Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective

Abstract

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease-modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of Phase II, Phase II/III and Phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15 000 people with amyotrophic lateral sclerosis. About 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis.

Keywords: amyotrophic lateral sclerosis; clinical trials; methodology; perspective; systematic review.

Graphical Abstract

Figure 1

PRISMA diagram of systematic review.

Figure 2

Number of pwALS participating in trials. (A) (top) shows number of pwALS recruited per trial by phase and year for trials with efficacy-based outcome measures. Published results were used as the source where available (denoted by circle), and registry data were unavailable (denoted by triangles). The 10 trials with highest number of pwALS/trial are labelled with the intervention tested—these trials were two-arm trials with the exception of the following dose-ranging trials: tirasemtiv Phase III (4-arm), masitinib (3-arm), CK-2127107 (4-arm) and talampanel (3-arm). The dashed horizontal lines reflect our sample size calculations using PROACT data: the red line indicates n = 200 (100/arm) required for a 2-arm RCT with randomization of 1:1, powered at 85% to detect a 25% difference in rate of ALSFRS-R decline over 12 months with a test conducted with a two-sided 20% significance level. The blue line indicates n = 500 (250/arm) required to evaluate one IMP in a two-arm RCT with randomization of 1:1, powered of 90% to detect a HR of 0.65 for survival over 2 years with a two-sided 5% significance level. (B) (bottom) shows a box and whiskers plot of the number of pwALS recruited per study arm according to CTIMP phase for Phase II (32 trials), Phase II/III (5 trials) and Phase III (12 trials) CTIMPs evaluating potential disease-modifying treatment of amyotrophic lateral sclerosis.

Figure 3

Example sample size requirements according to trial designs. (A): traditional 2-arm Phase II trial with randomization of 1:1 to evaluate 1 IMP against placebo or control with sample size calculated based on 85% power for a 20% two-sided significance level test to detect a 25% difference in rate of ALSFRS-R decline at 12 months calculated using data from PROACT. (B): a seamless Phase II/Phase III multi-arm multi-stage trial with randomization of 1:1:1 with interim analysis where arms can be stopped if predefined efficacy and safety criteria are not met.