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

Phase 3

Completed

Conditions: Progressive Familial Intrahepatic Cholestasis (PFIC)

Interventions: Drug: Maralixibat
Other: Placebo

Registration Number: NCT03905330

Lead Sponsor: Mirum Pharmaceuticals, Inc.

Brief Summary: 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).

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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 93

Inclusion Criteria

Informed consent and assent (as applicable) per Institutional Review Board/Ethics Committee (IRB/EC)
Male or female subjects with a body weight ≥5 kg, who are ≥12 months and <18 years of age at time of baseline
Cholestasis as manifested by total sBA ≥3× ULN (applies to primary cohort only)
An average AM ItchRO(Obs) score ≥1.5 during 4 consecutive weeks of the screening period, leading to the baseline visit (Visit 1)
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)
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.
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
Access to email or phone for scheduled remote visits
Ability to read and understand the questionnaires (both caregivers and subjects above the age of assent)
Access to consistent caregiver(s) during the study
Subject and caregiver willingness to comply with all study visits and requirements.

Exclusion Criteria

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Maralixibat	Maralixibat	Participants will receive Maralixibat oral solution (up to 600 microgram per kilogram \[mcg/kg\]) orally twice daily for 26 weeks.
Placebo	Placebo	Participants will receive placebo matched to maralixibat oral solution twice daily for 26 weeks.

Primary Outcome Measures

Name	Time	Method
Mean Change in the Average Morning ItchRO(Obs) Severity Score in the Primary Cohort	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.	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.

Secondary Outcome Measures

Name	Time	Method
Mean Change in Total sBA Level in the Primary Cohort.	Baseline and average of Weeks 18, 22 and 26	Mean change in total sBA level between 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)	Between Baseline and Week 15 through Week 26	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.
Mean Change in Total sBA Level in Participants With PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)	Between Baseline and average of Weeks 18, 22 and 26	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)
Proportion of ItchRO(Obs) Responders in the Primary Cohort	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 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.
Proportion of sBA Responders in the Primary Cohort	Average value from Weeks 18, 22 and 26	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.
Proportion of ItchRO(Obs) Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)	From Week 15 to Week 26	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.
Proportion of sBA Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)	Week 18 to Week 26	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.

Trial Locations

Locations (31): Medizinische Hochschule Hannover
🇩🇪
Hanover, Germany
Cincinnati Children's Hospital
🇺🇸
Cincinnati, Ohio, United States
Hospices Civils de Lyon - Hopital Femme Mere Enfant Service de Gastroenterologie, Hepatologie et Nutrition
🇫🇷
Lyon, France
CHU de Toulouse - Hôpital des Enfants
🇫🇷
Toulouse, France
Instytut Pomnik Centrum Zdrowia Dziecka
🇵🇱
Warsaw, Poland
Semmelweis Egyetem - Altalanos Orvostudomanyi Kar (SE AOK)
🇭🇺
Budapest, Hungary
Koc University Hospital
🇹🇷
Istanbul, Turkey
Birmingham Children's Hospital
🇬🇧
Birmingham, United Kingdom
University of Alberta - Women and Children's Health Research Institute
🇨🇦
Edmonton, Canada
KK Women's and Children's Hospital
🇸🇬
Singapore, Singapore
CHU de Marseille, Hôpital de la Timone
🇫🇷
Marseille, France
Fundacion Cardioinfantil - Departamento de Investigaciones
🇨🇴
Bogotá, Colombia
Hospital Papa Giovanni XXIII / Unità di Pediatria
🇮🇹
Bergamo, Italy
Children's Hospital Los Angeles CHLA
🇺🇸
Los Angeles, California, United States
Medizinische Universität Wien, Universitätsklinik für Kinder- und Jugendheilkunde
🇦🇹
Wien, Austria
Universite Catholique de Louvain (UCLouvain) - Cliniques Universitaires Saint-Luc
🇧🇪
Bruxelles, Belgium
Advent Health
🇺🇸
Orlando, Florida, United States
Medstar Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
The Children's Hospital at Montefiore Yeshiva University - Montefiore Medical Center
🇺🇸
New York, New York, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
University of Texas - UT Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
Cleveland Clinic - Pediatric Institute
🇺🇸
Cleveland, Ohio, United States
Sociedade Beneficente de Senhoras Hospital Sírio-Libanês
🇧🇷
São Paulo, Brazil
Hospital Italiano de Buenos Aires
🇦🇷
Buenos Aires, Argentina
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
University of Texas, Health Science Center San Antonio
🇺🇸
San Antonio, Texas, United States
UPMC Children's Hospital of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
Consultario de Joshue David Covarrubias Esquer
🇲🇽
Zapopan, Mexico
Hotel Dieu de France
🇱🇧
Beirut, Lebanon
Ospedale Pediatrico Bambino Gesu
🇮🇹
Roma, Italy
King's College Hospital NHS
🇬🇧
London, United Kingdom