Clinical trial NCT03800524: Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
Official title: Safety and Efficacy of Tauroursodeoxycholic (TUDCA) as add-on Treatment in Patients Affected by Amyotrophic Lateral Sclerosis (ALS)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis (ALS)
Lead sponsor: Humanitas Mirasole SpA
Sponsor class: OTHER
Collaborators: name: University of Ulm
name: University of Sheffield
name: University Hospital, Tours
name: KU Leuven
name: UMC Utrecht
name: University of Dublin, Trinity College
name: Bruschettini S.r.l.
name: Istituto Superiore di Sanità
name: Motor Neurone Disease Association
name: European Commission
First posted: 2019-01-11
Enrollment: 337
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase III, multi-centre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate Safety and Efficacy of Tauroursodeoxycholic (TUDCA) as add-on Treatment in Patients Affected by Amyotrophic Lateral Sclerosis (ALS).

Detailed description: Enrolled patients will be randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The randomization will be performed in a ratio one to one for the two arms.

TUDCA will be administered orally at the dose of 1 g twice daily (2 g daily) for 18 months. Patients will be taking also riluzole at the dose of 50 mg twice daily (100 mg daily).

Patient randomization will take place after a screening (lead-in) period of 12 weeks (3 months) with 3 assessments at 6-week intervals. Clinical assessments during the trial phase will be performed every three months. This will allow measuring the progression rate before and after starting treatment (either active or placebo).

Eligibility criteria: Inclusion Criteria:

* Probable laboratory-supported, probable, or definite ALS, as defined by El Escorial Revised ALS diagnostic criteria at screening visit (month -3)
* Disease duration ≤ 18 months at screening visit (month -3)
* Able to perform reproducible pulmonary function tests at screening visit (month -3)
* Forced vital capacity or slow vital capacity ≥70% of normal at screening visit (month -3)
* Stable on riluzole treatment for 3 months in the lead-in period
* Signed informed consent at screening visit (month -3)

Exclusion Criteria:

* Treatment with edaravone
* Other causes of neuromuscular weakness
* Presence of other neurodegenerative diseases
* Significant cognitive impairment, clinical dementia or psychiatric illness
* Severe cardiac or pulmonary disease
* Other diseases precluding functional assessments
* Other life-threatening diseases
* Any use of non-invasive ventilation (e.g. continuous positive airway pressure, non-invasive bi-level positive airway pressure or non-invasive volume ventilation) for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation
* Gastrointestinal disorder that is likely to impair absorption of study drug from the gastrointestinal tract
* Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is longer, prior to dosing
* Any clinically significant laboratory abnormality
* Other concurrent investigational medications
* Active peptic ulcer
* Previous surgery or infections of small intestine
* Patients unable to easily swallow the treatment pills
* Acute inflammation of the gallbladder or bile ducts
* Occurrence of frequent biliary colic, biliary infections, severe pancreatic abnormalities
* Bile duct obstruction, calcified X-ray opaque gallstones and reduced mobility of the gallbladder
* Subjects who weigh 88 lbs (40 kg) or less
* Aspartate aminotransferase or alanine aminotransferase concentrations more than 3 times the upper limit of normal
* Creatinine clearance 50 ml/min or less
* Any clinically significant neurological, haematological, autoimmune, endocrine, cardiovascular, neoplastic, renal, gastrointestinal, or other disorder that, in the Investigator's opinion, could interfere with the subject's participation in the study, place the subject at increased risk, or confound interpretation of study results
* Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive TUDCA or that the subject is unable or unlikely to comply with the dosing schedule or study evaluations
* The patient of reproductive potential is sexually active and is not willing to use highly effective contraception during the study and up to 90 days after the day of last dose
* The patient is pregnant or breast feeding

Primary outcomes:
measure: Number of responder patients
timeFrame: 18 months
Secondary outcomes:
measure: Survival time
timeFrame: 18 months
measure: ALS disease functional rating scale - revised version (ALSFRS-R)
timeFrame: 18 months
measure: ALS Assessment Questionnaire-40 (ALSAQ-40)
timeFrame: 18 months
measure: Forced Vital Capacity
timeFrame: 18 months
measure: EuroQol 5-Dimension-5 Levels (EQ-5D-5L) scale
timeFrame: 18 months
measure: Medical Research Council (MRC) scale
timeFrame: 18 months
measure: Neurofilaments levels
timeFrame: 18 months
measure: MMP-9 levels
timeFrame: 18 months
measure: Long-term safety and tolerability
timeFrame: 18 months
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: Katholieke Universiteit Leuven
city: Bordeaux
country: France
facility: Centre Hospitalier Universitaire de Bordeaux
city: Limoges
country: France
facility: Centre Hospitalier Universitaire Limoges
city: Montpellier
country: France
facility: Centre Hospitalier Universitaire de Montpellier
city: Tours
country: France
facility: Centre Hospitalier Regional Universitaire de Tours
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden
city: Essen
country: Germany
facility: Alfried Krupp Krankenhaus Rüttenscheid
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Ulm
country: Germany
facility: Universität Ulm
city: Dublin
country: Ireland
facility: Trinity College Dublin
city: Milano
country: Italy
facility: IRCCS Istituto Auxologico Italiano
city: Milano
country: Italy
facility: NEuroMuscular Omnicentre. Fondazione Serena Onlus
city: Napoli
country: Italy
facility: AOU Università degli Studi della Campania "Luigi Vanvitelli"
city: Rozzano
country: Italy
facility: IRCCS Istituto Clinico Humanitas
city: Terni
country: Italy
facility: Azienda Ospedaliera Santa Maria di Terni
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza di Torino
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Liverpool
country: United Kingdom
facility: The Walton Centre NHS Foundation Trust
city: Plymouth
country: United Kingdom
facility: Plymouth Hospitals NHS Trust
city: Preston
country: United Kingdom
facility: Lancashire Teaching Hospitals NHS Foundation Trust
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
city: Sheffield
country: United Kingdom
facility: University of Sheffield
city: Stoke
country: United Kingdom
facility: Royal Stoke University Hospital
Study officials:
affiliation: Humanitas Mirasole SpA
name: Alberto Albanese, MD
role: STUDY_CHAIR
References:
citation: Albanese A, Ludolph AC, McDermott CJ, Corcia P, Van Damme P, Van den Berg LH, Hardiman O, Rinaldi G, Vanacore N, Dickie B; TUDCA-ALS Study Group. Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol. Front Neurol. 2022 Sep 27;13:1009113. doi: 10.3389/fneur.2022.1009113. eCollection 2022.