 (mitt) Table S11: Protocol amendments Figure S1: Day 84 survival probability (mitt population)

3 Table S1: Definitions of mitt population and mitt population by FDA galactomannan criteria Population Definition The mitt population consisted of ITT patients who had proven or probable IMD, as determined by the DRC. Patients with appropriate host mitt population factors and clinical features were considered to have probable IMD based on the galactomannan criteria set forth in the protocol (ie, two consecutive serum galactomannan values 0 5 or at least one serum galactomannan value 0 7). The mitt population by FDA galactomannan criteria consisted of ITT patients with proven or probable IMD. Patients with appropriate host mitt population by FDA galactomannan criteria factors and clinical features were considered to have probable IMD based on the galactomannan criteria recommended by the FDA (ie, two consecutive serum galactomannan values 0 5 or at least one serum or BAL galactomannan value 1 0), as determined by the DRC. BAL=bronchoalveolar lavage; DRC=data-review committee; FDA=US Food and Drug Administration; IMD=invasive mould disease; ITT=intent-to-treat; mitt=modified intent-to-treat. 2

4 Table S2: Description of the study population: inclusion and exclusion criteria Inclusion criteria Either patients and/or legally authorised representative(s), who had been fully informed and who gave voluntary informed consent and HIPAA Authorisation for US centres or equivalent privacy language as per national regulations Ability and willingness to comply with the protocol Male and female patients aged 18 years at time of signing the informed consent form Female patients were to be non-lactating and at no risk for pregnancy Patients with proven, probable or possible invasive fungal disease caused by Aspergillus species or other filamentous fungi Exclusion criteria Known history of allergy, hypersensitivity to, or any serious reaction to the azole class of antifungals or to any component of the study medication Patients for whom voriconazole was contra-indicated, including cardiovascular findings Patients at high risk for QT/QTc prolongation (baseline prolongation of QTcF 500 ms; risk factors for Torsades de Pointes; use of concomitant medications that prolong the QT/QTc interval) Patients with evidence of hepatic dysfunction at the time of randomisation, defined as total bilirubin 3 X ULN, alanine transaminase or aspartate transaminase 5 X ULN, or those with known cirrhosis or chronic hepatic failure Concomitant use of sirolimus, efavirenz, ritonavir, astemizole, cisapride, rifampin/rifampicin, rifabutin, ergot alkaloids, longacting barbiturates, carbamazepine, pimozide, quinidine, neostigmine, terfenadine, ketoconazole, valproic acid, or St. John s Wort in the 5 days prior to first dose of study drug Patients with any other invasive fungal infection other than Aspergillus spp. or other filamentous fungi and patients with mucormycosis or Scedosporium prolificans infection not expected to respond to voriconazole treatment Patients with chronic aspergillosis, aspergilloma or Allergic Bronchopulmonary Aspergillosis Microbiological findings or other conditions that were temporally related and suggested a different etiology of clinical features in absence of evidence of systemic aspergillosis 3

5 Inclusion criteria Exclusion criteria Patients who had been administered more than four cumulative days of itraconazole, voriconazole, or posaconazole within the 7 days prior to the first dose of study drug (patients who developed new evidence of IFD while on prophylactic therapy, for at least 14 days, with either an amphotericin B product or an echinocandin, and prior use of fluconazole of any duration and for any reason were eligible for enrolment) Advanced HIV infection with CD4 count <200 or acquired immunodeficiency syndrome-defining condition Any known or suspected condition of the patient that could jeopardise adherence to the protocol requirements or impede the accurate measurement of efficacy Patients with a concomitant medical condition that, in the opinion of the investigator, was an unacceptable additional risk to the patient Patients previously enrolled in a phase 3 study with isavuconazole Treatment with any investigational drug in any clinical trial within 30 days prior to the first dose of study drug, except open-label protocols Patients who were unlikely to survive 30 days or those on mechanical ventilation Patients with a body weight 40 kg Patients with evidence of moderate-to-severe renal dysfunction plus either creatinine clearance <50 ml/min at screening or requiring dialysis during administration of study drug HIPAA=health insurance portability and accountability act; IFD=invasive fungal disease; ULN=upper limit of normal. 4

6 Table S3: DRC-Assessment definitions of clinical, mycological and radiological response Outcome DRC-assessed clinical response Success Resolution of all attributable clinical symptoms and physical findings Partial resolution of attributable clinical symptoms and physical findings Failure No resolution of any attributable clinical symptoms and physical findings and/or worsening Not applicable No attributable signs and symptoms present at baseline and no symptoms attributable to invasive fungal disease developed post baseline Outcome DRC-assessed mycological response Success Eradication Presumed eradication Failure Persistence Presumed persistence Not applicable No mycological evidence available at baseline Time point DRC-assessed radiological response Day 42 Success (improvement of at least 25% from baseline) Failure No post-baseline radiology available for patient with baseline evidence of radiological disease Radiology not applicable at baseline Day 84 Success (improvement of at least 50% from baseline) Failure No post-baseline radiology available for patient with baseline evidence of radiological disease Radiology not applicable at baseline 5

