E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic Lateral Sclerosis (ALS) |
amyotrofische laterale sclerose (ALS) |
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E.1.1.1 | Medical condition in easily understood language |
Amyotrophic Lateral Sclerosis (ALS) |
amyotrofische laterale sclerose (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 |
Evaluatie van de werkzaamheid van TUDCA bij het vertragen van de ziekteprogressie bij patiënten met ALS tijdens de behandelingsperiode in vergelijking met de initiële observatiefase, beoordeeld met 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. |
• Evaluatie van de werkzaamheid van TUDCA bij het vertragen van de ziekteprogressie en de functionele beperkingen bij patiënten met ALS, gemeten op basis van de overlevingsduur, vragenlijst ALSAQ-40, FVC, EQ-5D en spierkracht • Evaluatie van de veiligheid op lange termijn en verdraagbaarheid van TUDCA tot 18 maanden bij patiënten met ALS De verkennende doelstellingen van deze studie zijn: • Evaluatie van het effect van TUDCA op mogelijke biomarkers: liquor- of serumwaarden van neurofilamenten, MMP-9-expressie in serum, plasmacreatininespiegels
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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 7. Signed informed consent |
1. Door laboratoriumonderzoek gestaafde waarschijnlijke of zekere diagnose van ALS, volgens de El Escorial Revised diagnostische criteria voor ALS 2. Duur van de ziekte ≤ 18 maanden 3. Geen moeite met slikken (4 in subitem slikken van de ALSFRS-R) 4. In staat om longfunctietests te ondergaan die tot reproduceerbare resultaten leiden 5. Geforceerde vitale capaciteit ≥ 70% van de normale waarde 6. Geen onregelmatigheden bij de behandeling met riluzol gedurende de aanloopperiode van 3 maanden 7. Geïnformeerde toestemming getekend
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E.4 | Principal exclusion criteria |
8. Treatment with edaravone or other unaccepted concomitant therapy 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 pres-sure, 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 halflives 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, neo-plastic, 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 interpre-tation of study results 28. Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to re-ceive 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 |
1. Behandeling met edaravone of met een andere niet toegestane therapie (stoffen die de intestinale absorptie van galzuren remmen; maagzuurremmers die aluminiumhydroxide e/o smectiet bevatten; oestrogenen en serumcholesterolverlagende middelen; geneesmiddelen die cholesterolafscheiding via de gal verhogen; hepatotoxische geneesmiddelen) 2. Andere oorzaken van neuromusculaire zwakte 3. Aanwezigheid van andere neurodegeneratieve ziekten 4. Significante cognitieve stoornissen, klinische dementie of psychiatrische aandoeningen 5. Ernstige hart- of longaandoening 6. Andere ziekten die functionele evaluaties uitsluiten 7. Andere levensbedreigende ziekten 8. Op het moment van screening, elke toepassing van niet-invasieve beademing gedurende de dag, of mechanische beademing via een tracheotomie of zuurstofsuppletie, in welke vorm dan ook 9. Gastro-intestinale stoornissen die de opname van het studiegeneesmiddel kunnen belemmeren 10. Inname van het onderzochte geneesmiddel in de 30 dagen voorafgaand aan de aanmelding 11. Alle klinisch significant afwijkende laboratoriumresultaten 12. Andere geneesmiddelen bij een gelijktijdig experiment 13. Actieve maagzweer 14. Eerdere operatie aan of infecties van de dunne darm 15. Patiënten die op het moment van inschrijving moeite hebben met het doorslikken van de pillen voor de behandeling 16. Aanwezigheid van frequente galkolieken, galweginfecties, ernstige pancreasafwijkingen 17. Proefpersonen die bij screening 40 kg of minder wegen 18. Concentraties aspartaat-aminotransferase of alanine-aminotransferase die 3 maal hoger zijn dan de bovengrens van de normaalwaarden 19. Creatinineklaring van 50 ml/min of minder 20. Elke neurologische, hematologische, auto-immune, endocriene, cardiovasculaire, neoplastische, renale, gastro-intestinale of andere stoornis die volgens de onderzoeker zou kunnen interfereren met de deelname van persoon aan het onderzoek, het risico voor de proefpersoon verhoogt of kan leiden tot een onjuiste interpretatie van de onderzoeksresultaten 21. Elk vermoeden dat een kandidaat niet geschikt is om TUDCA toegediend te krijgen of niet in staat is om het onderzoeksprogramma strikt te volgen 22. Een seksueel actieve patiënt die niet bereid is om uiterst effectieve anticonceptiemethoden te gebruiken tijdens het onderzoek en tot 90 dagen na de laatste dosis
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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 | 25 |
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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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 | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |