A Study to Evaluate the Efficacy and Safety of Maralixibat in Subjects With Progressive Familial Intrahepatic Cholestasis (MARCH-PFIC) (MARCH-PFIC)

MRX-502: Randomized Double-blind Placebo-controlled Phase 3 Study to Evaluate the Efficacy and Safety of Maralixibat in the Treatment of Subjects With Progressive Familial Intrahepatic Cholestasis (PFIC) - MARCH-PFIC

The purpose of this study is to determine whether the investigational treatment (maralixibat) is safe and effective in pediatric participants with Progressive Familial Intrahepatic Cholestasis (PFIC).

Study Overview

• Status: Completed
• Conditions: Progressive Familial Intrahepatic Cholestasis (PFIC)
• Intervention / Treatment: Drug: Maralixibat; Other: Placebo

Detailed Description

This study was conducted at multiple sites in North America, Europe, Asia and South America.

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital Italiano de Buenos Aires
• Austria
  • Wien, Austria
    • Medizinische Universität Wien, Universitätsklinik für Kinder- und Jugendheilkunde
• Belgium
  • Bruxelles, Belgium
    • Universite Catholique de Louvain (UCLouvain) - Cliniques Universitaires Saint-Luc
• Brazil
  • São Paulo, Brazil
    • Sociedade Beneficente de Senhoras Hospital Sirio-Libanes
• Canada
  • Edmonton, Canada
    • University of Alberta - Women and Children's Health Research Institute
• Colombia
  • Bogotá, Colombia
    • Fundacion Cardioinfantil - Departamento de Investigaciones
• France
  • Lyon, France
    • Hospices Civils de Lyon - Hopital Femme Mere Enfant Service de Gastroenterologie, Hepatologie et Nutrition
  • Marseille, France
    • CHU de Marseille, Hôpital de la Timone
  • Toulouse, France, 31059
    • CHU de Toulouse - Hôpital des Enfants
• Germany
  • Hanover, Germany
    • Medizinische Hochschule Hannover
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem - Altalanos Orvostudomanyi Kar (SE AOK)
• Italy
  • Bergamo, Italy
    • Hospital Papa Giovanni XXIII / Unità di Pediatria
  • Roma, Italy
    • Ospedale Pediatrico Bambino Gesù
• Lebanon
  • Beirut, Lebanon
    • Hotel Dieu de France
• Mexico
  • Zapopan, Mexico
    • Consultario de Joshue David Covarrubias Esquer
• Poland
  • Warsaw, Poland
    • Instytut Pomnik Centrum Zdrowia Dziecka
• Singapore
  • Singapore, Singapore
    • KK Women's and Children's Hospital
• Turkey
  • Istanbul, Turkey
    • Koc University Hospital
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Children's Hospital
  • London, United Kingdom
    • King's College Hospital NHS
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles CHLA
  • District of Columbia
    • Washington, District of Columbia, United States, 20007-2113
      • MedStar Georgetown University Hospital
  • Florida
    • Orlando, Florida, United States, 32803
      • Advent Health
  • New York
    • New York, New York, United States, 10461
      • The Children's Hospital at Montefiore Yeshiva University - Montefiore Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic - Pediatric Institute
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Hospital of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas - UT Southwestern Medical Center
    • San Antonio, Texas, United States, 78229
      • University of Texas, Health Science Center San Antonio
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 15 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Informed consent and assent (as applicable) per Institutional Review Board/Ethics Committee (IRB/EC)
2. Male or female subjects with a body weight ≥5 kg, who are ≥12 months and <18 years of age at time of baseline
3. Cholestasis as manifested by total sBA ≥3× ULN (applies to primary cohort only)
4. An average AM ItchRO(Obs) score ≥1.5 during 4 consecutive weeks of the screening period, leading to the baseline visit (Visit 1)
5. Completion of at least 21 valid* morning ItchRO(Obs) entries during 4 consecutive weeks of the screening period, leading to the baseline visit (Visit 1) (*valid = completed and not answered as "I don't know"; maximum allowed invalid reports = 7, no more than 2 invalid reports during the last 7 days before randomization)