7 EOT Success (improvement of at least 25% from baseline, if EOT occurs prior to day 42; if EOT occurs after day 42, at least 50% improvement from baseline) Failure No post-baseline radiology available for patient with baseline evidence of radiological disease Radiology not applicable at baseline DRC=data-review committee; EOT=end of treatment. 6

8 Table S4: Summary of trough plasma concentrations of isavuconazole (pharmacokinetic analysis set) Day 7 Day 14 Assumed steady state* n Mean (ng/ml) Median (ng/ml) Range (ng/ml) *Trough concentrations from day 21 through 24 h after the last dose of isavuconazole. Troughs were averaged for patients with >1 trough sample within this time-frame. 7

9 Table S5: Most common TEAEs ( 5% of patients in either treatment group)* Isavuconazole (n=257), n (%) Voriconazole (n=259), n (%) Patients with 1 TEAE 247 (96 1) 255 (98 5) Nausea 71 (27 6) 78 (30 1) Vomiting 64 (24 9) 73 (28 2) Diarrhoea 61 (23 7) 60 (23 2) Pyrexia 57 (22 2) 78 (30 1) Hypokalaemia 45 (17 5) 56 (21 6) Headache 41 (16 0) 38 (14 7) Constipation 36 (14 0) 54 (20 8) Dyspnoea 34 (13 2) 29 (11 2) Cough 33 (12 8) 35 (13 5) Febrile neutropenia 32 (12 5) 38 (14 7) Chills 27 (10 5) 23 (8 9) Fatigue 27 (10 5) 18 (6 9) Back pain 26 (10 1) 19 (7 3) Oedema peripheral 26 (10 1) 31 (12 0) Abdominal pain 25 (9 7) 36 (13 9) Hypertension 25 (9 7) 31 (12 0) Insomnia 23 (8 9) 24 (9 3) Mucosal inflammation 23 (8 9) 14 (5 4) Decreased appetite 22 (8 6) 28 (10 8) Epistaxis 21 (8 2) 28 (10 8) Hypotension 21 (8 2) 28 (10 8) Anxiety 20 (7 8) 17 (6 6) Pruritus 19 (7 4) 15 (5 8) Rash 17 (6 6) 28 (10 8) Asthenia 16 (6 2) 20 (7 7) 8

10 Isavuconazole (n=257), n (%) Voriconazole (n=259), n (%) Confusional state 16 (6 2) 20 (7 7) Gamma-glutamyl transferase increased 16 (6 2) 22 (8 5) Haemoptysis 16 (6 2) 17 (6 6) Abdominal pain upper 15 (5 8) 25 (9 7) Cytomegalovirus infection 15 (5 8) 23 (8 9) Dyspepsia 15 (5 8) 13 (5 0) Septic shock 15 (5 8) 10 (3 9) Hypomagnesaemia 14 (5 4) 27 (10 4) Oropharyngeal pain 14 (5 4) 14 (5 4) Respiratory failure 14 (5 4) 17 (6 6) Alanine aminotransferase increased 13 (5 1) 17 (6 6) Oedema 13 (5 1) 18 (6 9) Oral herpes 13 (5 1) 14 (5 4) Anaemia 12 (4 7) 23 (8 9) Blood alkaline phosphatase increased 12 (4 7) 15 (5 8) Tachycardia 12 (4 7) 21 (8 1) Aspartate aminotransferase increased 11 (4 3) 14 (5 4) Pain in extremity 11 (4 3) 15 (5 8) Thrombocytopaenia 11 (4 3) 25 (9 7) Dizziness 10 (3 9) 15 (5 8) Hyperglycaemia 10 (3 9) 13 (5 0) Erythema 9 (3 5) 15 (5 8) Staphylococcal bacteraemia 7 (2 7) 13 (5 0) Hypoglycaemia 5 (1 9) 13 (5 0) Rales 5 (1 9) 14 (5 4) Bacteraemia 4 (1 6) 14 (5 4) Visual impairment 4 (1 6) 19 (7 3) 9

11 *One patient received voriconazole for the first 7 days. This patient was included in the voriconazole treatment group in the safety population TEAE=treatment-emergent adverse event. 10

