| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Biliary atresia (BA) is a rare, inflammatory condition of the biliary tree that presents in the first weeks of life and leads to bile duct obstruction and consequent liver injury, fibrosis and cirrhosis which lead to portal hypertension and a decline in hepatic synthetic function. Untreated, the outcome of BA is uniformly fatal. The 2 most important improvements in the care of BA patients to date are the Kasai hepatoportoenterostomy (HPE; Kasai procedure) and orthotopic liver transplantation. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Biliary atresia (BA) is a rare disease of newborn children, which leads to bile duct obstruction and consequent liver injury. |
|
| 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 | LLT |
| E.1.2 | Classification code | 10004653 |
| E.1.2 | Term | Biliary atresia |
| E.1.2 | System Organ Class | 100000004850 |
|
| 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 efficacy of maralixibat on biliary drainage after hepatoportoenterostomy (HPE) in participants with BA |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives and Endpoints of the Double-Blind Period-
• To evaluate the rate of clinically relevant reductions in cholestatic
biomarkers with maralixibat treatment.
• To evaluate the rate of liver-related clinical events.
• To evaluate the safety, tolerability, and pharmacokinetics of
maralixibat.
Open-Label Extension Objectives and Endpoints-
• To assess all of the above primary and secondary objectives analyzed
over the full study duration, including the open-label extension period |
|
| 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/Independent Ethics Committee (EC)
2.Male or female participants with a body weight ≥2500 g (before or
during the
screening period) who are ≥21 days old and <90 days old at the time of HPE or Kasai procedure
3.Gestational age ≥36 weeks at birth (Those with gestational age <36 weeks with no present clinical or developmental preterm complications that could impact participation in the study may be included after evaluation and approval by the Medical Monitor).
4.HPE or Kasai Procedure within 3 weeks prior to randomization
5.Clinical diagnosis of BA at laparotomy (with subsequent confirmation on histology of the biliary remnant)
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 study medication per investigator training and written instructions
7. Caregiver access to email or phone for remote participant contacts |
|
| E.4 | Principal exclusion criteria |
1.Chronic diarrhea requiring ongoing IV fluid or nutritional intervention at screening, during the screening period, or during the 30 days prior to screening
2.History of surgical disruption of the enterohepatic circulation other than HPE
3.Has had any of the following: HPE performed by laparoscopy,
undergone a second HPE, or has undergone an exploratory bile duct
procedure
4.Not tolerating enteral feeds at screening or during the screening period
5.Evidence of another pathology involving the intrahepatic bile ducts (e.g., paucity, sclerosing cholangitis)
6.Diagnosis of polysplenia syndrome, including evidence of BA splenic malformation syndrome, or major malformation of another organ system
7.Diagnosis of cystic BA (based on clinician judgment, including but not limited to ultrasonography and cholangiography results)
8.Decompensated cirrhosis (international normalized ratio [INR] >1.5 after correction of possible vitamin K deficiency, history or presence of clinically significant ascites, known varices, variceal hemorrhage, and/or encephalopathy)
9.Previous or imminent need for liver transplantation
10.Known hypersensitivity to maralixibat or any of its excipients
11.Previous use of an IBAT inhibitor, N-acetyl cysteine,
immunoglobulins, or traditional or herbal medicine remedies that are
used to treat liver diseases or with a safety profile known to impact liver
parameters
12.Receipt of investigational drug, biologic, or medical device within 30 days or 5 half-lives (whichever is longer) prior to screening
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 caregiver history of unreliability, 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 participant, or lead to nonadherence with the study protocol or inability to conduct the study procedures
15.Presence of other significant liver disease or any other conditions or abnormalities which, in the opinion of the investigator or sponsor medical monitor, may compromise the safety of the participant or interfere with participation in or completion of the study (prior or
current cytomegalovirus infection is allowed)
16.History or 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
• Mean change in total serum bilirubin levels from baseline through Week 26 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| - From baseline through Week 26 |
|
| E.5.2 | Secondary end point(s) |
Secondary Objectives and Endpoints of the Double-Blind Period-
• Proportion of participants with total serum bilirubin levels <2 mg/dL
at Week 26
• Mean change in total sBA levels from baseline through Week 26
• Proportion of participants with sBA levels ≤40 mmol/L at Week 26
• Proportion of participants with total serum bilirubin levels ≤1.2 mg/dL
at Week 26
• Proportion of participants observed to have a liver-related clinical
event, including liver transplantation, liver decompensation (hepatic
encephalopathy, variceal bleeding, new persistent ascites) or death
through Week 26
• Proportion of participants undergoing liver transplantation or death
through Week 26
• Proportion of participants observed to develop clinically evident portal
hypertension defined as splenomegaly (spleen size >2 cm below the
costal margin palpated on physical examination) and thrombocytopenia
(platelet count <150 x 109/L) or clinically evident ascites or endoscopic
evidence of esophageal or gastric varices through Week 26
• Incidence of treatment-emergent adverse events (TEAEs), including
serious, related to study medication, leading to withdrawal, special
interest TEAEs, along with TEAEs by severity and by relationship to study
medication
• Change from baseline in safety laboratory, physical examination
findings, vital signs, neurodevelopmental assessment, and maralixibat
PK profile.
Open-Label Extension Objectives and Endpoints-
• All of the above primary and secondary endpoints but for study data
through Week 104 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Double-Blind Period
- Week 26
Open-label extension period
- Week 104 |
|
| 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 | 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 | 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 | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 |
| Singapore |
| Hong Kong |
| Taiwan |
| China |
| Mexico |
| United Kingdom |
| United States |
| Viet Nam |
| France |
| Germany |
| Italy |
| Poland |
|
| 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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