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

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Amyotrophic Lateral Sclerosis (ALS)

Intervention / Treatment
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* Drug: Tauroursodeoxycholic Acid
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tauroursodeoxycholic acid (TUDCA)<br>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<br>* 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<br>* Other names: Taurolite;|
| Placebo Comparator: Reference therapy<br>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<br>* Placebo 250 mg capsules Doses: 4 capsules (1 g) twice daily 10-15 minutes after a meal Mode of administration: orally Duration: 18 months<br>|

What is the study measuring?
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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 |