A Placebo-controlled Study of Maralixibat (SHP625) in Pediatric Subjects With Progressive Familial Intrahepatic Cholestasis (PFIC)

Progressive Familial Intrahepatic Cholestasis (PFIC) Clinical Trial

Official title:

Randomized Double-blind Placebo-controlled Phase 3 Study to Evaluate the Efficacy and Safety of Maralixibat (SHP625) in the Treatment of Pediatric Subjects With Progressive Familial Intrahepatic Cholestasis (PFIC)

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03353454
• Other study ID #: SHP625-306
• Secondary ID: 2017-003138-99
• Status: Withdrawn
• Phase: Phase 3
• Start date: October 25, 2018
• Est. completion date: June 15, 2020

Study information

• Verified date: March 2019
• Source: Mirum Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: June 15, 2020
• Est. primary completion date: June 15, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

Key Inclusion Criteria:

• Informed consent and assent (as applicable for participants less than or equal to (<=) 18 years per Institutional Review Board/Ethics Committee (IRB)/Ethics Committee (EC) as appropriate.

• Male or female participants between the ages of 12 months and 18 years inclusive (primary cohort) or birth to 18 years inclusive (exploratory cohort) at time of consent, with a body weight greater than or equal to (>=) 5 kilogram (kg).

• Cholestasis as manifested by total sBA greater than (>) 3*upper limit of normal (ULN)

• An average AM ItchRO(Obs) score >= 1.5 during the 4 weeks leading to the baseline visit

• Diagnosis of PFIC based on:

a. Primary cohort: i. Participants with 2 documented mutant alleles in ABCB11 (PFIC2); participants without bile salt export pump (BSEP) function (biallelic truncating mutations in ABCB11) will not be enrolled into the primary cohort. b. Exploratory cohort: i. Participants with PFIC1/3/4 or PFIC2 with biallelic truncating mutationsiii.Infants from birth to <12 months of age with PFIC ii. Participants with PFIC after internal or external (eg, PEBD) biliary diversion surgery with unsatisfactory pruritus control or where biliary diversion was reversed.

Key Exclusion Criteria:

• Chronic diarrhea requiring intravenous fluid or nutritional intervention for the diarrhea and/or its sequelae.

• History of surgical disruption of the enterohepatic circulation (applies to primary cohort only).

• Liver transplant

• Decompensated cirrhosis (international normalized ratio [INR] >1.5, albumin <30 gram per liter [g/L], history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy).

• ALT >15*ULN at screening.

• History or presence of other liver disease.

• 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 (example [eg], inflammatory bowel disease), per investigator discretion.

• Liver mass on imaging

• Known diagnosis of human immunodeficiency virus (HIV) infection.

• Any prior cancer diagnosis except for in situ carcinoma or cancers treated within 5 years of the screening visit (Visit 0) with no evidence of recurrence.

Related Conditions & MeSH terms

• Cholestasis
• Cholestasis, Intrahepatic
• Progressive Familial Intrahepatic Cholestasis (PFIC)

Intervention

Drug:
• Maralixibat
Maralixibat oral solution (up to 600 mcg/kg) orally twice daily for 26 weeks.
• Placebo
Placebo matching to maralixibat orally twice daily for 26 weeks.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Mirum Pharmaceuticals, Inc.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Treatment Response as Measured by the Observer Itch Reported Outcome (ItchRO[Obs])	Compare the percentage of participants on active treatment versus (vs.) placebo who meet response criteria which is defined as improvement in before midday (AM) Observer Itch Reported Outcome (ItchRO[Obs]) severity decrease from baseline demonstrated on at least 2 of the last 3 study visits.	Baseline up to Week 26
Secondary	Treatment Response as Measured by the Observer Itch Reported Outcome (ItchRO[Obs]) and Serum Bile Acids (sBA)	Compare the percentage of participants on active treatment versus (vs.) placebo who meet response criteria which is defined as improvement in average before midday (AM) Observer Itch Reported Outcome (ItchRO[Obs]) severity decrease from baseline and normalization or reduction from baseline sBA demonstrated on at least 2 of the last 3 study visits.	Baseline up to Week 26
Secondary	Normalization or Reduction From Baseline in Serum Bile Acids (sBA)	Compare the percentage of participants on active treatment vs. placebo with normalization or significant reduction from baseline in sBA.	Baseline up to Week 26
Secondary	Change Over Time in Daily Average Itch Reported Outcome (ItchRO[Obs]) Score	Change over time in daily average ItchRO scores will be reported.	Baseline up to Week 26
Secondary	Change Over Time in Before Midday (AM) Itch Reported Outcome (ItchRO[Obs]) Score	Change over time in AM ItchRO scores will be reported.	Baseline up to Week 26
Secondary	Change Over Time in After Midday (PM) Itch Reported Outcome (ItchRO[Obs]) Score	Change over time in PM ItchRO scores will be reported.	Baseline up to Week 26
Secondary	Disappearance of Pruritus as Measured by Observer Itch Reported Outcome (ItchRO[Obs])	Compare the percentage of participants on active treatment vs. placebo of participants who experience disappearance of pruritus as measured by ItchRO(Obs).	Baseline up to Week 26
Secondary	Improvement in Height	Number of participants on active treatment vs. placebo with a height z-score change from baseline >0.	Baseline up to Week 26
Secondary	Improvement in Weight	Number of participants on active treatment vs. placebo with a weight z-score change from baseline >0.	Baseline up to Week 26
Secondary	Change From Baseline in Nutritional Status as Measured by Mid-arm Circumference	Compare the change in nutritional status as measured by mid-arm circumference in participants on active treatment vs. placebo.	Baseline, Week 26
Secondary	Change From Baseline in Nutritional Status as Measured by Triceps Skin Fold	Compare the change in nutritional status as measured by triceps skin fold in participants on active treatment vs. placebo.	Baseline, Week 26
Secondary	Change From Baseline in Clinician Scratch Scale (CSS)	Compare the change in Clinician Scratch Scale score in participants on active treatment vs. placebo.	Baseline, Week 26
Secondary	Change From Baseline in Quality of Life as Measured by Pediatric Quality of Life Inventory (PedsQL)	Compare the change from baseline of PedsQL in participants on active treatment vs. placebo.	Baseline, Week 26
Secondary	Change From Baseline in Quality of Sleep as Measured by Children's Sleep Habits Questionnaire (CSHQ)	Compare the change from baseline of CSHQ in participants on active treatment vs. placebo.	Baseline, Week 26
Secondary	Normalization or Meaningful Reduction From Baseline of Alanine Aminotransferase (ALT)	Number of participants whose ALT normalizes on treatment or has decreased >=50%.	Baseline up to Week 26
Secondary	Normalization or Meaningful Decrease From Baseline of Total Bilirubin	Number of participants whose total bilirubin normalizes on treatment or has decreased >=50%.	Baseline up to Week 26
Secondary	Change From Baseline in Biomarkers of Bile Acid Synthesis	Change from baseline in biomarkers of bile acid synthesis (serum 7 alpha-hydroxy-4-cholesten-3-one [C4]).	Baseline, Week 26
Secondary	Evaluate the safety of SHP625	Adverse events, changes in vital signs, laboratory, and other safety parameters will be compared between participants on active treatment vs. placebo.	Baseline up to Week 26
Secondary	Plasma Levels of Maralixibat Over Time	Systemic concentrations of maralixibat in plasma will be assessed.	Baseline, Week 6, 10, 14, 18, 22 and 26