The Combined Assessment of Function and Survival (CAFS): A new endpoint for ALS clinical trials

Abstract

Our objective was to describe a new endpoint for amyotrophic lateral sclerosis (ALS), the Combined Assessment of Function and Survival (CAFS). CAFS ranks patients’ clinical outcomes based on survival time and change in the ALS Functional Rating Scale–Revised (ALSFRS-R) score. Each patient's outcome is compared to every other patient's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS score indicates a better group outcome. Historically, ALS clinical trials have assessed survival and function as independent endpoints. Combined endpoints have been used in other diseases to decrease the confounding effect of mortality on analysis of functional outcomes. We explored the application of a similar approach in ALS, the CAFS endpoint, which was used as a pre-specified secondary analysis in a phase II study of dexpramipexole. Those results and some hypothetical examples based on modeling exercises are presented here. CAFS is the primary endpoint of a dexpramipexole phase III study in ALS. In conclusion, the CAFS is a robust statistical tool for ALS clinical trials and appropriately accounts for and weights mortality in the analysis of function.

Trial registration: ClinicalTrials.gov identifier: NCT01281189.

Key words::

• Amyotrophic lateral sclerosis
• clinical trials
• study design
• ALS survival
• ALS function
• primary endpoint

Acknowledgements

Medical writing assistance was provided by Aruna Seth of UBC Scientific Solutions and funded by Biogen Idec, Inc.

Declaration of interests: J. D. Berry has served as a consultant to Biogen Idec, Inc. and as a paid speaker for Oakstone Publishing. He is a site co-investigator for the EMPOWER study. He receives research support from the Muscular Dystrophy Association and the ALS Therapy Alliance. R. Miller served on a Biogen Idec advisory board. M. E. Cudkowicz is the principal investigator of the ongoing EMPOWER study and receives a grant from Biogen Idec, Inc. for this role. In the past 2 years, she has served as a consultant for Teva Pharmaceuticals, Millenium, and Trophos (Data and Safety Monitoring Board) and has served on an advisory board for Biogen Idec, Inc. L. H. van den Berg has served on a Biogen Idec, Inc. advisory board and has received travel grants from Baxter. D. A. Kerr and Y. Dong are employees of Biogen Idec, Inc. E. Ingersoll and D. Archibald are employees of Knopp Biosciences LLC.