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
Authors: Lombardo Flavia L. , Spila Alegiani Stefania , Mayer Flavia , Cipriani Marta , Lo Giudice Maria , Ludolph Albert Christian , McDermott Christopher J. , Corcia Philippe , Van Damme Philip , Van den Berg Leonard H. , Hardiman Orla , Nicolini Gabriele , Vanacore Nicola , Dickie Brian , Albanese Alberto , Puopolo Maria ,   TUDCA-ALS Study Group, Tornese Paolo , Cocco Antoniangela , Matteoli Michela , Lauranzano Eliana , Malosio Maria Luisa , Elia Chiara Adriana , Chiò Adriano , Manera Umberto , Moglia Cristina , Calvo Andrea , Salamone Paolina , Fuda Giuseppe , Colosimo Carlo , Spera Cristina , Ranchicchio Prabha Cristina , Stipa Giuseppe , Frondizi Domenico , Lunetta Christian , Sansone Valeria , Tarlarini Claudia , Gerardi Francesca , Silani Vincenzo , Doretti Alberto , Colombo Eleonora , Demirtzidis Gianluca , Tedeschi Gioacchino , Trojsi Francesca , Passaniti Carla , Ballestrero Stefania , Dorst Johannes , Weiland Ulrike , Fromm Andrea , Wiesenfarth Maximilian , Kandler Katharina , Witzel Simon , Otto Markus , Schuster Joachim , Meyer Thomas , Maier André , Kettemann Dagmar , Petri Susanne , Müschen Lars , Wohnrade Camilla , Sarikidi Anastasia , Osmanovic Alma , Grosskreutz Julian , Rödiger Annekathrin , Steinbach Robert , Ilse Benjamin , Smesny Uta , Untucht Robert , Günther René , Vidovic Maximilian , Shaw Pamela , Collins Alexis , Wollff Helen , Walsh Theresa , Tuddenham Lee , Kazoka Mbombe , White David , Young Stacy , Thompson Benjamin , Madarshahian Daniel , Chhetri Suresh K. , Chaouch Amina , Young Carolyn A. , Arndt Heike , Hanemann Coliver , Lambert Thomas , Beltran Stephane , Couratier Philippe , Esselin Florence , Camu William , De La Cruz Elisa , Lemasson Gwendal , Masrori Pegah , Maguire Sinead , Fogarty Liz , Atoyebi Toyosi , Obáin Niamh Ní 
Published: December 2023

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.