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Clinical Trial
. 2023 Dec 5;24(1):792.
doi: 10.1186/s13063-023-07638-w.

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

Flavia L Lombardo #  1 , Stefania Spila Alegiani #  2 , Flavia Mayer  2 , Marta Cipriani  3   4 , Maria Lo Giudice  5 , Albert Christian Ludolph  6   7 , Christopher J McDermott  8 , Philippe Corcia  9   10   11   12 , Philip Van Damme  13   14 , Leonard H Van den Berg  15 , Orla Hardiman  16   17 , Gabriele Nicolini  18 , Nicola Vanacore  19 , Brian Dickie  20 , Alberto Albanese  5 , Maria Puopolo  4 ; TUDCA-ALS Study Group
Collaborators, Affiliations
Clinical Trial

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

Flavia L Lombardo et al. Trials. .

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 3 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 the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment 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 through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 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 the 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.

Keywords: Amyotrophic lateral sclerosis; Bile acids; Clinical trial; Double-blind; Phase III; Randomized; Statistical analysis plan.

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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, VectorY, and Amylyx (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 GN 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 medical director. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Timeline of the study and visit schedule
Fig. 2
Fig. 2
TUDCA-ALS flow diagram (CONSORT 2010)
See this image and copyright information in PMC

References

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