Clinical trial NCT03905330: A Study to Evaluate the Efficacy and Safety of Maralixibat in Subjects With Progressive Familial Intrahepatic Cholestasis (MARCH-PFIC)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Progressive Familial Intrahepatic Cholestasis (PFIC)
Keywords: Cholestasis
Maralixibat
Mutation
PFIC
PFIC2
Bile Duct Diseases
Liver Diseases
Biliary Tract Diseases
Digestive System Diseases
Pediatric
Lead sponsor: Mirum Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2019-04-05
Enrollment: 93
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Mean Change in the Average Morning ItchRO(Obs) Severity Score in the Primary Cohort
timeFrame: 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 outcomes:
measure: Mean Change in Total sBA Level in the Primary Cohort.
timeFrame: Baseline and average of Weeks 18, 22 and 26
measure: Mean Change in the Average Morning ItchRO(Obs) Severity Score in Participants With PFIC (PFIC1, Nt-PFIC2, PFIC3, PFIC4 and PFIC6)
timeFrame: Between Baseline and Week 15 through Week 26
measure: Mean Change in Total sBA Level in Participants With PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)
timeFrame: Between Baseline and average of Weeks 18, 22 and 26
measure: Proportion of ItchRO(Obs) Responders in the Primary Cohort
timeFrame: Week 15 to Week 26 using the average value from the three 4-week periods (Weeks 15-18, 19-22 and 23-26)
measure: Proportion of sBA Responders in the Primary Cohort
timeFrame: Average value from Weeks 18, 22 and 26
measure: Proportion of ItchRO(Obs) Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)
timeFrame: From Week 15 to Week 26
measure: Proportion of sBA Responders PFIC (PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6)
timeFrame: Week 18 to Week 26
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles CHLA
state: California
city: Washington
country: United States
facility: Medstar Georgetown University Hospital
state: District of Columbia
city: Orlando
country: United States
facility: Advent Health
state: Florida
city: New York
country: United States
facility: The Children's Hospital at Montefiore Yeshiva University - Montefiore Medical Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic - Pediatric Institute
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: University of Texas - UT Southwestern Medical Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas, Health Science Center San Antonio
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Wien
country: Austria
facility: Medizinische Universität Wien, Universitätsklinik für Kinder- und Jugendheilkunde
city: Bruxelles
country: Belgium
facility: Universite Catholique de Louvain (UCLouvain) - Cliniques Universitaires Saint-Luc
city: São Paulo
country: Brazil
facility: Sociedade Beneficente de Senhoras Hospital Sírio-Libanês
city: Edmonton
country: Canada
facility: University of Alberta - Women and Children's Health Research Institute
city: Bogotá
country: Colombia
facility: Fundacion Cardioinfantil - Departamento de Investigaciones
city: Lyon
country: France
facility: Hospices Civils de Lyon - Hopital Femme Mere Enfant Service de Gastroenterologie, Hepatologie et Nutrition
city: Marseille
country: France
facility: CHU de Marseille, Hôpital de la Timone
city: Toulouse
country: France
facility: CHU de Toulouse - Hôpital des Enfants
city: Hanover
country: Germany
facility: Medizinische Hochschule Hannover
city: Budapest
country: Hungary
facility: Semmelweis Egyetem - Altalanos Orvostudomanyi Kar (SE AOK)
city: Bergamo
country: Italy
facility: Hospital Papa Giovanni XXIII / Unità di Pediatria
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesu
city: Beirut
country: Lebanon
facility: Hotel Dieu de France
city: Zapopan
country: Mexico
facility: Consultario de Joshue David Covarrubias Esquer
city: Warsaw
country: Poland
facility: Instytut Pomnik Centrum Zdrowia Dziecka
city: Singapore
country: Singapore
facility: KK Women's and Children's Hospital
city: Istanbul
country: Turkey
facility: Koc University Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: London
country: United Kingdom
facility: King's College Hospital NHS
Study officials:
References: