E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
amyotrophic lateral sclerosis |
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E.1.1.1 | Medical condition in easily understood language |
A neurological disease affecting the nerve cells responsible for controlling voluntary muscle movement. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002026 |
E.1.2 | Term | Amyotrophic lateral sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of tauroursodeoxycholic acid (TUDCA) in slowing disease progression in patients with amyotrophic lateral sclerosis (ALS) during the treatment period compared to the lead-in phase, as measured by the ALS disease functional rating scale - revised version (ALSFRS-R). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are: - To assess the efficacy of TUDCA in slowing disease progression and functional impairment in patients with ALS as measured by survival time, the ALSAQ-40 questionnaire, forced vital capacity (FVC), the EQ-5D and muscle force. - To assess the long term safety and tolerability of TUDCA for up to 18 months in patients with ALS.
The exploratory objectives of this study are: - To evaluate the effect of TUDCA on possible biomarkers: cerebrospinal fluid (CSF) and serum neurofilament levels, serum MMP-9 expression, and plasma creatinine levels. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 Patients already taking riluzole are eligible candidates, as well as those who start it for the purposes of en-tering the trial. |
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E.4 | Principal 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 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 30. The patient is pregnant or breast feeding |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is measured through identification of the responder patients defined as those showing an improvement of at least 20% in the ALSFRS-R slope during the 18 months compared to the lead-in period. For each randomised patient, slope coefficients of ALSFRS-R are calculated by linear regression models separately during the lead-in period and during the 18 months of treatment period.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 3 months during the treatment period. |
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E.5.2 | Secondary end point(s) |
- Survival time measured by death or respiratory insufficiency (DRI; defined as tracheostomy or the use of non-invasive ventilation for ≥22 h per day for ≥10 consecutive days) - Difference in change from baseline in ALSFRS-R - ALSAQ-40 questionnaire - Forced Vital Capacity - EQ-5D scale - Muscle force assessed by the MRC sum-score - Safety is assessed through adverse reaction, concomitant treatment, physical examination, vital signs and routine labs (haematology, biochemistry) - Neurofilament levels in the CSF and serum; MMP-9 expression in serum - Plasma creatinine levels as indicators of muscle waste |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Every 3 months during the treatment period. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS. Sites will be closed once data cleaning is completed and the regulatory authority and ethics committee will be informed. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 31 |