| 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 |
To demonstrate the efficacy of repeated daily doses of 40 μg/kg and 120 μg/kg A4250 in children with PFIC Types 1 and 2, as determined by the following:
• The proportion of patients experiencing at least a 70% reduction in fasting s-BA concentration from baseline to end of treatment or a reduction to a specified level, compared to placebo after 24 weeks of treatment
• The proportion of positive pruritus assessments at the subject level over the 24-week Treatment Period |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of A4250 on serum ALT concentration
• To evaluate the effect of A4250 on growth
• To evaluate the effect of A4250 on sleep disturbance
• To evaluate the effect of A4250 on the need for surgical treatment (biliary diversion or liver transplantation)
• To assess the safety and tolerability of repeated daily doses of A4250 for 24 weeks |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. A male or female patient, with clinical diagnosis of PFIC Type 1 or 2, between the ages of ≥6 months and ≤18 years at Visit 1 with a body weight above 5 kg
2. Patient must have genetic confirmation of PFIC-1 or PFIC-2 through identification of biallelic pathogenic variants in either the ATP8B1 or ABCB11 genes
3. Patient must have elevated s-BA concentration specifically measured to be ≥100 µmol/L, taken as the average of 2 samples at least 7 days apart (Visits 1 and 2) prior to randomization
4. Patient must have history of significant pruritus and a caregiver-reported observed scratching in the eDiary in the 2 weeks prior
to randomization
5. Patient and/or legal guardian must sign 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 in order to remain in the study
6. Patients will be expected to have a consistent caregiver(s) for the duration of the study
7. Caregivers and age-appropriate patients (≥8 years of age) must be willing and able to use an eDiary device as required by the study |
|
| E.4 | Principal exclusion criteria |
1. Patient with pathologic variations of the ABCB11 gene that predict complete absence of the BSEP function
2. Patient with past medical history or ongoing presence of other types of liver disease including, but not limited to, the following:
a) Biliary atresia of any kind
b) Benign recurrent intrahepatic cholestasis
c) Suspected or proven liver cancer or metastasis to the liver on imaging studies
d) Histopathology on liver biopsy is suggestive of alternate non-PFIC related etiology of cholestasis
3. Patient with past medical history of ongoing chronic diarrhea
4. Any patient with suspected or confirmed cancers except for basal cell carcinoma
5. Patient with a past medical history of chronic kidney disease with an impaired renal function and a glomerular filtration rate <70 mL/min/1.73 m2
6. Patient with surgical history of disruption of the enterohepatic circulation (biliary diversion surgery) within 6 months prior to start of Screening Period.
7. Patient has had a liver transplant or a liver transplant is planned within 6 months of randomization
8. Decompensated liver disease, coagulopathy, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy
9. Patient suffers from uncontrolled, recalcitrant pruritic condition other than PFIC.
10. Patient who has been previously treated with an IBAT inhibitor whose pruritus has not responded to treatment |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of patients experiencing at least a 70% reduction in fasting s-BA concentration from baseline to end of treatment or a reduction to a specified level, compared to placebo after 24 weeks of treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Randomization (baseline), Week 24, follow-up visit |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include the following:
EU and RoW: Proportion of positive pruritus assessments at the subject level over the 24-week Treatment Period. A positive pruritus assessment is defined as a scratching score of ≤1 or at least a one-point drop from baseline on the Albireo ObsRO instrument.
All Regions
All secondary endpoints are compared to placebo:
•Change from baseline to Week 12 and to Week 24 in fasting s-BA
•Change from baseline to Week 12 and to Week 24 in serum ALT concentration
•Change in growth from baseline to Week 12 and to Week 24
•Proportion of responders for pruritus scores at Weeks 12 and 24 based on the Albireo PRO and ObsRO instruments
•Change in sleep parameters measured with the Albireo PRO and ObsRO instruments from baseline over the 24-week Treatment Period
•Proportion of individual assessments meeting the definition of a positive pruritus assessment at the subject level over the 24-week Treatment Period; only patients ≥8 years of age will complete the Albireo PRO instrument
•Proportion of individual assessments meeting the definition of a positive pruritus assessment at the subject level from Weeks 0-4, Weeks 0-8, Weeks 0-12, Weeks 0-18, Weeks 0-24, respectively, or the proportion of positive pruritus assessments at each 4-week interval
•Proportion of individual AM assessments meeting the definition of a positive pruritus assessment at the subject level from Weeks 0-4, Weeks 0-8, Weeks 0-12, Weeks 0-18, Weeks 0-24, respectively, or the proportion of positive pruritus assessments at each 4-week interval
•Proportion of individual PM assessments meeting the definition of a positive pruritus assessment at the subject level from Weeks 0-4, Weeks 0-8, Weeks 0-12, Weeks 0-18, Weeks 0-24, respectively, or the proportion of positive pruritus assessments at each 4-week interval
•Number of patients undergoing biliary diversion surgery or liver transplantation |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 9 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| 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 |
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