E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic Lateral Sclerosis (ALS) |
sclérose latérale amyotrophique (SLA). |
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E.1.1.1 | Medical condition in easily understood language |
Amyotrophic Lateral Sclerosis (ALS) |
sclérose latérale amyotrophique (SLA). |
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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 |
Évaluer l'efficacité de TUDCA dans le ralentissement de la progression de la maladie chez les patients atteints de SLA au cours de la période de traitement par rapport à la phase d'observation initiale, évaluée avec 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. |
• Evaluer l'efficacité de TUDCA dans le ralentissement de la progression de la maladie et de la déficience fonctionnelle chez les patients atteints de SLA, mesurée par: la durée de survie, le questionnaire AL-SAQ-40, la FVC, la EQ-5D et la force musculaire • évaluer l'innocuité et la tolérance à long terme de TUDCA jusqu'à 18 mois chez des patients atteints de SLA Les objectifs exploratoires de cette étude sont: • Évaluer l'effet du TUDCA sur des biomarqueurs possibles: valeurs de neurofilaments liquides ou sériques, expression de la MMP-9 dans le sérum, taux de créatinine plasmatique.
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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 at screening visit (month -3) 38 2. Disease duration ≤ 18 months at screening visit (month -3) 3. Able to perform reproducible pulmonary function tests at screening visit (month -3) 4. Forced vital capacity or slow vital capacity ≥70% of normal at screening visit (month -3) 5. Stable on riluzole treatment for 3 months in the lead-in period 6. Signed informed consent at screening visit (month -3)
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1. Diagnostic de SLA supporté par des examens de laboratoire, probable ou défini selon les critères de diagnostic de l'ALS El Escorial Revised à la visite d’évaluation (M-3) 2. Durée de la maladie ≤ 18 mois à la visite d’évaluation (M-3) 3. Capable d’effectuer des tests de fonction pulmonaire repro-ductibles à la visite d’évaluation (M-3) 4. FVC ou SVC ≥70% de la normale à la visite d’évaluation (M-3) 5. Traitement avec riluzole stable dans les 3 mois de la période lead-in 6. Consentement éclairé signé à la visite d’évaluation (M-3)
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E.4 | Principal exclusion criteria |
1. Treatment with edaravone or other unaccepted concomitant therapy (as per section 8) 2. Other causes of neuromuscular weakness 3. Presence of other neurodegenerative diseases 4. Significant cognitive impairment, clinical dementia or psychiatric 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 (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 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 dosing 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 reduced mobility of the gallbladder 19. Subjects who weigh 88 lbs (40 kg) or less 20. 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, 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 23. 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 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 (see Contraceptive Guidance in Appendix A) 25. The patient is pregnant or breast feeding
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Patients des deux sexes âgés entre 18 et 80 ans (inclus)
Critères d'inclusion: 1. Diagnostic de SLA supporté par des examens de laboratoire, probable ou défini selon les critères de diagnostic de l'ALS El Escorial Revised à la visite d’évaluation (M-3) 2. Durée de la maladie ≤ 18 mois à la visite d’évaluation (M-3) 3. Capable d’effectuer des tests de fonction pulmonaire reproductibles à la visite d’évaluation (M-3) 4. FVC ou SVC ≥70% de la normale à la visite d’évaluation (M-3) 5. Traitement avec riluzole stable dans les 3 mois de la période lead-in 6. Consentement éclairé signé à la visite d’évaluation (M-3)
Critères d'exclusion: 1. Traitement avec édaravone ou autre traitement concomitant pas accepté (substances qui inhibent l'absorption intestinale des acides biliaires; antiacides contenant de l'hydroxyde d'aluminium et/ou de la smectite; œstrogènes et agents réduisant le cholestérol sérique; médicaments augmentant l'élimination biliaire du cholestérol; médicaments hépatotoxiques) 2. Autres causes de faiblesse neuromusculaire 3. Présence d'autres maladies neurodégénératives 4. Déficit cognitif important, démence clinique ou maladie psychiatrique 5. Maladie cardiaque ou pulmonaire grave 6. Autres maladies qui empêchent les évaluations fonctionnelles 7. Autres maladies potentiellement mortelles 8. Toute utilisation de la ventilation non invasive pour une partie de la journée ou de la ventilation mécanique par trachéotomie ou toute forme de supplémentation d’oxygène 9. Troubles gastro-intestinaux pouvant compromettre l'absorption du médicament à l'étude 10. Assomption du médicament expérimental dans les 30 jours précédant l'inscription 11. Toute anomalie de laboratoire cliniquement significative 12. Autres médicaments expérimentaux concomitants 13. Ulcère peptique actif 14. Chirurgie précédente ou infections de l'intestin grêle 15. Les patients ne peuvent pas avaler facilement les comprimés de traitement 16. Inflammation aiguë de la vésicule biliaire ou des voies biliaires 17. Présence de coliques biliaires fréquentes, infections des voies biliaires, anomalies pancréatiques sévères 18. Obstruction des voies biliaires, calculs biliaires calcifiés opaques aux rayons X et mobilité réduite de la vésicule biliaire. 19. Sujets qui pesent 40 kg ou moins 20. Aspartate aminotransférase ou alanine amino-transférase supérieures à 3 fois la limite supérieure de la normale 21. Clairance de la créatinine 50 ml / min ou moins 22. Tout trouble neurologique, hématologique, auto-immun, endocrinien, cardiovasculaire, néoplasique, rénal, gastro-intestinal ou tout autre trouble qui, de l’avis du chercheur, pourrait à la interférer avec la participation du sujet à l’étude ou exposer le sujet à un risque plus grand, ou pourrait causer une mauvaise interprétation des résultats de l'étude 23. Le candidat est jugé pas adéquat pour recevoir TUDCA ou incapable de se conformer au programme de l’étude 24. Le patient est sexuellement actif et ne veut pas utiliser de méthode contraceptive extrêmement efficace au cours de l'étude et jusqu'à 90 jours après la dernière dose. 25. La patiente est enceinte ou allaite
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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 | No |
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 | 0 |
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 |
E.8.9.2 | In all countries concerned by the trial days | 0 |