| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Progressive Familial Intrahepatic Cholestasis Types 1 and 2 |
|
| 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. |
|
| 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 |
|
| 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 |
Primary Objective (Cohort 1)
To demonstrate a sustained effect of A4250 on serum bile acids and pruritus in children with PFIC Types 1 and 2.
Primary Objective (Cohort 2)
To evaluate the effect of A4250 on serum bile acids and pruritus in patients with PFIC who either (1) do not meet eligibility criteria for Study A4250-005 (PEDFIC 1) or (2) who do meet the eligibility criteria for Study A4250-005 after recruitment of Study A4250-005 has been completed. |
|
| E.2.2 | Secondary objectives of the trial |
Cohorts 1 and 2:
• 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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Cohort 1:
1. Completion of the 24-week Treatment Period of Study A4250-005 or withdrawn from Study A4250-005 due to patient/caregiver judgment of intolerable symptoms after completing at least 12 weeks of treatment. Patients who withdraw from A4250-005 due to a study drug related AE will not be eligible.
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
Cohort 2:
1. A male or female patient of any age, with a clinical diagnosis of PFIC, including episodic forms (i.e., benign recurrent intrahepatic cholestasis [BRIC]), and with a body weight ≥5 kg at Visit S-1
2. Patient must have clinical genetic confirmation of PFIC.
3. Patients with PFIC, excluding BRIC, must have elevated serum bile acid concentration.
4. Patients with PFIC, excluding BRIC, must have history of significant pruritus.
5. Patients with episodic forms of PFIC (i.e., BRIC) must have an emerging flare characterized by clinically significant pruritus and elevated serum bile acid levels / cholestasis as judged by the investigator.
6. Patient and/or legal guardian must sign informed consent (and assent) as appropriate.
7. Age appropriate patients are expected to have a consistent caregiver for the duration of the study
8. Caregivers and age-appropriate patients (≥8 years of age, if able) must be willing and able to use an eDiary device as required by the study |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria at Visit 1 or Visit S-1 will not be eligible for study participation:
Cohort 1:
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
Cohort 2:
1. Known pathologic variations of the ABCB11 gene that have been demonstrated to result in complete absence of the BSEP protein.
2. Patient with past medical history or ongoing presence of other types of liver disease.
Note: Patients with clinically significant portal hypertension are allowed.
3. Patient has had a liver transplant, or a liver transplant is planned within 6 months of the Screening/Inclusion Visit.
4. Decompensated liver disease, coagulopathy, history, or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy.
5. INR >1.4 (the patient may be treated with Vitamin K intravenously, and if INR is ≤1.4 at resampling the patient may be randomized).
6. Serum ALT >10 × upper limit of normal (ULN) at Screening.
7. Serum ALT >15 × ULN at any time point during the last 6 months unless an alternate etiology was confirmed for the elevation.
8. Total bilirubin >5 × ULN at Screening
9. Patient suffers from uncontrolled, recalcitrant pruritic condition other than PFIC.
10. Administration of bile acid or lipid binding resins and medications that slow GI motility.
11. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is:
Change from baseline in serum bile acids after 72 weeks of treatment.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Screening/ Inclusion Visit and week 72 |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include:
• Proportion of positive pruritus assessments at the patient level over the 72-week treatment period using the Albireo ObsRO instrument.
• Change from baseline in serum bile acids to Week 76.
• Proportion of individual assessments meeting the definition of a positive pruritus assessment at the patient level using the Albireo ObsRO instrument to Week 70.
• Proportion of individual AM assessments meeting the definition of a positive pruritus assessment at the patient level using the Albireo ObsRO instrument to Week 72.
• Proportion of individual PM assessments meeting the definition of a positive pruritus assessment at the patient level using the Albireo ObsRO instrument to Week 72.
• All-cause mortality, number of patients undergoing biliary diversion surgery or 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| • Weeks 24, 48, 72 and 76 |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
|
| 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 |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 24 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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