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

Abstract

Background: Amyotrophic 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.

Methods: The 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.

Conclusion: This 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 registration: ClinicalTrials.gov, identifier: NCT03800524.

Keywords: amyotrophic lateral sclerosis; bile acids; clinical trial; phase III; therapy.

Conflict of interest statement

Author AL declares participation in Advisory Boards of Roche Pharma AG, Biogen, Alector, and Amylyx. Author CJM reports consultancy with Biogen, Amylyx, and Cytokinetics. Author PV declares participation in Advisory Board meetings for Biogen, UCB, argenx, Cytokinetics, Ferrer, Muna Therapeutics, Augustine Therapeutics, Alector, Alexion, QurAlis, and VectorY (paid to institution) and grant from CSL Behring (E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders; paid to institution). Author OH declares participation in Advisory Boards for Accelsiors, Biogen Idec, Cytokinetics, NeuroSense Therapeutics, Neuropath Therapeutics, Novartis, Orion, Denali, and Wave Pharmaceuticals; role as Principal Investigator on the PRECISION ALS Project; Academic/Industry Collaboration funded by Science Foundation Ireland; Research collaboration with Biogen, Cytokinetics, and Ionis in delivering the IMPACT ALS survey and with Cytokinetics in delivering the REVEALS study of respiratory decline in ALS; Editor-in-Chief of ALS and the Frontotemporal Degeneration; Editorial board member of the Journal of Neurology, Neurosurgery, and Psychiatry. Author GR declares that Bruschettini S.R.L is the pharmaceutical company providing the investigational medicinal product and industrial partner of the project, in which he is an employee as Scientific Director. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Albanese, Ludolph, McDermott, Corcia, Van Damme, Van den Berg, Hardiman, Rinaldi, Vanacore, Dickie and TUDCA-ALS Study Group.

Figures

Figure 1

SPIRIT schedule of enrollment, interventions, and assessments. In compliance with current marketing authorization for TUDCA, the following liver function parameters are monitored: AST, ALT, GGT, and bilirubin. Considering that there is yet insufficient information on possible teratogenic effects, a urine pregnancy test is performed monthly (from M0 to M18) and 30 days (1 month) after the last IMP dose.

Figure 2

Timeline of the study and visit schedule.

Figure 3

TUDCA-ALS management structure. Coordinating bodies are shown in red. The Project Coordinator is responsible for the core management tasks and the overall progress of the project; the Project Management Team is in charge of the project management and administration, in close collaboration with the Project Coordinator; the Steering Committee implements decisions taken by the General Assembly and reviews the project results. The General Assembly (shown in blue) is the decision-making body of the project overseeing the six work packages. The Innovation Management Committee (shown in green) monitors the principles for Intellectual Property rights and the dissemination and exploitation of project results. The Independent Advisory Board provides external advice on the conduct of the project, to bring maximum impact. The Independent Ethics Board provides guidance on ethical issues. The Data Protection Officer assures that trial activities conform to current EU and national legislation.

Figure 4

Trial management structure is nestled into activities of workpackages 1 and 2 of the TUDCA-ALS consortium. Workpackage 1 is responsible for trial implementation and monitoring, and workpackage 2 is dedicated to trial setup and harmonization. These core activities are implemented through intertwined interactions between the Trial Management Team, the Trial General Assembly, the Trial Steering Committee, and the contract research organization.