A multicenter, randomized phase III study of bortezomib and ...

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HOVON 104 AL AMYLOIDOSIS Clinical trial protocol version 7, 27 November 2012 14.2.1 Efficacy analysis Per treatment arm, the CHR 6mo rate will be determined with a 95% confidence interval (CI). The formal comparison of the CHR 6mo rate between the two treatment arms will be performed using logistic regression analysis with adjustment for the stratification factor cardiac stage (I vs II vs III). Patients with a CHR at six months (± 2 weeks) after auto-SCT will be considered a success. In case a CHR is available before 5.5 months after auto-SCT and the next CHR only after 6.5 months post- SCT, then it will be assumed that the response at 6 months after auto-SCT was also CHR, and such a patient will also be considered as a success. All other patients will be considered a failure. Per treatment arm, the best hematological response during protocol treatment will be determined. Per treatment arm, the actuarial curves for PFS and OS from randomization will be computed using the Kaplan-Meier method and 95% Cis will be constructed. Cox regression analyses will be used to compare the survival endpoints between the two treatment arms. Organ response will be tabulated for the different time points as described in the protocol. 14.2.2 Toxicity analysis The analysis of toxicity will be done primarily by tabulation of the incidence of adverse events with CTCAE grade 2 or more, after each induction cycle separately, for the collective induction cycles per patient, and after HDM + auto-SCT. 14.2.3 Additional analyses Additional analyses may be added. However, these analyses should be regarded as exploratory, and therefore only as hypothesis-generating. 14.2.4 Statistical analysis plan (optional) A detailed statistical analysis plan (SAP) will be made for the final analysis. It will be discussed with the study coordinators and can only affect the exploratory analyses, but not the primary (confirmatory) analysis on which the sample size is based. Page 42 of 75 EudraCT-No: 2010-021445-42
HOVON 104 AL AMYLOIDOSIS Clinical trial protocol version 7, 27 November 2012 14.3 Interim analysis One interim analysis is planned, primarily to guard against unfavourable results in the bortezomib arm. Results of the interim analysis will be presented confidentially to a DSMB. Only if the DSMB recommends that the study should be stopped or modified the results will be made public to the principal investigators for further decisions. The interim analysis is planned when the CHR data at 6 months post-transplant of the first 50% of the patients (18 in arm A and 36 in arm B) are available, which is the primary endpoint for this analysis. At this interim analysis a detailed report will be generated and presented to the DSMB. The report includes by treatment arm the number of entered patients and at that time evaluable patients, treatment given, CHR rate, the number of events on the actuarial (secondary) endpoints, actuarial estimates for those endpoints and incidence of SAE’s and other adverse events by grade. Adverse events will be described by summary tables broken by site, grade and relation to trial treatment. The DSMB is free in her public recommendations to the study coordinators and the confidential recommendations to the study statistician. A lower CHR rate in the experimental arm with a P-value < 0.1 is a good reason to recommend the stopping of the trial or recommendations for modifications. A benefit in terms of CHR rate at 6 months post-transplant in the experimental arm is in general no reason to recommend early stopping of the study, unless the associated P-value is very extreme (P < 0.001). The study will be closely and sequentially monitored before the interim analysis. Monitoring will be based on the reported SAE's, which are not subjected to data delay. The difference in the number of patients with an SAE in both arms and the difference in the number of deaths in both arms are tested using the logrank test. We repeatedly test whether those incidences in the experimental arm are higher at a significance level of 0.05. If one of both incidences is significantly higher in the experimental arm an early report will be presented to the DSMB. In addition, a separate report on the incidence of SAE's and other adverse events and infections, as described before, will be sent to the DSMB once every 3 months. Again, the DSMB is free in her public recommendations to the study coordinators and the confidential recommendations to the study statistician. 14.4 Stopping rules The present study is set up as a phase III study based on the results of 3 previous performed phase II studies of the HOVON and the Heidelberg Amyloidosis center. The safety of the experimental arm is guarded as described above and reported to the DSMB. Criteria on which the sponsor may decide to Page 43 of 75 EudraCT-No: 2010-021445-42
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Page 75: Appendix L HOVON 104 AL AMYLOIDOSIS

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