Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis

Abstract

Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (–0.80 vs. –0.84 T40, –0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.

Keywords:

• Creatine
• tamoxifen
• trial
• selection design

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Acknowledgements

The authors sincerely thank all the ALS participants and families who participated in the trial. The authors extend their gratitude to all the sub-investigators, research nurses, pharmacists, study staff and data support teams for their dedicated contributions to this study. Creatine and its matching placebo powder were provided by Avicena Group.

Data availability statement

The data that support the findings of this study are available upon reasonable request from the corresponding author (SB). The study data will also be provided to the PRO-ACT database.

Declaration of interest

Mazen Dimachkie is a consultant or on the speaker’s bureau for Alnylam, Audentes, Biomarin, Catalyst, CSL-Behring, Genzyme, Mallinckrodt, Momenta, Novartis, NuFactor, Octapharma, RMS Medical, Sanofi, Shire, and Terumo. Dr. Dimachkie received grants from Alexion, Alnylam, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, CSL-Behring, FDA/OPD, GlaxoSmithKline, Genentech, Grifols, MDA, NIH, Novartis, Genzyme, Octapharma, Orphazyme, UCB Biopharma, Viromed, and TMA. Merit Cudkowicz provides consultation for Biogen, Biohaven, Avexis, Lilly, and Revalesio Nazem Atassi reports no financial conflicts of interest related to this trial. He works for Sanofi-Genzyme, Cambridge, MA. He provided consultation for Biogen and MT Pharma.

Additional information

Funding

This project was funded by a research grant from ALS Therapy Alliance (ATA).