A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial

Abstract

Abstract Background: Amyotrophic Lateral Sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately three months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities. Methods: The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is defined as a minimum 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomisation period (18 months) compared to the lead-in period (3 months), Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle. Data recruitment commenced on February 22, 2019, and was closed on 23rd December 2021. The database will be locked in September 2023. Discussion: This paper provides a comprehensive description of the statistical analysis plan in order to ensure reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the Coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS. Trial registration: ClinicalTrials.gov NCT03800524. Registered on January 11, 2019, https://clinicaltrials.gov/study/NCT03800524