The PRO-ACT database: design, initial analyses, and predictive features

Abstract

Objective: To pool data from completed amyotrophic lateral sclerosis (ALS) clinical trials and create an open-access resource that enables greater understanding of the phenotype and biology of ALS.

Methods: Clinical trials data were pooled from 16 completed phase II/III ALS clinical trials and one observational study. Over 8 million de-identified longitudinally collected data points from over 8,600 individuals with ALS were standardized across trials and merged to create the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. This database includes demographics, family histories, and longitudinal clinical and laboratory data. Mixed effects models were used to describe the rate of disease progression measured by the Revised ALS Functional Rating Scale (ALSFRS-R) and vital capacity (VC). Cox regression models were used to describe survival data. Implementing Bonferroni correction, the critical p value for 15 different tests was p = 0.003.

Results: The ALSFRS-R rate of decline was 1.02 (±2.3) points per month and the VC rate of decline was 2.24% of predicted (±6.9) per month. Higher levels of uric acid at trial entry were predictive of a slower drop in ALSFRS-R (p = 0.01) and VC (p < 0.0001), and longer survival (p = 0.02). Higher levels of creatinine at baseline were predictive of a slower drop in ALSFRS-R (p = 0.01) and VC (p < 0.0001), and longer survival (p = 0.01). Finally, higher body mass index (BMI) at baseline was associated with longer survival (p < 0.0001).

Conclusion: The PRO-ACT database is the largest publicly available repository of merged ALS clinical trials data. We report that baseline levels of creatinine and uric acid, as well as baseline BMI, are strong predictors of disease progression and survival.

Figure 1. Flow of data processing for inclusion in the PRO-ACT database

ALS = amyotrophic lateral sclerosis; PRO-ACT = Pooled Resource Open-Access ALS Clinical Trials.

Figure 2. Kaplan-Meier curves, product-limit survival estimates

(A) Kaplan-Meier curve for all amyotrophic lateral sclerosis (ALS) trials. The median survival time in the Pooled Resource Open-Access ALS Clinical Trials database is 479 days from trial entry. (B) Kaplan-Meier curves for site of onset. People with limb-onset ALS (red) had better survival (p < 0.0001) compared to people with bulbar-onset ALS (blue). This survival advantage for people with limb-onset ALS remained significant (p = 0.04) even after controlling for age, sex, and time from symptom onset to diagnosis. (C) Kaplan-Meier curves for age at onset. People with younger age (<50 years) at ALS onset (blue) show longer survival (p < 0.0001) compared to people with older age (≥50 years) at ALS onset (red). This survival advantage for younger age remained significant (p < 0.0001) even after controlling for site of onset, sex, and time from symptom onset to diagnosis. (D) Kaplan-Meier curves for body mass index (BMI). People who were obese (hazard ratio [HR] 0.46, p < 0.0001) or overweight (HR 0.65, p < 0.0001) at trial entry had less risk of dying compared to people who were underweight or had normal BMI.