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

Amyotrophic Lateral Sclerosis (ALS) Clinical Trial

— TUDCA-ALS  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03800524
• Other study ID #: H2020/755094/2017/IT-01
• Secondary ID: 2018-002722-2275
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: February 22, 2019
• Est. completion date: December 31, 2023

Study information

• Verified date: July 2023
• Source: Humanitas Mirasole SpA
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 337
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Amyotrophic Lateral Sclerosis (ALS)
• Motor Neuron Disease
• Sclerosis

Intervention

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
• 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

Locations

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

Sponsors (11)

Lead Sponsor	Collaborator
Humanitas Mirasole SpA	Bruschettini S.r.l., European Commission, Istituto Superiore di Sanità, KU Leuven, Motor Neurone Disease Association, UMC Utrecht, University Hospital, Tours, University of Dublin, Trinity College, University of Sheffield, University of Ulm

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Ireland,  Italy,  Netherlands,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Survival time	Survival time measured by death or respiratory insufficiency	18 months
Secondary	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
Secondary	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
Secondary	Forced Vital Capacity	Difference in change from baseline in Forced Vital Capacity	18 months
Secondary	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
Secondary	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
Secondary	Neurofilaments levels	Effect of TUDCA on Neurofilament levels in comparison to placebo	18 months
Secondary	MMP-9 levels	Effect of TUDCA on MMP-9 expression in comparison to placebo	18 months
Secondary	Long-term safety and tolerability	assessed through adverse reaction, concomitant treatment, physical examination, vital signs and routine haematology and biochemistry analyses	18 months

External Links

•   TUDCA-ALS Consortium website