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Note: This record shows only 22 elements of the WHO Trial Registration Data Set. To view changes that have been made to the source record, or for additional information about this trial, click on the URL below to go to the source record in the primary register.
Register: EUCTR
Last refreshed on: 26 October 2020
Main ID:  EUCTR2020-000974-22-GB
Date of registration: 21/10/2020
Prospective Registration: Yes
Primary sponsor: Mirum Pharmaceuticals Inc.
Public title: Clinical study to evaluate the Efficacy and Safety of Maralixibat used in treatment of Biliary Atresia subjects after Hepatoportoenterostomy
Scientific title: Randomized, Double-blind, Placebo-Controlled Phase 2 Study to Evaluate the Efficacy and Safety of Maralixibat in the Treatment of Subjects with Biliary Atresia after Hepatoportoenterostomy - EMBARK: Evaluation of Maralixibat in Biliary Atresia Response post Kasai
Date of first enrolment:
Target sample size: 72
Recruitment status: NA
URL:  https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-000974-22
Study type:  Interventional clinical trial of medicinal product
Study design:  Controlled: yes
Randomised: yes
Open: no
Single blind: no
Double blind: yes
Parallel group: no
Cross over: no
Other: no
If controlled, specify comparator, Other Medicinial Product: no
Placebo: yes
Other: no
Number of treatment arms in the trial: 2
 
Phase:  Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no
Countries of recruitment
Canada France Germany Italy Poland United Kingdom United States
Contacts
Name: Chief Development Officer   
Address:  950 Tower Lane, Suite 1050 CA 94404 Foster City California United States
Telephone: 16506674085
Email: medinfo@mirumpharma.com
Affiliation:  Mirum Pharmaceuticals, Inc.
Name: Chief Development Officer   
Address:  950 Tower Lane, Suite 1050 CA 94404 Foster City California United States
Telephone: 16506674085
Email: medinfo@mirumpharma.com
Affiliation:  Mirum Pharmaceuticals, Inc.
Key inclusion & exclusion criteria
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
Are the trial subjects under 18? yes
Number of subjects for this age range: 72
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes
Health Condition(s) or Problem(s) studied
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.
MedDRA version: 20.0 Level: LLT Classification code 10004653 Term: Biliary atresia System Organ Class: 100000004850
Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
Intervention(s)

Product Name: Maralixibat
Pharmaceutical Form: Oral solution
INN or Proposed INN: MARALIXIBAT CHLORIDE
CAS Number: 228113-66-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Oral solution
Route of administration of the placebo: Oral use

Product Name: Maralixibat
Pharmaceutical Form: Oral solution
INN or Proposed INN: MARALIXIBAT CHLORIDE
CAS Number: 228113-66-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Oral solution
Route of administration of the placebo: Oral use

Product Name: Maralixibat
Pharmaceutical Form: Oral solution
INN or Proposed INN: MARALIXIBAT CHLORIDE
CAS Number: 228113-66-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 15-
Pharmaceutical form of the placebo: Oral solution
Route of administration of the placebo: Oral use

Product Name: Maralixibat
Pharmaceutical Form: Oral solution
INN or Proposed INN: MARALIXIBAT CHLORIDE
CAS Number: 228113-66-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Oral solution
Route of administration of the placebo: Oral use

Primary Outcome(s)
Main Objective: •To evaluate the efficacy of maralixibat on biliary drainage after hepatoportoenterostomy (HPE) in participants with BA
Primary end point(s): Primary Efficacy Endpoint:
• Mean change in total bilirubin levels from baseline to Week 26
Secondary Objective: •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
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.
Secondary Outcome(s)
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, ?-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 7a-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
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.
Secondary ID(s)
MRX-701
NCT04524390
Source(s) of Monetary Support
Mirum Pharmaceuticals, Inc.
Secondary Sponsor(s)
Ethics review
Status:
Approval date:
Contact:
Results
Results available:
Date Posted:
Date Completed:
URL:
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