Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol

Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects.MethodsThe TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers.ConclusionThis trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care.Clinical trial registrationClinicalTrials.gov, identifier: NCT03800524.

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

“…This unforeseen event required the prompt implementation of speci c and unprecedented mitigation measures. The COVID-19 Amendment to the TUDCA-ALS protocol, dated 23rd March 2020, included several interventions aimed at ensuring the completion of the trial, such as sample size reduction, introduction of telemedicine for inperson visit replacements, and collection of information on COVID-19-related intercurrent events [9].…”

“…The study protocol has been registered at www.clinicaltrials.gov (NCT03800524). An updated version of the protocol, providing detailed information on background, design and rationale, has been published elsewhere [9]. The trial is being conducted in accordance with the Helsinki declaration and the local laws and regulations of the respective countries, prioritizing the highest level of patient protection.…”

“…Such sample size provides 83.3% power to detect a 13% absolute difference in survival (de ned as death or respiratory insu ciency) between the two treatment groups, corresponding to a hazard ratio of 0.616, assuming an 18-month survival of 60% in the placebo group. However, due to the impact of the COVID-19 outbreak on recruitment, a COVID-19 amendment dated 23 rd March 2020 [9] was implemented, and the recruitment was planned to be closed at 320 randomized patients. This sample size of 320 subjects allows to detect an absolute difference of 11% in the proportion of responders between TUDCA and placebo arm.…”

“…The main exclusion criteria include cognitive impairment or psychiatric illness, active peptic ulcer, previous surgery or infections of the small intestine. Detailed inclusion and exclusion criteria can be found in the study protocol [9]. All eligibility criteria must be met by the time of the randomisation visit (Month 0).…”

Nucleocytoplasmic transport at the crossroads of proteostasis, neurodegeneration and neuroprotection

“…However, no significant differences were observed between the drug-treated group and the placebo group in secondary clinical and biomarker outcomes (e.g., the time to death, muscle strength, plasma phosphorylated axonal neurofilament H subunit) [213]. The contribution of each of the drugs to the clinical outcomes of the combo therapy remains unknown, but a phase 3 clinical trial of tauroursodeoxycholic acid alone (NCT03800524) may shed some light to the clinical efficacy of this drug in ALS [214].…”