Study title	Safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS)
UK Chief Investigator	Professor Chris McDermott
Research summary	Amyotrohic lateral sclerosis (ALS) is a neurodegenerative disease which affects around 40,000 people throughout Europe. Riluzole is the only drug currently available which can slow the progression of ALS. The TUDCA-ALS study will look at a new drug called taurousodeoxycholic acid (TUDCA). The aim of the study is to determine whether TUDCA has an impact on the progression of ALS. The study will be conducted in hospital sites across Europe with around 7 hospitals taking part in the UK. Participants will be randomly allocated to receive TUDCA or placebo twice a day for 18 months. TUDCA will usually be administered as an add-on treatment to riluzole although it may be administered alone for patients who are unable to tolerate riluzole. Participants will be required to undergo a 3 month lead-in phase prior to starting study treatment. During the lead-in phase, 3 study visits will take place at 6-weekly intervals. After starting study treatment, visits will take place every 3 months during the 18 month treatment phase. Disease progression will be measured throughout the treatment period and other assessments will also be completed to assess quality of life as well as the safety and tolerability of TUDCA.
Inclusion/exclusion criteria	INCLUSION CRITERIA 1. Probable laboratory-supported, probable, or definite ALS, as defined by El Escorial Revised ALS diagnostic criteria 2. Disease duration < = 18 months 3. No swallowing difficulty (4 at ALSFRS-R swallowing subscore) 4. Able to perform reproducible pulmonary function tests 5. Forced vital capacity > = 70% of normal 6. Stable on riluzole treatment for 3 months in the lead-in period or no riluzole treatment (if not tolerated) 7. Signed informed consent EXCLUSION CRITERIA 8. Treatment with edaravone 9. Other causes of neuromuscular weakness 10. Presence of other neurodegenerative diseases 11. Significant cognitive impairment, clinical dementia or psychiatric illness 12. Severe cardiac or pulmonary disease 13. Other diseases precluding functional assessments 14. Other life-threatening diseases 15. 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 16. Gastrointestinal disorder that is likely to impair absorption of study drug from the gastrointestinal tract 17. Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is longer, prior to dosing 18. Any clinically significant laboratory abnormality 19. Other concurrent investigational medications 20. Active peptic ulcer 21. Previous surgery or infections of small intestine 22. Patients unable to easily swallow the treatment pills at time of enrolment 23. Occurrence of frequent biliary colic, biliary infections, severe pancreatic abnormalities 24. Subjects who weigh 88 lbs (40 kg) or less at screening 25. Aspartate aminotransferase or alanine aminotransferase concentrations more than 3 times the upper limit of normal 26. Creatinine clearance 50 ml/min or less 27. 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 28. 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 29. 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
Current status	Closed to Recruitment
Locations	Liverpool Plymouth Preston Salford Sheffield Stoke
Contact details
Recruitment group(s)	Patients with MND.
Recruitment target(s)	70 patients within the UK.
Key dates	Actual opening date: 04 September 2017 Recruitment planned end date: 08 October 2021
Funder(s)	European Commission - Horizon 2020
Sponsor	Irccs Istituto Nazionale Tumori - Fondazione Pascale
Study design	Interventional, randomised controlled trial
Intervention (if applicable)	Drug: tauroursodeoxycholic acid (TUDCA) Placebo
Phase (if applicable)	Phase 3
Outcome measures	Primary Outcome Measures: 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 : Survival time [ Time Frame: 18 months ] Survival time measured by death or respiratory insufficiency 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. 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 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). Forced Vital Capacity [ Time Frame: 18 months ] Difference in change from baseline in Forced Vital Capacity 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 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. 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). Neurofilaments levels [ Time Frame: 18 months ] Effect of TUDCA on Neurofilament levels in comparison to placebo MMP-9 levels [ Time Frame: 18 months ] Effect of TUDCA on MMP-9 expression in comparison to placebo
Publications / Results reports	Links will be provided when papers are published.
Participant Information Sheet