Phase 3 Randomized Double-Blind Placebo-Controlled Study on Maralixibat Chloride Efficacy and Safety in Cholestatic Pruritus Treatment

Trial ID: 2024-511287-85-00
Protocol: MRX-802
Sponsor: Mirum Pharmaceuticals Inc.

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Diseases & Conditions

Cholestatic pruritus

Objectives

The primary objective of this randomized, double-blind, placebo-controlled Phase 3 study is to evaluate the **efficacy** of maralixibat versus placebo in reducing the severity of **pruritus** in participants with **cholestatic pruritus**. This is clinically relevant as pruritus significantly impacts the quality of life in patients with cholestatic liver diseases, and effective management is crucial for improving patient outcomes.

Secondary objectives include:

Evaluating the efficacy of maralixibat versus placebo in reducing total serum bile acid (sBA) levels. This is important as elevated sBA levels are associated with cholestatic liver conditions and their reduction may correlate with clinical improvement.

Participants

The clinical trial investigating the efficacy of maralixibat versus placebo in reducing the severity of **pruritus** involves a total of 58 participants. The study population includes both male and female subjects, with an age range starting from 6 months. Participants are diagnosed with cholestatic liver disease accompanied by cholestatic pruritus, characterized by chronic liver biochemical abnormalities or pathological evidence of progressive liver disease, and persistent pruritus. The trial includes individuals with various liver diseases, such as Alpha-1 antitrypsin deficiency, ARC syndrome, and others. Participants were selected based on their ability to provide informed consent, willingness to comply with study requirements, and completion of specific itch assessment entries during the screening period. The trial also considers lifestyle factors, requiring stable dosing regimens for any antipruritics or ursodeoxycholic acid taken by participants. Both vulnerable populations and individuals with access to necessary technology for study communications are included. The study ensures that non-pregnant, non-lactating females of childbearing potential use acceptable contraception methods and have a negative pregnancy test result before participation.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** Phase 3 study to evaluate the efficacy and safety of **maralixibat chloride** in the treatment of participants with **cholestatic pruritus**. The primary objective is to assess the efficacy of maralixibat versus placebo in reducing the severity of pruritus. The trial is expected to commence recruitment on October 25, 2024, and conclude by February 26, 2027. Participants will be involved in the study for a maximum treatment period of 40 weeks, with the study drug administered as an oral solution.

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as a diagnosis of cholestatic liver disease with persistent pruritus and completion of daily ItchRO(Obs) entries. Following the screening, participants will undergo a baseline visit to establish initial measurements. Subsequent visits will occur at regular intervals to monitor the participants' response to treatment and ensure compliance with the study protocol. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted.

Participants are expected to adhere to the study requirements, including maintaining a stable dosing regimen of any concomitant medications and using acceptable contraception methods if applicable. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events, or withdrawal of consent. The primary endpoint is the mean change in the average worst Observer-rated Itch-Reported Outcome (ItchRO[Obs]) severity score from baseline through Weeks 13-20. Secondary endpoints include changes in total serum bile acids and the proportion of participants with significant reductions in pruritus severity.

Treatment

The clinical trial involves the administration of **Maralixibat chloride**, an experimental medication, which is formulated as an oral solution. The active substance, maralixibat chloride, is a chemical compound classified as an ileal bile acid transporter (IBAT) inhibitor. The pharmaceutical form is an oral solution, and the medication is administered via oral use. The dosing regimen involves a maximum daily dose of 600 µg/kg, with a total maximum dose of 168,000 µg/kg over a treatment period of up to 40 days. The primary objective of the trial is to evaluate the efficacy of maralixibat in reducing the severity of pruritus in participants with cholestatic pruritus.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is also provided in the form of an oral solution and is administered orally. The use of a placebo is essential to assess the true efficacy of maralixibat chloride by providing a baseline for comparison. The placebo is designed to be indistinguishable from the active treatment in terms of appearance and administration to maintain the integrity of the blinding process.

