| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Long-term safety study with Maralixibat, in treatment of subjects with cholestatic liver disease including, but not limited to, Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC). |
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| E.1.1.1 | Medical condition in easily understood language |
| Cholestatic liver disease including Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC), which are life-threating disease due to liver problems. |
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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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10053870 |
| E.1.2 | Term | Alagille syndrome |
| 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 |
| Evaluate the long-term safety of maralixibat in subjects with cholestatic liver disease including, but not limited to, ALGS and PFIC. |
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| E.2.2 | Secondary objectives of the trial |
•Evaluate the long-term effect of maralixibat on pruritus
•Evaluate the long-term effect of maralixibat on serum bile acid levels
•Evaluate the long-term effect of maralixibat on time to liver-associated events (i.e., partial external biliary diversion (PEBD) or liver transplantation)
•Evaluate the long-term effects of maralixibat on growth
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Provide informed consent and assent (as applicable) per the Institutional Review Board/Ethics Committee (IRB/EC).
2.Previously participated in a maralixibat study and with approval of the Medical Monitor. Previous participation is defined as:
•Having completed the EOT Visit, for subjects coming from the maralixibat Phase 2 studies (LUM001-303, LUM001-304, and LUM001-305 in ALGS and LUM001-501 in PFIC).
•Having completed the entire duration of the study (i.e., core and extension, if applicable), for subjects coming from other maralixibat studies (e.g., MRX 503 and other open-label maralixibat studies).
3.Males, and females of non-childbearing potential. Males and non-pregnant, non lactating females of childbearing potential who are sexually active must agree to use acceptable contraception during the study and 30 days following the last dose of the study medication. Females of childbearing potential must have a negative pregnancy test.
4.Caregivers (and/or age appropriate subjects) must have access to email or phone for scheduled remote visits if applicable.
5.Subject and caregiver willingness to comply with all study visits and requirements.
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| E.4 | Principal exclusion criteria |
1.Experienced an adverse event (AE) or serious adverse event (SAE) related to maralixibat during the lead-in protocol that led to permanent discontinuation of the subject from maralixibat.
2.Any conditions or abnormalities (including laboratory abnormalities) which, in the opinion of the Investigator or Medical Monitor may compromise the safety of the subject or interfere with the subject participating in or completing the study.
3.History of non-adherence to medical regimens, unreliability, medical condition, mental instability or cognitive impairment that, in the opinion of the Investigator or Sponsor medical monitor, could compromise the validity of informed consent, compromise the safety of the subject, or lead to nonadherence with the study protocol or inability to conduct the study procedures. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The following safety and tolerability endpoints will be assessed:
•AEs including serious, non-serious, related, non-related AEs
•Clinical laboratory tests (hematology, chemistry, urinalysis; serum pregnancy test, if appropriate)
•Vital signs (temperature, systolic and diastolic blood pressure, heart rate, respiratory rate, weight and height assessments)
•Physical examination
•Concomitant treatment/medication usage
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| A Data Monitoring Committee (DMC) will review safety and study data at specified intervals for the duration of the study. |
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| E.5.2 | Secondary end point(s) |
The efficacy endpoints:
•Change from maralixibat baseline over the course of the study in the weekly average morning ItchRO(Obs)™ severity score
•Change from maralixibat baseline over the course of the study in the weekly average morning ItchRO(Obs)™ frequency score
•Change from maralixibat baseline over the course of the study in the Clinician Scratch Score
•Change from maralixibat baseline over the course of the study in sBA levels
•Time from maralixibat baseline to liver-associated events (PEBD surgery, listing for liver transplantation, liver decompensation [hepatic encephalopathy, variceal bleeding, ascites, and spontaneous bacterial peritonitis] events, HCC, death from a liver associated event).
•Comparison between treatment responders (defined as sBA normalization/≥ 70% CFMB (change from maralixibat baseline) AND ≥ 1.0 CFMB ItchRO(Obs)™) and partial/non-responder (PFIC)
•Comparison between treatment responders (defined as sBA ≥ 50% CFMB (change from maralixibat baseline) AND ≥1.0 CFMB ItchRO(Obs)™) and partial/non-responder (ALGS)
•Proportion of days at or below 1.0 point on the weekly morning ItchRO(Obs)™ severity score
•Durability of treatment response
•Change from maralixibat baseline in height and weight Z-score over the course of the study
•Change from maralixibat baseline in xanthomas over the course of the study, as measured by the Clinician Xanthoma Scale (ALGS)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All such analyses will be interpreted cautiously and not used for formal inference, although inferential statistics may be used as part of the data summary. |
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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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of life measurement |
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| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Poland |
| Spain |
| 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
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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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