| 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. |
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| 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. |
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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 | LLT |
| E.1.2 | Classification code | 10004653 |
| E.1.2 | Term | Biliary atresia |
| E.1.2 | System Organ Class | 100000004850 |
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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 |
| •To evaluate the efficacy of maralixibat on biliary drainage after hepatoportoenterostomy (HPE) in participants with BA |
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| E.2.2 | Secondary objectives of the trial |
•To evaluate changes in total serum bile acid (sBA) levels with maralixibat treatment
•To evaluate the rate of bilirubin normalization with maralixibat treatment
•To evaluate native liver survival with maralixibat treatment
•To evaluate biochemical markers of cholestasis and liver disease with maralixibat treatment
•To evaluate the safety, tolerability, and pharmacokinetics of maralixibat
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| 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 (IRB/EC)
2.Male or female participants with a body weight ≥2500 g who are ≥21 days old and <90 days old at the time of HPE or Kasai procedure
3.Post-conception age ≥36 weeks at birth
4.HPE or Kasai Procedure within 3 weeks prior to randomization
5.≥31 days old at start of study treatment
6.Clinical diagnosis of BA at laparotomy (with subsequent confirmation on histology of the biliary remnant)
7.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
8. 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.HPE performed by laparoscopy
4.Not tolerating full 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 ileal bile acid transporter inhibitor, an ASBT inhibitor, N-acetyl cysteine, or immunoglobulins
12.Receipt of investigational drug, biologic, or medical device within 30 days or 5 half-lives (whichever is longer) prior to screening
13.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
14.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 the participant participating in or completing the study
15.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 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
• Mean change in total bilirubin levels from baseline to Week 26 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis on the primary efficacy endpoint will be conducted over the primary cohort in the ITT population. A restricted maximum likelihood (REML)-based mixed-effects model for repeated measures (MMRM) will be used as the primary analysis method. The repeated measures include post-baseline visits during the double-blind phase up through Week 26, with the change from baseline in total bilirubin as the dependent variable. The treatment group-by-visit interaction will be tested for inclusion in the model before finalizing it. If the interaction term is positive (p < 0.10), the effect size will be considered to depend on visit and marginal analyses by visit will be presented. Otherwise, the primary test will be conducted using the main effects model. |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
•Mean change from baseline in total preprandial sBA to Week 26
•Proportion of subjects with total bilirubin levels <2 mg/dL to Week 26
•Time to liver transplantation or death to Week 26
•Mean change from baseline in laboratory parameters, including ALT, γ-glutamyltransferase (GGT), platelets, and to Week 26
Exploratory Efficacy Endpoints:
•Time to clinical event, including liver transplantation, liver decompensation (hepatic encephalopathy, variceal bleeding, new persistent ascites) and death
•Time to liver-associated events (liver decompensation [hepatic encephalopathy, variceal bleeding], liver-related death)
•Proportion of subjects with total bilirubin levels <1 mg/dL, 1–2 mg/dL, 2–6 mg/dL or >6 mg/dL up to Week 26
•Mean change in total bilirubin levels from baseline to Week 26 by total bilirubin levels at Week 13 (<2 mg/dL, 2–6 mg/dL, and >6 mg/dL)
•Proportion of subjects with total bilirubin levels <2 mg/dL at Week 26 by total bilirubin levels at Week 13 (<2 mg/dL, 2–6 mg/dL, and >6 mg/dL)
•Time to liver transplantation or death by total bilirubin levels at Week 13 (<2 mg/dL, 2–6 mg/dL, and >6 mg/dL)
•Relationship between stool color at screening and difference between maralixibat and placebo groups in mean change from baseline in total bilirubin levels at Week 26
•Markers of liver fibrosis (serum matrix metalloproteinase-7 [if blood volumes allow]; FIB-4, APRI, elastography [where available]) up to Week 26
•Mean change from baseline in 7α-hydroxy-4-cholesten-3-one (C4) and PELD score (if blood volume allows) up to Week 26
•Mean change in growth parameters (height, weight, mid-arm circumference [z-scores]) over time during the study period
•Mean change in health-related quality of life as assessed by Pediatric Quality of Life Inventory (PedsQL) over time during the study period
•Impact of maralixibat treatment on healthcare utilization (incidence of BA-related hospitalization, total inpatient days, selected surgical procedures, emergency room visits, etc.) over time during the study period
•Incidence of diagnosed cholangitis during the study period
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| 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. |
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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 | 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 | Yes |
| 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
| 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 |
| Canada |
| France |
| Germany |
| Italy |
| Poland |
| 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 | 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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