6. Diagnosis of PFIC based on the following:

   • Chronic cholestasis as manifested by persistent (>6 months) pruritus in addition to biochemical abnormalities and/or pathological evidence of progressive liver disease and
   • Primary Cohort: Subjects with genetic testing results consistent with biallelic disease-causing variation in ABCB11 (PFIC2), based on standard of care genotyping
   • Supplemental Cohort: i. Subjects with genetic testing results consistent with biallelic disease-causing variation in ATP8B1 (PFIC1), ABCB4 (PFIC3), or TJP2 (PFIC4), based on standard of care genotyping. ii. Subjects with PFIC phenotype without a known mutation or with another known mutation not described above or with intermittent cholestasis as manifested by fluctuating sBA levels. iii. Subjects with PFIC after internal or external biliary diversion surgery or for whom internal or external biliary diversion surgery was reversed.
7. Male 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 methods of 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
8. Access to email or phone for scheduled remote visits
9. Ability to read and understand the questionnaires (both caregivers and subjects above the age of assent)
10. Access to consistent caregiver(s) during the study
11. Subject and caregiver willingness to comply with all study visits and requirements.

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 (applies to primary cohort only). Subjects can enter the study in the Supplemental Cohort (under inclusion criteria 6.ii or 6.iii).
2. Recurrent intrahepatic cholestasis, indicated by a history of sBA levels <3x ULN or intermittent pruritus (applies to primary cohort only)
3. Current or recent history (<1 year) of atopic dermatitis or other non-cholestatic diseases associated with pruritus.
4. History of surgical disruption of the enterohepatic circulation (applies to primary cohort only)
5. Chronic diarrhea requiring intravenous fluid or nutritional intervention for the diarrhea and/or its sequelae at screening or during the 6 months prior to screening
6. Previous or need for imminent liver transplant
7. Decompensated cirrhosis (international normalized ratio [INR] >1.5, albumin <30 g/L, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy)
8. ALT or total serum bilirubin (TSB) >15× ULN at screening
9. Presence of other liver disease
10. 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
11. Possibly malignant liver mass on imaging, including screening ultrasound
12. Known diagnosis of human immunodeficiency virus (HIV) infection
13. Any prior cancer diagnosis (except for in situ carcinoma) within 5 years of the screening visit (Visit 0)
14. Any known history of alcohol or substance abuse
15. Administration of bile acids or lipid binding resins, or phenylbutyrates during the screening period
16. Criterion has been deleted as of Amendment 3
17. Administration of any investigational drug, biologic, or medical device during the screening period
18. Previous use of an ileal bile acid transporter inhibitor (IBATi)
19. 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
20. Known hypersensitivity to maralixibat or any of its excipients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants will receive placebo matched to maralixibat oral solution twice daily for 26 weeks.	Other: Placebo; Placebo matching to maralixibat orally twice daily for 26 weeks.
Experimental: Maralixibat; Participants will receive Maralixibat oral solution (up to 600 microgram per kilogram [mcg/kg]) orally twice daily for 26 weeks.	Drug: Maralixibat; Maralixibat oral solution (up to 600 mcg/kg) orally twice daily for 26 weeks.; Other Names: Formerly LUM001 and SHP625

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in the Average Morning ItchRO(Obs) Severity Score in the Primary Cohort	The primary efficacy endpoint is the mean change in the average morning ItchRO(Obs) severity score between baseline and Weeks 15-26, using 4-week average morning ItchRO(Obs) severity scores (Mixed Model Repeated Measures). The baseline average morning ItchRO(Obs) severity score is defined as the 4-week average morning ItchRO(Obs) severity score prior to the first dose of the study medication. ItchRo(Obs) Severity Score = Itch Reported Outcome Observer assessment severity score; scale between 0 (not itchy at all) and 4 (extremely itchy); the lower the score the better.	MMRM model was used with inputs of the average changes from baseline (BL) to Weeks 1-6, 7-10, 11-14, 15-18, 19-22, 23-26, and other covariates. The average change from BL over Weeks 15-26 is calculated in the model and presented as a single number.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Total sBA Level in the Primary Cohort.	Mean change in total sBA level between baseline and average of Weeks 18, 22 and 26.	Baseline and average of Weeks 18, 22 and 26
Mean Change in the Average Morning ItchRO(Obs) Severity Score in Participants With PFIC (PFIC1, Nt-PFIC2, PFIC3, PFIC4 and PFIC6)	Mean change in the average morning ItchRO(Obs) severity score between baseline and Week 15 through Week 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6). ItchRo(Obs) Severity Score = Itch Reported Outcome Observer assessment severity score; scale between 0 (not itchy at all) and 4 (extremely itchy); the lower the score the better.	Between Baseline and Week 15 through Week 26
Mean Change in Total sBA Level in Participants With PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)	Mean change in total sBA level between baseline and average of Weeks 18, 22, and 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)	Between Baseline and average of Weeks 18, 22 and 26
Proportion of ItchRO(Obs) Responders in the Primary Cohort	Proportion of ItchRO(Obs) responders from Week 15 to Week 26 in participants with PFIC2 using the average value from the three 4-week periods (Weeks 15-18, 19-22 and 23-26). The number in the Subject Analysis Set refers to the number of responders. ItchRO responders are defined as a subject having a 4-week average morning ItchRO(Obs) severity change from baseline of ≤-1.0 or an average severity score of ≤1.0.	Week 15 to Week 26 using the average value from the three 4-week periods (Weeks 15-18, 19-22 and 23-26)
Proportion of sBA Responders in the Primary Cohort	Proportion of sBA responders from Week 18 to Week 26 in participants with PFIC2, using the average value from Weeks 18, 22 and 26 values. The number in the Subject Analysis Set refers to the number of responders. sBA responders are defined as a subject having an average sBA level of <102 umol/L (applies only if baseline sBA level was ≥102 umol/L), OR a ≤-75% average percent change from baseline.	Average value from Weeks 18, 22 and 26
Proportion of ItchRO(Obs) Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)	Proportion of ItchRO(Obs) responders from Week 15 to Week 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6). The number in the Subject Analysis Set refers to the number of responders. ItchRO responders are defined as a subject having a 4-week average morning ItchRO(Obs) severity change from baseline of ≤-1.0 OR an average severity score of ≤1.0.	From Week 15 to Week 26
Proportion of sBA Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)	Proportion of sBA responders from Week 18 to Week 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6). The number in the Subject Analysis Set refers to the number of responders. sBA responders are defined as a subject having an average sBA level of <102 umol/L (applies only if baseline sBA level was ≥102 umol/L), or a ≤-75% average percent change from baseline.	Week 18 to Week 26

Collaborators and Investigators

• Sponsor: Mirum Pharmaceuticals, Inc.

Publications and helpful links

Helpful Links

• Genetics Home Reference - PFIC
• US FDA Resources
• Mirum Pharmaceuticals homepage

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2019
• Primary Completion (Actual): September 1, 2022
• Study Completion (Actual): September 1, 2022

Study Registration Dates

• First Submitted: April 1, 2019
• First Submitted That Met QC Criteria: April 4, 2019
• First Posted (Actual): April 5, 2019

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Pediatric; Digestive System Diseases; Liver Diseases; Mutation; Cholestasis; Maralixibat; PFIC; PFIC2; Bile Duct Diseases; Biliary Tract Diseases
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis; Cholestasis, Intrahepatic
• Other Study ID Numbers: MRX-502; 2019-001211-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No