The PRO-ACT database

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 5 0.003. Results:The ALSFRS-R rate of decline was 1.02 (62.3) points per month and the VC rate of decline was 2.24% of predicted (66.9) per month. Higher levels of uric acid at trial entry were predictive of a slower drop in ALSFRS-R (p 5 0.01) and VC (p , 0.0001), and longer survival (p 5 0.02). Higher levels of creatinine at baseline were predictive of a slower drop in ALSFRS-R (p 5 0.01) and VC (p , 0.0001), and longer survival (p 5 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. Neurology ® 2014;83:1719-1725 GLOSSARY ALS 5 amyotrophic lateral sclerosis; ALSFRS 5 ALS Functional Rating Scale; ALSFRS-R 5 revised ALS Functional Rating Scale; BMI 5 body mass index; CDS 5 common data structure; CI 5 confidence interval; HR 5 hazard ratio; PRO-ACT 5 Pooled Resource Open-Access ALS Clinical Trials; VC 5 vital capacity.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects motor neurons in the brain and spinal cord. People with ALS have progressive voluntary muscle weakness involving the arms, legs, speech, swallowing, and breathing. Because ALS is a rare disease with an annual incidence of 2/100,000, 2 clinical trials have typically been relatively small, with the largest studies including fewer than 1,000 participants. Therefore, aggregation of studies is needed to allow enough statistical power to answer important questions about ALS natural history and clinical symptoms in order to overcome some of the barriers associated with drug development for orphan diseases.The Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database was designed to provide just such an opportunity. This database represents the largest aggregation of ALS clinical trial data available. Sixteen phase II and III ALS trials and one large observational s...

Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS

“…Nevertheless, similar to our prior analysis,16 to gain insight into potential benefit and plan for a future trial, participants from the Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) dataset18, 19 and the ceftriaxone trial (dataset provided by the Northeast ALS Consortium)20 served as historical controls. The PRO‐ACT dataset contains open‐access ALS Functional Rating Scale revised (ALSFRS‐R) and survival data for over 10,723 participants from 23 Phase 2 and 3 ALS trials conducted between 1990 and 2013, including the ceftriaxone cohort 18, 19, 21. The large data volume collected under controlled environments justifies its use as a noncontemporaneous historical dataset.…”

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

“…Progression Inverse association [22][23][24] Inverse association [25][26][27][28] No association [29,30] Inverse association in HD, MSA, MCI [31][32][33] Laboratory…”

“…Higher urate levels are associated with slower clinical progression in Huntington's disease, multiple system atrophy, and mild cognitive impairment [29][30][31]. In ALS, most [25][26][27][28] but not all [32,33] studies found urate to represent a prognostic factor for survival. The reasons for these conflicting results in ALS are not completely clear and may be related to methodological differences, variable sample size, and a modest effect size.…”

Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis

“…Urate, the end‐product of human purine metabolism, is an endogenous antioxidant10, 11 and proposed neuroprotectant12, 13, 14, 15 and its levels may be increased by edaravone treatment 6, 16. High urate levels correlate with improved survival in ALS epidemiologic studies17, 18, 19, 20, 21, 22, 23 and with favorable outcomes in other neurodegenerative diseases, most notably Parkinson's disease (PD) 24, 25, 26. Further, urate is neuroprotective in several models of neurodegeneration 12, 27, 28, 29, 30, 31, 32…”