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

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Progressive Familial Intrahepatic Cholestasis (PFIC)

Intervention / Treatment
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* Drug: Maralixibat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maralixibat (SHP625)<br>Participants will be randomized to Maralixibat oral solution (up to 600 microgram per kilogram [mcg/kg]) orally twice daily for 26 weeks. | Drug: Maralixibat<br>* Maralixibat oral solution (up to 600 mcg/kg) orally twice daily for 26 weeks.<br>* Other names: SHP625;|
| Placebo Comparator: Placebo<br>Participants will receive placebo matched to maralixibat oral solution twice daily for 26 weeks. | Drug: Placebo<br>* Placebo matching to maralixibat orally twice daily for 26 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Plasma Levels of Maralixibat Over Time | Systemic concentrations of maralixibat in plasma will be assessed. | Baseline, Week 6, 10, 14, 18, 22 and 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cholestasis, Maralixibat, Mutation