12 Table S6: Efficacy summary for mitt population by FDA galactomannan criteria Efficacy outcomes Isavuconazole Voriconazole Adjusted treatment difference, % (95% CI)* Day 42 all-cause mortality, n/n (%) 28/147 (19 0) 28/128 (21 9) 2 1 ( 11 4, 7 2) DRC-assessed overall response at EOT, n/n (%) Success 52/147 (35 4) 47/128 (36 7) 1 8 ( 9 0, 12 6) Complete 19/147 (12 9) 14/128 (10 9) Partial 33/147 (22 4) 33/128 (25 8) Failure 95/147 (64 6) 81/128 (63 3) Stable 43/147 (29 3) 34/128 (26 6) Progression 52/147 (35 4) 47/128 (36 7) *Isavuconazole voriconazole for all-cause mortality; voriconazole isavuconazole for overall, clinical, mycologic, and radiologic responses. Calculated by a stratified Cochran-Mantel-Haenszel method (strata: geographic region, allogeneic BMT/HSCT, and uncontrolled malignancy status). EOT=end of treatment; FDA=US Food and Drug Administration; mitt=modified intention-to-treat. 11

13 Table S7: All-cause mortality in the per protocol ITT and mitt populations Isavuconazole Voriconazole Treatment difference % (95% CI) n/n % n/n % PP-ITT population PP-mITT population 26/ / ( 10 3, 5 1) 16/ / ( 15 2, 5 0) PP-ITT=per-protocol intention-to-treat; PP-mITT=per-protocol modified intention-to-treat. 12

14 Table S8: Outcome in patients with culture positive results at baseline Baseline Aspergillus species MIC (µg/ml) >8 Isavuconazole (n=37) n/n (%) n/n (%) n/n (%) n/n (%) n/n (%) Day 42 all-cause mortality 2/23 (8 7%) 2/6 (33 3%) 0/6 (0%) 0/1 (0%) 1/1 (100%) Overall response at EOT success 10/23 (43 5%) 2/6 (33 3%) 3/6 (50 0%) 1/1 (100%) 0/1 (0%) Voriconazole (n=23) n/n (%) n/n (%) n/n (%) n/n (%) n/n (%) Day 42 all-cause mortality 6/17 (35 3%) 1/4 (25 0%) 0/2 (0%) 0 0 Overall response at EOT success 6/17 (35 3%) 3/4 (75 0%) 1/2 (50 0%) 0 0 EOT=end of treatment; MIC=minimum inhibitory concentration. 13

15 Table S9: All cause mortality for the mitt patients plus patients with baseline BAL GM 1 Endpoints, n (%) Isavuconazole (n=156) Voriconazole (n=136) Treatment difference % (95% CI) Day 42 all-cause mortality 30 (19 2%) 31 (22 8%) 2.4 ( 11 6, 6 8) Overall response at EOT 55 (35 3%) 50 (36 8%) 2.1 ( 8 5, 12 6) BAL=bronchoalveolar lavage; EOT=end of treatment; GM=galactomannan; mitt=modified intention-to-treat. 14

16 Table S10: DRC assessed overall response at days 42 and 84 (mitt) Endpoints Isavuconazole (n=143) Voriconazole (n=129) Day 42 Success, n (%)* 51 (35 7%) 46 (35 7%) Adjusted difference (voriconazole isavuconazole), % (95% CI) 0 5 ( 11 28, 10 33) Complete, n (%) 7 (4 9) 7 (5 4) Partial, n (%) 44 (30 8) 39 (30 2) Failure, n (%) 92 (64 3) 83 (64 3) Stable, n (%) 36 (25 2) 28 (21 7) Progression, n (%) 18 (12 6) 19 (14 7) Death, n (%) 25 (17 5) 26 (20 2) Missing, n (%) 13 (9 1) 10 (7 8) Day 84 Success, n (%)* 36 (25 2) 42 (32 6) Adjusted difference (voriconazole isavuconazole), % (95% CI) 8 2 ( 1 99, 18 38) Complete, n (%) 14 (9 8) 13 (10 1) Partial, n (%) 22 (15 4) 29 (22 5) Failure, n (%) 107 (74 8) 87 (67 4) Stable, n (%) 30 (21 0) 14 (10 9) Progression, n (%) 5 (3 5) 8 (6 2) Death, n (%) 43 (30 1) 44 (34 1) Missing, n (%) 29 (20 3) 21 (16 3) *Crude success rates were calculated within treatment group. Adjusted treatment difference (voriconazole isavuconazole) was calculated by a stratified Cochran Mantel Haenszel method with the strata of geographical regions, allogeneic bone marrow/haematopoietic stem cell transplant status and uncontrolled malignancy status. The 95% CI for the treatment difference was calculated based upon a normal approximation. CI=confidence interval; DRC=data-review committee; mitt=modified intention-to-treat. 15

