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

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.

Metadata

Item Type:	Article
Authors/Creators:	Lombardo, F.L. https://orcid.org/0000-0001-6183-0735 Spila Alegiani, S. Mayer, F. Cipriani, M. Lo Giudice, M. Ludolph, A.C. McDermott, C.J. https://orcid.org/0000-0002-1269-9053 Corcia, P. Van Damme, P. Van den Berg, L.H. Hardiman, O. Nicolini, G. Vanacore, N. Dickie, B. Albanese, A. Puopolo, M. Tornese, P. Cocco, A. Matteoli, M. Lauranzano, E. Malosio, M.L. Elia, C.A. Chiò, A. Manera, U. Moglia, C. Calvo, A. Salamone, P. Fuda, G. Colosimo, C. Spera, C. Ranchicchio, P.C. Stipa, G. Frondizi, D. Lunetta, C. Sansone, V. Tarlarini, C. Gerardi, F. Silani, V. Doretti, A. Colombo, E. Demirtzidis, G. Tedeschi, G. Trojsi, F. Passaniti, C. Ballestrero, S. Dorst, J. Weiland, U. Fromm, A. Wiesenfarth, M. Kandler, K. Witzel, S. Otto, M. Schuster, J. Meyer, T. Maier, A. Kettemann, D. Petri, S. Müschen, L. Wohnrade, C. Sarikidi, A. Osmanovic, A. Grosskreutz, J. Rödiger, A. Steinbach, R. Ilse, B. Smesny, U. Untucht, R. Günther, R. Vidovic, M. Shaw, P. Collins, A. Wollff, H. Walsh, T. Tuddenham, L. Kazoka, M. White, D. Young, S. Thompson, B. Madarshahian, D. Chhetri, S.K. Chaouch, A. Young, C.A. Arndt, H. Hanemann, C. Lambert, T. Beltran, S. Couratier, P. Esselin, F. Camu, W. De La Cruz, E. Lemasson, G. Masrori, P. Maguire, S. Fogarty, L. Atoyebi, T. Obáin, N.N.
Copyright, Publisher and Additional Information:	© 2023 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Keywords:	Statistical analysis plan; Randomized; Double-blind; Clinical trial; Phase III; Amyotrophic lateral sclerosis; Bile acids
Dates:	Published: 5 December 2023 Published (online): 5 December 2023 Accepted: 22 August 2023
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Funding Information:	Funder Grant number EUROPEAN COMMISSION - HORIZON 2020 755094
Depositing User:	Symplectic Sheffield
Date Deposited:	11 Dec 2023 15:14
Last Modified:	11 Dec 2023 15:14
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1186/s13063-023-07638-w
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:206434

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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

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