E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic Lateral Sclerosis (ALS) |
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E.1.1.1 | Medical condition in easily understood language |
Amyotrophic Lateral Sclerosis (ALS) |
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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 asses the efficacy of TUDCA in slowing disease prograssion in patients with ALS during the treatment period compared to the lead-in phase as measured by ALSFRS-R |
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E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of TUDCA in slowing disease progression and functional impairment in patients with ALS, as measured by the survival time, the ALSAQ-40 questionnaire, 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: 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 | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Open label extension see protocol attachment E The primary objective of the sub-study is: • To assess the long-term safety and tolerability of TUDCA during the open-label phase. The secondary objectives of the sub-study are: • To assess survival time in ALS patients during the open-label phase. • To assess disease progression and functional impairment in ALS patients during the open-label phase. |
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E.3 | Principal inclusion criteria |
1. laboratory-supported, probable, or definite ALS diagnosis, as defined by El Escorial Revised ALS diagnostic criteria at screen-ing visit (M-3) 2. Disease duration ≤ 18 months at screening visit (M-3) 3. Able to perform reproducible pulmonary function tests at screening visit (M-3) 4. FVC or SVC ≥70% of normal at screening visit (M-3) 5. Stable on riluzole treatment for 3 months in the lead-in period 6. Signed informed consent at screening visit (M-3)
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E.4 | Principal exclusion criteria |
1. Treatment with edaravone or other unaccepted concomitant therapy (substances inhibiting the intestinal absorption of bili-ary acids, antacids containing aluminium hydroxide and/or smectites, estrogens and drugs acting by lowering plasmatic cholesterol; drugs increasing biliary clearance of cholesterol, hepatolesive drugs) 2. Other causes of neuromuscular weakness 3. Presence of other neurodegenerative diseases 4. Significant cognitive impairment, clinical dementia or psychiat-ric illness 5. Severe cardiac or pulmonary disease 6. Other diseases precluding functional assessments 7. Other life-threatening diseases 8. Any use of non-invasive ventilation for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation 9. Gastrointestinal disorder that is likely to impair absorption of study drug from the gastrointestinal tract 10. Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is longer, prior to dos-ing 11. Any clinically significant laboratory abnormality 12. Other concurrent investigational medications 13. Active peptic ulcer 14. Previous surgery or infections of small intestine 15. Patients unable to easily swallow the treatment pills 16. Acute inflammation of the gallbladder or bile ducts 17. Occurrence of frequent biliary colic, biliary infections, severe pancreatic abnormalities 18. Bile duct obstruction, calcified X-ray opaque gallstones and re-duced mobility of the gallbladder 19. Subjects who weigh 88 lbs (40 kg) or less 20. Sieric Aspartate aminotransferase or alanine aminotransferase concentrations more than 3 times the upper limit of normal 21. Creatinine clearance 50 ml/min or less 22. Any clinically significant neurological, haematological, autoim-mune, endocrine, cardiovascular, neo-plastic, renal, gastroin-testinal, 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 23. Consideration by the investigator, for any reason, that the sub-ject is an unsuitable candidate to receive TUDCA or that the subject is unable or unlikely to comply with the dosing sched-ule or study evaluations 24. 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 25. The patient is pregnant or breast feeding
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E.5 End points |
E.5.1 | Primary end point(s) |
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 sep-arately 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 |
This endpoint will be evaluate during the initial observation period and during the 18 months of 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 disease progression and functional impairment between TUDCA and placebo over 18 months (as measured by ALSFRS-R, ALSAQ-40 questionnaire, Forced Vital Capacity , EQ-5D scale and MRC sum-score ). • Long-term safety and tolerability of TUDCA treatment in patients with ALS for up to 18 months (as assessed through adverse reaction, concomitant treatment, physical examination, vital signs and routine haematology and biochemistry analyses). • Effect of TUDCA on biomarkers of disease progression (such as CSF and serum Neurofilament levels, serum MMP-9 expression and plasma creatinine levels) over 18 months in comparison to placebo |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All efficacy and safety endpoints will be compared between the two randomization groups at the end of the study |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |