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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03800524
Recruitment Status : Not yet recruiting
First Posted : January 11, 2019
Last Update Posted : January 11, 2019
University of Ulm
University of Sheffield
University Hospital, Tours
KU Leuven
UMC Utrecht
University of Dublin, Trinity College
Information provided by (Responsible Party):
Humanitas Mirasole SpA

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).

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis (ALS) Drug: Tauroursodeoxycholic acid (TUDCA) Drug: Placebo Phase 3

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 (see dia-gram). This will allow measuring the progression rate before and after starting treatment (either active or placebo).

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 440 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Tauroursodeoxycholic (TUDCA) as add-on Treatment in Patients Affected by Amyotrophic Lateral Sclerosis (ALS)
Estimated Study Start Date : January 2019
Estimated Primary Completion Date : December 1, 2019
Estimated Study Completion Date : June 1, 2022

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 (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
Other Name: a hydrophilic bile acid

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

Primary Outcome Measures :
  1. Number of responder patients [ Time Frame: 18 months ]
    Identification of the responder patients defined as those showing an improvement of at least 20% in the ALSFRS-R slope

Secondary Outcome Measures :
  1. Survival time [ Time Frame: 18 months ]
    Survival time measured by death or respiratory insufficiency

  2. ALS disease functional rating scale - revised version (ALSFRS-R) [ Time Frame: 18 months ]
    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.

  3. ALS Assessment Questionnaire‐40 (ALSAQ-40) [ Time Frame: 18 months ]
    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 pa-tient 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).

  4. Forced Vital Capacity [ Time Frame: 18 months ]
    Difference in change from baseline in Forced Vital Capacity

  5. EuroQol 5‐Dimension-5 Levels (EQ-5D-5L) scale [ Time Frame: 18 months ]
    Difference in change from baseline in EQ-5D-5L scale. The EQ-5D-5L descriptive system comprises 5 dimensions (mobility, self-care, usual activi-ties, pain/discomfort and anxiety/depression). Each dimension has 5 levels: 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 express-ing 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.

  6. Medical Research Council (MRC) scale [ Time Frame: 18 months ]
    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).

  7. Neurofilaments levels [ Time Frame: 18 months ]
    Effect of TUDCA on Neurofilament levels in comparison to placebo

  8. MMP-9 levels [ Time Frame: 18 months ]
    Effect of TUDCA on MMP-9 expression in comparison to placebo

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Probable laboratory-supported, probable, or definite ALS, as defined by El Escorial Revised ALS di-agnostic criteria 34
  • Disease duration ≤ 18 months
  • No swallowing difficulty (4 at ALSFRS swallowing subscore)
  • Able to perform reproducible pulmonary function tests
  • Forced vital capacity ≥70% of normal
  • Stable on riluzole treatment for 3 months in the lead-in period or no-riluzole
  • Able to perform reproducible pulmonary function tests
  • Signed informed consent

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
  • At the time of screening, 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, which-ever 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 at time of enrolment
  • Occurrence of frequent biliary colic, biliary infections, severe pancreatic abnormalities
  • Subjects who weigh 88 lbs (40 kg) or less at screening
  • Aspartate aminotransferase or alanine aminotransferase concentrations more than 3 times the upper limit of normal
  • Creatinine clearance 50 ml/min or less
  • Previous exposure to bile acids
  • Any clinically significant neurological, haematological, autoimmune, endocrine, cardiovascular, neo-plastic, renal, gastrointestinal, or other disorder that, in the Investigator's opinion, could in-terfere with the subject's participation in the study, place the subject at increased risk, or con-found 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 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

Responsible Party: Humanitas Mirasole SpA Identifier: NCT03800524     History of Changes
Other Study ID Numbers: 755094
First Posted: January 11, 2019    Key Record Dates
Last Update Posted: January 11, 2019
Last Verified: January 2019

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Tauroursodeoxycholic acid
Taurochenodeoxycholic Acid
Antiviral Agents
Anti-Infective Agents
Cholagogues and Choleretics
Gastrointestinal Agents