E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Progressive Familial Intrahepatic Cholestasis Types 1 and 2 |
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E.1.1.1 | Medical condition in easily understood language |
An inherited condition causing reduced bile acid flow and progressive
liver disease in children and young people. |
Maladie héréditaire entraînant une réduction du débit des acides biliaires et une maladie hépatique évolutive chez les enfants et les patients jeunes. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10076033 |
E.1.2 | Term | Progressive familial intrahepatic cholestasis |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 |
The primary objective of this study is to demonstrate a sustained effect of A4250 on serum bile acid (s-BAs) and pruritus in children with PFIC Types 1 and 2. |
L'objectif principal de cette étude est de démontrer l’effet durable du A4250 sur les acides biliaires sériques (s-BA) et le prurit chez les enfants atteints de cholestase intrahépatique progressive familiale (PFIC) de types 1 et 2. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the long-term safety and tolerability of repeated daily doses of A4250
• To evaluate the effect of A4250 on growth
• To evaluate the effect of A4250 on biliary diversion and/or listing for liver transplantation
• To evaluate the effect of A4250 on biochemical markers of cholestasis and liver disease |
• Évaluer l’innocuité et la tolérance à long terme de doses quotidiennes répétées de A4250
• Évaluer l’effet du A4250 sur la croissance
• Évaluer l’effet du A4250 sur la dérivation biliaire et/ou inscription sur une liste pour greffe de foie
• Évaluer l’effet du A4250 sur les marqueurs biochimiques de la cholestase et des maladies hépatiques |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Completion of the 24-week Treatment Period of Study A4250-005 or withdrawn from Study A4250-005 due to patient/caregiver judgment of lack of improvement/intolerable symptoms after completing at least 12 weeks of treatment
2. Signed informed consent and assent as appropriate. Patients who turn 18 years of age (or legal age per country) during the study will be required to re-consent to remain on the study
3. Patients expected to have a consistent caregiver for the duration of the study
4. Caregivers (and age appropriate patients) must be willing and able to use an eDiary device as required by the study |
1. Achèvement de la période de traitement de 24 semaines de l’étude A4250-005 ou retrait de l’étude A4250-005 en raison d’un manque d’amélioration/de symptômes intolérables de l’avis du patient/de l’aidant après avoir suivi au moins 12 semaines de traitement.
2. Signature du consentement éclairé et de l’assentiment), selon le cas. Les patients qui atteignent l’âge de 18 ans (ou l’âge légal du pays) pendant l’étude devront à nouveau donner leur consentement pour poursuivre l’étude.
3. Les patients peuvent être accompagnés par le même aidant pendant toute la durée de l’étude.
4. Les aidants (et les patients ayant l’âge approprié) doivent vouloir et pouvoir utiliser un journal électronique comme l’exige l’étude. |
|
E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria at Visit 1 will not be eligible for study participation:
1. Decompensated liver disease: coagulopathy, history, or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy
2. Sexually active males and females who are not using a reliable contraceptive method with ≤1% failure rate (such as barrier protection, hormonal contraception, intra-uterine device, or complete abstinence) throughout the duration of the study and 90 days thereafter (from signed informed consent through 90 days after last dose of study drug).
3. Patients not compliant with treatment in study A4250-005
4. Any other conditions or abnormalities which, in the opinion of the investigator or Medical Monitor, may compromise the safety of the patient, or interfere with the patient participating in or completing the study |
Les patients satisfaisant à l'un des critères suivants au cours de la Visite 1 ne seront pas éligibles à participer à l'étude:
1. Hépatopathie décompensée : coagulopathie, ascite cliniquement significative passée ou présente, saignement de varices œsophagiennes et/ou encéphalopathie.
2. Hommes et femmes sexuellement actifs qui n'utilisent pas une méthode contraceptive fiable ayant un taux d'échec ≤ 1 % (telle qu'une méthode barrière, une contraception hormonale, un dispositif intra-utérin ou l'abstinence totale) pendant toute la durée de l'étude et dans les 90 jours suivant la fin de l'étude (à partir de la signature du consentement éclairé jusqu'à 90 jours après la prise de la dernière dose du médicament de l'étude).
3. Patients non observants dans l'étude A4250-005
4. Toute autre pathologie ou anomalie qui, de l'avis de l'investigateur ou de l’attaché de recherche clinique, peut compromettre la sécurité du/de la patiente ou l’empêcher de participer à l’étude ou de la terminer.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is:
Change from baseline in s-BA after 72 weeks of treatment.
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Critère principal d’évaluation de l’efficacité:
Variation par rapport à la valeur de référence du taux de s-BA après 72 semaines de traitement. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening/ Inclusion Visit and week 72 |
Visite de sélection/ d’inclusion et semaine 72 |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include:
• All-cause mortality, number of patients undergoing biliary diversion
surgery, or being listed for liver transplantation.
• Change in growth after initiation of A4250 treatment
• Change in AST to platelet ratio index (APRI) score and Fib-4 score
from baseline to Week 72
• Change in pediatric end-stage liver disease (PELD)/model for endstage
liver disease (MELD) score from baseline to Week 72
• Change in use of antipruritic medication |
Les critères d'évaluation secondaires sont, notamment :
• La mortalité, toutes causes confondues, le nombre de patients subissant une chirurgie de dérivation biliaire ou inscrits sur une liste d'attente de transplantation hépatique.
• Modification de la croissance après l'instauration du traitement par A4250.
• Variation du score APRI (rapport ASAT/plaquettes) et du score Fib-4 entre l’entrée dans l’étude et la Semaine 72.
• Variation du score PELD (pediatric end-stage liver disease)/MELD (model for end-stage liver disease) entre l’entrée dans l’étude et la Semaine 72.
• Modification du recours aux médicaments antiprurigineux.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Weeks 24, 48, and 72 |
• Semaines 24, 48, et 72 |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Quality of Life Assessment (using PedsQL) |
|
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 |
Australia |
Belgium |
Canada |
France |
Germany |
Israel |
Italy |
Netherlands |
Poland |
Saudi Arabia |
Spain |
Sweden |
Turkey |
United Kingdom |
United States |
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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
|
End of study in one country: last patient last visit (LPLV) and sites are closed.
End of study globally: LPLV globally and all sites closed |
Fin d'étude dans un pays: Dernière visite du dernier patient et les centres sont fermés.
Fin d'étude au niveau mondiale : Dernière visite du dernier patient au niveau mondiale et tous les centres sont fermés. |
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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 | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |