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

NCT03905330 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: MRX-5022019-001211-22
• Study Type: interventional
• Target: 93
• Locations: 17 countries
• Sites: 31

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).

Conditions

Progressive Familial Intrahepatic Cholestasis (PFIC)

Keywords

Cholestasis; Maralixibat; Mutation; PFIC; PFIC2; Bile Duct Diseases; Liver Diseases; Biliary Tract Diseases; Digestive System Diseases; Pediatric

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Mean Change in Total sBA Level in the Primary Cohort.

  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 Total sBA Level 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

  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

  Average value from Weeks 18, 22 and 26

Study Arms (2)

Maralixibat

EXPERIMENTAL

Participants will receive Maralixibat oral solution (up to 600 microgram per kilogram \[mcg/kg\]) orally twice daily for 26 weeks.

Drug: Maralixibat

Placebo

PLACEBO COMPARATOR

Participants will receive placebo matched to maralixibat oral solution twice daily for 26 weeks.

Other: Placebo

Interventions

Maralixibat DRUG

Maralixibat oral solution (up to 600 mcg/kg) orally twice daily for 26 weeks.

Also known as: Formerly LUM001 and SHP625

Maralixibat

Placebo OTHER

Placebo matching to maralixibat orally twice daily for 26 weeks.

Placebo

Eligibility Criteria

• Age: 1 Year - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Mirum Pharmaceuticals, Inc.: lead

Study Sites (31)

Children's Hospital Los Angeles CHLA

Los Angeles, California, 90027, United States

Location

Medstar Georgetown University Hospital

Washington D.C., District of Columbia, 20007-2113, United States

Location

Advent Health

Orlando, Florida, 32803, United States

Location

The Children's Hospital at Montefiore Yeshiva University - Montefiore Medical Center

New York, New York, 10461, United States

Location

Cincinnati Children's Hospital

Cincinnati, Ohio, 45229, United States

Location

Cleveland Clinic - Pediatric Institute

Cleveland, Ohio, 44195, United States

Location

UPMC Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15224, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

University of Texas - UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

University of Texas, Health Science Center San Antonio

San Antonio, Texas, 78229, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Hospital Italiano de Buenos Aires

Buenos Aires, Argentina

Location

Medizinische Universität Wien, Universitätsklinik für Kinder- und Jugendheilkunde

Vienna, Austria

Location

Universite Catholique de Louvain (UCLouvain) - Cliniques Universitaires Saint-Luc

Brussels, Belgium

Location

Sociedade Beneficente de Senhoras Hospital Sírio-Libanês

São Paulo, Brazil

Location

University of Alberta - Women and Children's Health Research Institute

Edmonton, Canada

Location

Fundacion Cardioinfantil - Departamento de Investigaciones

Bogotá, Colombia

Location

Hospices Civils de Lyon - Hopital Femme Mere Enfant Service de Gastroenterologie, Hepatologie et Nutrition

Lyon, France

Location

CHU de Marseille, Hôpital de la Timone

Marseille, France

Location

CHU de Toulouse - Hôpital des Enfants

Toulouse, 31059, France

Location

Medizinische Hochschule Hannover

Hanover, Germany

Location

Semmelweis Egyetem - Altalanos Orvostudomanyi Kar (SE AOK)

Budapest, 1083, Hungary

Location

Hospital Papa Giovanni XXIII / Unità di Pediatria

Bergamo, Italy

Location

Ospedale Pediatrico Bambino Gesu

Roma, Italy

Location

Hotel Dieu de France

Beirut, Lebanon

Location

Consultario de Joshue David Covarrubias Esquer

Zapopan, Mexico

Location

Instytut Pomnik Centrum Zdrowia Dziecka

Warsaw, Poland

Location

KK Women's and Children's Hospital

Singapore, Singapore

Location

Koc University Hospital

Istanbul, Turkey (Türkiye)

Location

Birmingham Children's Hospital

Birmingham, United Kingdom

Location

King's College Hospital NHS

London, United Kingdom

Location

Related Publications (1)

• Miethke AG, Moukarzel A, Porta G, Covarrubias Esquer J, Czubkowski P, Ordonez F, Mosca A, Aqul AA, Squires RH, Sokal E, D'Agostino D, Baumann U, D'Antiga L, Kasi N, Laborde N, Arikan C, Lin CH, Gilmour S, Mittal N, Chiou FK, Horslen SP, Huber WD, Jaecklin T, Nunes T, Lascau A, Longpre L, Mogul DB, Garner W, Vig P, Hupertz VF, Gonzalez-Peralta RP, Ekong U, Hartley J, Laverdure N, Ovchinsky N, Thompson RJ. Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2024 Jul;9(7):620-631. doi: 10.1016/S2468-1253(24)00080-3. Epub 2024 May 6.

  PMID: 38723644 DERIVED

Related Links

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

MeSH Terms

Conditions

Cholestasis, progressive familial intrahepatic 1; Cholestasis; Bile Duct Diseases; Liver Diseases; Biliary Tract Diseases; Digestive System Diseases

Interventions

maralixibat

Results Point of Contact

• Title: Mirum Clinical Trials
• Organization: Mirum Pharmaceuticals

medinfo@mirumpharma.com

650-667-4085

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 1, 2019
• First Posted: April 5, 2019
• Study Start: July 9, 2019
• Primary Completion: September 1, 2022
• Study Completion: September 1, 2022
• Last Updated: December 11, 2023
• Results First Posted: December 11, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

CO (1); SG (1); BR (1); GB (2); AR (1); IT (2); LE (1); AU (1); HU (1); ME (1); PL (1); CA (1); US (11); BE (1); FR (3); DE (1); TU (1)