| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
In patients with progressive familial intrahepatic cholestasis (PFIC),
impairment of the egress of bile acids from the liver leads to cholestasis,
hepatocellular injury and damage, and progressive liver disease that
may ultimately lead to the need for liver transplantation. Itch is a
common symptom associated with cholestasis, it can occur at all stages
of cholestatic liver disease, with or without jaundice. |
|
| E.1.1.1 | Medical condition in easily understood language |
PFIC is a long-term debilitating and life-threatening disease
due to liver and heart problems. |
|
| 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 |
| The primary objective of the study is to evaluate the long-term safety and tolerability of maralixibat. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the long-term efficacy of maralixibat, including the maintenance of severity and frequency of pruritus as well as serum bile acids (sBA) over time and growth in the primary cohort |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Provide informed consent and assent (as applicable) per Institutional Review Board/Ethics Committee.
- Completion of study MRX-502; treatment interruption between MRX-502 and MRX-503 should be avoided. Subjects who do not complete the study MRX-503 Baseline Visit (Day 0) on the same day as the study MRX 502 EOT Visit will be considered for participation in study MRX-503 only after discussion with the Medical Monitor.
- Males and females of nonchildbearing potential. Males and nonpregnant, nonlactating females of childbearing potential who are sexually active must agree to use acceptable methods of contraception during the study through 30 days after the last dose of maralixibat.
- Females of childbearing potential must have a negative urine pregnancy test result at the Baseline Visit (Day 0).
- Access to email or telephone for scheduled remote visits.
- Ability to read and understand the questionnaires (both caregivers and subjects above the age of assent).
- Access to consistent caregiver(s) during the study.
- Subject and caregiver willingness to comply with all study visits and requirements.
|
|
| E.4 | Principal exclusion criteria |
- Any female who is pregnant or lactating or who is planning to become pregnant.
- Administration of prohibited medication between the MRX-502 EOT visit and the MRX 503 Baseline Visit (Day 0).
- History of noncompliance in study MRX-502, nonadherence to medical regimens, unreliability, mental instability, or incompetence that could compromise the validity of informed consent or lead to nonadherence with the study protocol based on Investigator judgment.
- Experienced an adverse event (AE) or serious adverse event (SAE) related to maralixibat during the MRX-502 study that led to permanent discontinuation of the subject from maralixibat.
- Any other conditions (including decompensated liver disease) or laboratory abnormalities that, in the opinion of the Investigator or Sponsor Medical Monitor, may compromise the safety of the subject, or interfere with the subject participating in or completing the study.
- Cognitive impairment of the subject or caregiver that would, in the opinion of the Investigator, preclude appropriate understanding of study information and compliance with study procedures. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The evaluation of long-term safety and tolerability of maralixibat is the primary objective of the study.
The primary endpoints related to safety and tolerability include:
•Incidence of treatment-emergent adverse events during the study by system organ class and preferred term (serious, nonserious, related, and non-related)
•Safety laboratory parameters (clinical laboratory tests [hematology, chemistry, urinalysis, lipid-soluble vitamins, and related measures)] over time
Additional safety and tolerability endpoints include the following:
•Change from baseline in physical examination findings (including body weight, height, and body mass index)
•Change from baseline in vital signs
•Concomitant treatment usage |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety analyses will be conducted using data from the Safety Population. Safety variables include TEAEs and clinical laboratory values. No formal inferential analyses will be conducted for safety variables, unless otherwise noted. Analyses will be conducted separately on the primary cohort and all cohorts combined. |
|
| E.5.2 | Secondary end point(s) |
The evaluation of efficacy is the secondary objective of the study. The secondary efficacy endpoints include the following:
•Mean change from maralixibat baseline in the average morning Observer Reported Itch Reported Outcome Instrument (ItchRO[Obs]) severity score over time
•Maintenance of treatment effect based on the average morning ItchRO(Obs) severity scores over time
•Mean change from maralixibat baseline over time in sBA levels
•Mean change from maralixibat baseline over time in the average morning ItchRO(Obs) frequency score
•Proportion of subjects who experience an sBA control over time (sBA control definition is detailed in the statistical analysis plan [SAP])
•Proportion of responders over time (responder definitions are detailed in the SAP)
•Mean change from maralixibat baseline over time in height and weight z scores
•Time from maralixibat baseline to liver-associated events |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary and exploratory endpoints will be analyzed as described in the supplemental cohort in the Safety Population, overall and by treatment sequence. Additional subgroupings of the supplemental cohort may also be explored depending on the sample sizes.
|
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | 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.8.3 |
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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Argentina |
| Colombia |
| Singapore |
| Brazil |
| Canada |
| Lebanon |
| Mexico |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Türkiye |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 20 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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