| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Progressive Familial Intrahepatic Cholestasis and Alagille Syndrome |
|
| E.1.1.1 | Medical condition in easily understood language |
| Liver disorder Progressive Familial Intrahepatic Cholestasis and Alagille Syndrome |
|
| 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.1.2 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 |
|
| 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 evaluate the safety and tolerability of maralixibat in infant participants with ALGS or PFIC. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the treatment effect of maralixibat on serum bile acid (sBA) levels
• To evaluate the effect on liver enzymes (ALT, AST) and bilirubin
• To evaluate the effect on lipid-soluble vitamins
• To evaluate the pharmacokinetics of maralixibat in infant participants |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed consent (by the legally authorized representative) per the Institutional Review Board/Ethics Committee
2. Body weight of ≥2.5 kg
3. <12 months of age at the baseline visit (At least 3 participants in each cohort must be <9 months of age at the baseline visit)
4. Gestational age ≥36 weeks at birth. For children born with gestational age between 32 and 36 weeks, a postmenstrual age of ≥36 weeks is required. Postmenstrual age is defined as the time elapsed between the first day of the last menstrual period and birth plus the time elapsed after birth.
5. Diagnosis of PFIC or ALGS based on the following:
PFIC: Participants with genetic testing results consistent with at least 1 disease-causing mutation associated with PFIC alongside clinical or biochemical evidence of cholestasis (as defined below).
ALGS: Participants meeting the ALGS diagnostic criteria outlined in the protocol alongside clinical or biochemical evidence of cholestasis as defined below) Evidence of cholestasis (one or more of the following):
•Total BA>2× ULN for age
•Conjugated bilirubin >1 mg/dL
•LSV deficiency otherwise unexplainable
•Gamma-glutamyl transferase (GGT) > 3 × ULN for age
•Intractable pruritus explainable only by liver disease
6. Caregiver willingness to comply with all study visits and requirements, including ability to read and understand the questionnaires and, if applicable, capable of diluting maralixibat per investigator training and written instructions
7. Caregiver access to email or phone for remote participant contacts. |
|
| E.4 | Principal exclusion criteria |
1. Predicted complete absence of bile salt excretion pump (BSEP) function based on the type of ABCB11 mutation (PFIC2), as determined by a standard-of-care genotyping.
2. History of surgical disruption of the enterohepatic circulation.
3. Chronic diarrhea requiring ongoing intravenous fluid or nutritional intervention at screening, during the screening period, or during the 30 days prior to screening.
4. History of liver transplant or imminent need for liver transplant.
5. Decompensated cirrhosis (international normalized ratio >1.5 despite vitamin K supplementation, albumin <30 g/L, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy).
6. ALT or total serum bilirubin (TSB) > 15× the upper limit of normal at screening.
7. Presence of any other disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs, including bile salt metabolism in the intestine (e.g., inflammatory bowel disease), per investigator discretion.
8. Presence of other significant liver disease or any other conditions or abnormalities which, in the opinion of the investigator or medical monitor, may compromise the safety of the participant or interfere with the participant's participation in or completion of the study.
9. Liver mass on imaging, including screening ultrasound, suspected to be hepatocellular carcinoma.
10. Presence of clinical or developmental preterm complications that could impact safe participation in the study, as determined by the investigator after evaluation.
11. Receipt of investigational drug, biologic, or medical device within 30 days or 5 half-lives (whichever is longer) prior to screening.
12. Previous treatment with an IBAT inhibitor.
13.Treatment with other medications containing propylene glycol (PG) or alcohol or any substrate for alcohol dehydrogenase (e.g., ethanol; for participants <1 month of age only).
14. Known hypersensitivity to maralixibat or any of its excipients.
15. Known caregiver history of unreliability, mental instability, or cognitive impairment that, in the opinion of the investigator or medical monitor, could compromise the validity of informed consent, compromise the safety of the participant, or lead to nonadherence with the study protocol or inability to conduct the study procedures. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety (incidence of treatment-emergent adverse events [TEAEs], including those that are serious, are related to maralixibat, that lead to withdrawal, are of special interest, along with TEAEs by severity and
change from baseline in safety laboratory [including measurement of osmolality, osmolar gap and anion gap when clinically indicated] and physical examination findings, vital signs, and neurodevelopmental
assessment) and tolerability. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout this study, the safety of participants will be closely monitored by an independent data monitoring committee (DMC). The DMC will comprise three disease experts (including pediatric hepatologists) and a biostatistician and will be governed by a DMC Charter. A Data Monitoring Committee will review safety and study data at specified intervals for the duration of the study. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints:
• Change from baseline to Week 13 in fasting sBA levels
• Change from baseline to Week 13 in liver enzymes (serum ALT, AST) and TSB
• Change from baseline to Week 13 in vitamins A, D, E, and K
• Systemic maralixibat concentrations in plasma before dosing and 2.5 hours after the morning dose at specified time points
Exploratory endpoints:
• Change from baseline in morning Itch Reported Outcome Observer (ItchRO[Obs]) instrument severity score
• Change from baseline in evening ItchRO(Obs) severity score
• Change from baseline in daily ItchRO(Obs) severity score (defined as maximum of the morning and evening score on a given day)
• Change from baseline in Clinician Scratch Scale (CSS) score
• Changes from baseline in height and weight and in mid-upper-arm and head circumferences
• Number of hospitalizations; emergency ward visits; and the length of
stay for hospitalization, surgeries, and procedures related to the participant's disease type;
• Number of days the caregiver misses work. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary and exploratory efficacy endpoints will be displayed by study
visit, using summary statistics including the number of observations, the
mean, median, standard deviation, and range for continuous measures
and counts and percentages for categorical measures. Actual values as
well as change from baseline will be presented.
Supportive and exploratory efficacy measures will be analyzed similarly
as above. Details of the analysis methods will be outlined in the
statistical analysis plan (SAP).
In addition, a responder analysis (based on change in serum bile acid
levels and bilirubin) will also be considered. The response definition and
its appropriate analysis methodology will be outlined in the SAP for the
study. |
|
| 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) | 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 | Yes |
| 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 | 2 |
| 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 | 4 |
| 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 |
| Belgium |
| Brazil |
| France |
| Mexico |
| Poland |
| 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 | 2 |
| 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 | 2 |
| 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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