Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS (TUDCA-ALS)

Safety and Efficacy of Tauroursodeoxycholic (TUDCA) as add-on Treatment in Patients Affected by Amyotrophic Lateral Sclerosis (ALS)

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Amyotrophic Lateral Sclerosis (ALS)
• Intervention / Treatment: Drug: Tauroursodeoxycholic Acid; Drug: Placebo

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).

• Study Type: Interventional
• Enrollment (Actual): 337
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • Katholieke Universiteit Leuven
• France
  • Bordeaux, France
    • Centre Hospitalier Universitaire de Bordeaux
  • Limoges, France
    • Centre Hospitalier Universitaire Limoges
  • Montpellier, France
    • Centre Hospitalier Universitaire de Montpellier
  • Tours, France
    • Centre Hospitalier Régional Universitaire de Tours
• Germany
  • Berlin, Germany
    • Charité - Universitätsmedizin Berlin
  • Dresden, Germany
    • Universitatsklinikum Carl Gustav Carus Dresden
  • Essen, Germany
    • Alfried Krupp Krankenhaus Rüttenscheid
  • Hannover, Germany
    • Medizinische Hochschule Hannover
  • Jena, Germany
    • Universitatsklinikum Jena
  • Ulm, Germany
    • Universität Ulm
• Ireland
  • Dublin, Ireland
    • Trinity College Dublin
• Italy
  • Milano, Italy
    • IRCCS Istituto Auxologico Italiano
  • Milano, Italy
    • NEuroMuscular Omnicentre. Fondazione Serena Onlus
  • Napoli, Italy
    • AOU Università degli Studi della Campania "Luigi Vanvitelli"
  • Rozzano, Italy
    • IRCCS Istituto Clinico Humanitas
  • Terni, Italy
    • Azienda Ospedaliera Santa Maria di Terni
  • Torino, Italy
    • AOU Città della salute e della scienza di Torino
• Netherlands
  • Utrecht, Netherlands
    • Universitair Medisch Centrum Utrecht
• United Kingdom
  • Liverpool, United Kingdom
    • The Walton Centre NHS Foundation Trust
  • Plymouth, United Kingdom
    • Plymouth Hospitals NHS Trust
  • Preston, United Kingdom
    • Lancashire Teaching Hospitals NHS Foundation Trust
  • Salford, United Kingdom
    • Salford Royal NHS Foundation Trust
  • Sheffield, United Kingdom
    • University of Sheffield
  • Stoke, United Kingdom
    • Royal Stoke University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tauroursodeoxycholic acid (TUDCA); Tauroursodeoxycholic acid (TUDCA) 250 mg capsules; Doses: 4 capsules (1 g) twice daily 10-15 minutes after a meal; Mode of administration: orally; Duration: 18 months	Drug: Tauroursodeoxycholic Acid; Tauroursodeoxycholic acid (TUDCA) 250 mg capsules; Doses: 4 capsules (1 g) twice daily 10-15 minutes after a meal; Mode of administration: orally; Duration: 18 months; Other Names: Taurolite; TUDCA; Tudcabil
Placebo Comparator: Reference therapy; Placebo capsules identical to active compound; Doses: 4 capsules (1 g) twice daily 10-15 minutes after a meal; Mode of administration: orally; Duration: 18 months	Drug: Placebo; Placebo 250 mg capsules; Doses: 4 capsules (1 g) twice daily 10-15 minutes after a meal; Mode of administration: orally; Duration: 18 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of responder patients	Identification of the responder patients defined as those showing an improvement of at least 20% in the ALSFRS-R slope	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival time	Survival time measured by death or respiratory insufficiency	18 months
ALS disease functional rating scale - revised version (ALSFRS-R)	Difference in change from baseline in ALSFRS-R. Each task of the scale is rated on a five-point scale from 0 = can't do, to 4 = normal ability. Individual item scores are summed to produce a reported score ranging from 0 = worst to 48 = best.	18 months
ALS Assessment Questionnaire-40 (ALSAQ-40)	Difference in change from baseline in ALSAQ-40. The instrument contains 40 statements that measure five dimensions of health state: Physical Mobility (10 statements), Activities of Daily Living and Independence (10 statements), Eating and Drinking (5 statements), Communication (5 statements), Emotional Functioning (10 statements). The patient must indicate how often (Never, Rarely, Sometimes, Often, or Always) the statement have been true. Dimension scores are coded on a likert scale, ranging from 0 (best health as assessed by the scale) to 100 (worse health as assessed by the measure).	18 months
Forced Vital Capacity	Difference in change from baseline in Forced Vital Capacity	18 months
EuroQol 5-Dimension-5 Levels (EQ-5D-5L) scale	Difference in change from baseline in EQ-5D-5L scale. The EQ-5D-5L descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). Each dimension has 5 levels: 1.no problems, 2.slight problems, 3.moderate problems, 4.severe problems, 5.extreme problems. The patient is asked to indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number expressing the level selected for that dimension. The digits for 5 dimensions can be combined in a 5-digit number describing the patient health state. Numbers 1-5 have no arithmetic properties and should not be used as a cardinal score.	18 months
Medical Research Council (MRC) scale	Difference in change from baseline in muscle force assessed by the MRC scale. The scale rates muscle strength of 6 muscles (3 at the upper and 3 at the lower limbs), bilaterally. Each muscle is graded from 0 = no movement, to 5 = normal strength, giving a total sum-score that ranges from 0 (total paralysis) to 60 (normal strength).	18 months
Neurofilaments levels	Effect of TUDCA on Neurofilament levels in comparison to placebo	18 months
MMP-9 levels	Effect of TUDCA on MMP-9 expression in comparison to placebo	18 months
Long-term safety and tolerability	assessed through adverse reaction, concomitant treatment, physical examination, vital signs and routine haematology and biochemistry analyses	18 months

