Refining eligibility criteria for amyotrophic lateral sclerosis clinical trials

Abstract

Objective: To assess the effect of eligibility criteria on exclusion rates, generalizability, and outcome heterogeneity in amyotrophic lateral sclerosis (ALS) clinical trials and to assess the value of a risk-based inclusion criterion.

Methods: A literature search was performed to summarize the eligibility criteria of clinical trials. The extracted criteria were applied to an incidence cohort of 2,904 consecutive patients with ALS to quantify their effects on generalizability and outcome heterogeneity. We evaluated the effect of a risk-based selection approach on trial design using a personalized survival prediction model.

Results: We identified 38 trials. A large variability exists between trials in all patient characteristics for enrolled patients (p < 0.001), except for the proportion of men (p = 0.21). Exclusion rates varied widely (from 14% to 95%; mean 59.8%; 95% confidence interval 52.6%-66.7%). Stratification of the eligible populations into prognostic subgroups showed that eligibility criteria lead to exclusion of patients in all prognostic groups. Eligibility criteria neither reduce heterogeneity in survival time (from 22.0 to 20.5 months, p = 0.09) nor affect between-patient variability in functional decline (from 0.62 to 0.65, p = 0.25). In none of the 38 trials were the eligibility criteria found to be more efficient than the prediction model in optimizing sample size and eligibility rate.

Conclusions: The majority of patients with ALS are excluded from trial participation, which questions the generalizability of trial results. Eligibility criteria only minimally improve homogeneity in trial endpoints. An individualized risk-based criterion could be used to balance the gains in trial design and loss in generalizability.

Figure 1. Overview of eligibility criteria and exclusion rates of ALS trials conducted between 2000 and 2017

Caterpillar plot of the exclusion rates at diagnosis per trial (n = 38). Exclusion rates ranged from 14% to 95%; numerical results per trial are given in table e-1 (available from Dryad, doi.org/10.5061/dryad.86f1m6g). ALS = amyotrophic lateral sclerosis; ALSFRS (n) = number of selection items on Amyotrophic Lateral Sclerosis Functional Rating Scale; Def = definite; FALS = familial ALS; FVC = forced vital capacity, percent predicted; G-CSF = granulocyte colony-stimulating factor; IGF-1 = insulin-like growth factor-1; LI = lead-in ALSFRS-R slope; LS = probable, laboratory supported; Prob = probable.

Figure 2. Between-trial variability in population characteristics of enrolled participants

Caterpillar plots of the reported summary data for the experimental and placebo groups (total number of patients 10,489). Solid black diamonds indicate the meta-analyzed average with 95% confidence interval. Study heterogeneity was present in all baseline characteristics except for the proportion of men (I² = 11%; p = 0.21). (A) Age at randomization; (B) proportion of men; (C) symptom duration; (D) bulbar onset; (E) vital capacity (VC); and (F) Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R).

Figure 3. Effect of selection criteria on overall mortality since diagnosis

Mortality since diagnosis for 5 prognostic subgroups defined by the European Network for the Cure of ALS personalized prediction model. Colors represent the 5 prognostic subgroups: very long (green), long (yellow), intermediate (orange), short (red), and very short (black) survival. Solid lines in the Kaplan-Meier plots represent the survival patterns for all patients (n = 2,904; A), whereas the dotted lines are the survival curves for the eligible population (n = 1,194; B), defined by all patients who are eligible for > 50% of the trials. Boxplots provide the variability in survival time per prognostic subgroup (left, all patients; right, eligible patients). Dotted lines in boxplot are the unstratified interquartile ranges (25th and 75th percentile); overall survival time variability was reduced by 6.9% (95% confidence interval −3.5% to 16.3%, p = 0.09). Bar charts provide the number of patients in each subgroup.

Figure 4. Longitudinal ALSFRS-R patterns in a subset of 696 patients

Colors of the boxplots represent the 5 prognostic subgroups: very long (green), long (yellow), intermediate (orange), short (red), and very short (black) survival. Purple dotted line is the average pattern of decline in the eligible population (n = 356). Solid purple line is the average pattern in the full dataset (n = 696). Boxplots provide the variability in rates of decline over time (points per month), estimated by the best unbiased linear predictors (BLUPs) from an linear mixed-effects model. Dotted lines in boxplots represent the average rate of decline. (A) All patients and (B) eligible patients. ALSFRS-R = Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised.

Figure 5. Effect of trial eligibility criteria and the ENCALS risk scores on sample size

Sample size calculations were performed for various populations, either selected by the trial eligibility criteria (n = 38, orange) or defined by different cutoffs for the European Network for the Cure of ALS (ENCALS) risk scores (n = 1,050 combinations). Results are expressed as sample size inflation factor (IF; x-axis). To exemplify, an IF of 0.79 means that the sample size is 21% smaller compared to the sample size necessary when all patients are included (green triangle, 100% eligibility). Populations defined by the ENCALS risk scores for all possible combinations of cutoff values are shown in black and gray. Black dots are the selected populations that resulted in the largest reduction in sample size and highest eligibility rate. To exemplify, the Edaravone 2017 trial resulted in the largest reduction in sample size (−34%, IF 0.66), with a 10% eligibility rate. The ENCALS model could select a similarly sensitive population with 48% of the patients remaining eligible. Numerical effects of the different trials are provided in table e-1 (available from Dryad, doi.org/10.5061/dryad.86f1m6g).