17 Table S11: Protocol amendments Protocol amendment Amendment 1 (February 9, 2007) Details It was issued to clarify the definitions of mycological criteria and uncontrolled malignancy. The number of laboratory tests was reduced to minimize the total amount of blood drawn from seriously ill patients. This amendment also clarified that, for patients who consented but were not randomised, participation was to be considered completed on the day the decision was made to not randomise the patient. Amendment 2 (September 22, 2008) It was issued to clarify and amend the study s secondary objectives, the summary of the study visits and the wording of the blinding. The requirement was clarified that all systemic, oral or topical antifungal, antiviraland antibiotic agents administered and all diagnostic procedures performed, during the treatment period and during the 4-week posttreatment period, were to be reported in the ecrf. Exclusion criteria were amended to add medications (sirolimus, efavirenz and ritonavir) that should not be used within 5 days prior to the start of study drug administration and to remove chronic granulomatous disease and severe combined immunodeficiency disease from the exclusion criteria. The definition of complete and partial overall responses was amended and an overall response of failure or indeterminate was classified as an unsuccessful overall outcome. The pharmacokinetic substudy was amended to include at least 10 patients aged > 65 years. It was clarified that the IDSMB would review efficacy data for futility after the first 180 patients completed day 42 assessments or were withdrawn prior to day 42. The DRC assessment was amended to include categorisation of the diagnosis of IFD at enrolment (including data up to day 7 as relevant), as well as the patients radiological, clinical and mycological response at EOT and days 42 and 84. Amendment 3.1 (May 27, 2010) It reflected the change in study sponsorship; Basilea Pharmaceuticals was replaced with Astellas Pharma Global Development, Inc. The number of sites was reduced from 200 to approximately 150. The inclusion/exclusion criteria were amended and further clarified. The primary endpoint was amended to 16

18 compare overall outcome on day 42 following primary treatment with isavuconazole versus voriconazole in patients with IFD caused by Aspergillus species or other filamentous fungi. The secondary objectives of the study were changed to clarify which study day the endpoints were assessed (overall outcome and mycological response at day 42, EOT and day 84; survival rate at day 42 and day 84). Two exploratory objectives (pharmacokinetic), diagnostic tools, diagnosis definitions, requirements for GM values and IDSMB review were amended and clarified. Isavuconazole dosing and the fasting requirement for oral isavuconazole administration were amended. Host factors were clarified to enrich the study population with haematologic malignancies and to limit patients with rheumatologic conditions. Additional information was provided for QT interval corrected for heart rate (QT/QTc) definitions. Further clarifications were provided on the packaging, labelling, shipment, storage, preparation, administration, accountability and disposal of study drug. The collection of trough levels was amended to include samples from all patients. Additional medications were added to the list of prohibited concomitant medications or the list of concomitant medications to be used with caution. Visit requirements and study duration details were clarified. Additional stoppage criteria were also included for study drug. Bronchoalveolar lavage GM was added as allowable mycological criteria for enrolment of patients with Aspergillus as possible cases of IFD. Follow-up criteria for these patients were also added. Amendment 4 (November 5, 2010) It made a number of changes in the study objectives, variables, criteria for enrolment, planned sample size and power calculation, dosing schedule and timing of the first IV maintenance dose. The primary objective/variable was changed from overall outcome at day 42 to all-cause mortality through day 42 and the primary efficacy population was amended to the Intention-to-treat population. The sample size was re-estimated based on a non-inferiority trial design with a 10% NIM, 20% all-cause mortality from voriconazole treated patients and 80% statistical power for inference. The secondary 17

19 objectives/variables were amended to support the change in the primary variable. The exploratory objectives and variables were expanded to include the study drug and potential metabolites. Additional information was provided about the concomitant administration of nonstudy systemic antifungal and about the timing of the first maintenance dose of study drug. Exclusion criteria were revised to ensure patients with QT/QTc prolongation, hepatic impairment or renal impairment were not eligible for study participation for safety purposes. Additional medications were added to the list of prohibited concomitant medications to ensure patient safety. An eye examination consisting of visual acuity, confrontational visual field testing and colour perception testing was added to the safety measurements. ecrf=electronic case report form; GM=galactomannan; IDSMB=Independent Data and Safety Monitoring Board; IFD=invasive fungal disease; NIM=non-inferiority margin. 18

20 Figure S1: Day 84 survival probability (mitt population) Patients were censored on the day of their last known survival status, represented by the circles. 19