Collaborators and Investigators

• Sponsor: Humanitas Mirasole SpA
• Collaborators: KU Leuven; UMC Utrecht; University of Sheffield; Istituto Superiore di Sanità; University of Ulm; University Hospital, Tours; European Commission; University of Dublin, Trinity College; Bruschettini S.r.l.; Motor Neurone Disease Association
• Investigators: Study Chair: Alberto Albanese, MD, Humanitas Mirasole SpA

Publications and helpful links

General Publications

• 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.

Helpful Links

• TUDCA-ALS Consortium website

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2019
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): December 31, 2023

Study Registration Dates

• First Submitted: January 4, 2019
• First Submitted That Met QC Criteria: January 8, 2019
• First Posted (Actual): January 11, 2019

Study Record Updates

• Last Update Posted (Actual): July 10, 2023
• Last Update Submitted That Met QC Criteria: July 7, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Anti-Infective Agents; Antiviral Agents; Gastrointestinal Agents; Cholagogues and Choleretics; Ursodoxicoltaurine
• Other Study ID Numbers: H2020/755094/2017/IT-01; 2018-002722-22 (EudraCT Number); 755094 (Other Grant/Funding Number: European Commission)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Once the dataset has been analysed, a complete, cleaned, anonymized copy of the final data used in conducting the final analyses will be made available to be used in further studies by the research partners or by other research groups and clinicians.

To prevent misuse and misinterpretation, relevant study metadata (such as the study protocol, case report forms, documentation providing information about the methodology and procedures used to collect the data, definition of variables and statistical code) will be shared in a data repository with a stable URL. Patient anonymity and legal compliance will be assured throughout all the steps of data transfer.

• IPD Sharing Time Frame: Three months after the data-entry process and final data curation
• IPD Sharing Access Criteria: Data will be made available only to qualified designated persons (methodologists, biostatisticians) from other academic institutions, on request. User registration will be required in order to access files.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No