Efficacy

The efficacy of maralixibat in the treatment of **cholestatic pruritus** will be assessed through a randomized, double-blind, placebo-controlled Phase 3 clinical trial. The primary endpoint for evaluating efficacy is the mean change in the average worst Observer-rated Itch-Reported Outcome (ItchRO[Obs]) severity score from baseline through Weeks 13 to 20. The baseline score is determined by the 2-week average worst ItchRO(Obs) severity score prior to the first dose, considering the higher of the morning and evening scores.

Secondary endpoints include the change from baseline to the average of Week 12 and Week 20 in total serum bile acid (sBA) levels, the percentage of days with pruritus improvement (defined as a worst ItchRO(Obs) score of less than 1 or a decrease from baseline of at least 1), the proportion of participants achieving a 50% reduction in sBA levels from baseline to the average of Week 12 and Week 20, and the mean change in the average worst ItchRO(Pt) severity score from baseline through Weeks 13 to 20. These efficacy parameters will be measured using validated scales and laboratory tests at specified timepoints throughout the study duration.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Informed consent and assent (as applicable)
Age ≥6 months at time of baseline visit
Diagnosis of rare cholestatic liver disease with cholestatic pruritus based on the following: a. Chronic liver biochemical abnormalities (>90 days) and/or pathological evidence of progressive liver disease. Total sBA (...) is required. b. Persistent pruritus (>90 days). An average worst-daily (morning and evening) ItchRO(Obs)/ItchRO(Pt) score (...) weeks of the screening period leading to the baseline visit. Participants with the following rare diseases will be enrolled in the study: (...)
Completion of at (...) valid daily (morning and evening) ItchRO(Obs)/ItchRO(Pt) entries during (...) of the screening period, leading to the baseline visit. Each week should (...) (morning and evening) entries.

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Exclusion Criteria

Diagnosis of (...)
Active atopic dermatitis or other non-cholestatic diseases associated with pruritus that are not controlled by standard treatment and that may interfere with the severity assessment of cholestasis-associated pruritus
Decompensated cirrhosis or complications of cirrhosis (e.g., esophageal or gastric variceal bleeding in the last 6 months, high-risk esophageal or gastric varices [e.g., large, coiled, occupying >1/3 of the esophageal lumen, red varices or red signs], ascites, hepatic encephalopathy, hepatorenal syndrome). Patients with compensated cirrhosis with preserved hepatic synthetic function (see Exclusion Criterion #6) and absence of complications are eligible.
Suspected or proven cholangiocarcinoma or hepatocellular carcinoma
Unstable and/or serious medical disease that is likely to impair the ability to participate in all aspects of the study, confound efficacy and/or safety assessments, or result in substantially shortened life expectancy (e.g., any active malignancy including hematological malignancy, end-stage heart failure, active infection, acute and chronic diarrhea). Exceptionally, previous history of malignancy, adequately treated/in remission, that in opinion of investigator and medical monitor does not impact participant safety and participation in the study, may be allowed. The investigator should contact the medical monitor to discuss these cases and seek approval before the screening period.
Laboratory results during the screening visit as follows: Platelet count (...); albumin (...); INR (...) (after intravenous or subcutaneous supplementation of vitamin K); total bilirubin: for participants <18 years of age: total bilirubin (...), for participants ≥18 years of age: total bilirubin (...); ALT: for participants <18 years of age: ALT (...), for participants ≥18 years of age: ALT (...)
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., clinically relevant inflammatory bowel disease involving the terminal ileum), per investigator discretion
Use of an IBAT inhibitor within 8 weeks prior to the screening visit
Use of any other investigational medication within 30 days or 5 times the half-life, whichever is greater, prior to the screening visit
History of liver transplant

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Not Recruiting	25 Oct 2024	7
Germany	Not Recruiting	25 Oct 2024	10
Italy	Not Recruiting	25 Oct 2024	9
Poland	Not Recruiting	25 Oct 2024	3
Spain	Not Recruiting	25 Oct 2024	8