Cholestatic Liver Disease (Except ALGS, PFIC, PBC and PSC)
Conditions
Keywords
Pruritus, Cholestatic Liver Disease, Biliary Atresia
Brief summary
The purpose of this study is to determine whether the investigational treatment (maralixibat) is safe and effective in pediatric and adult participants who have cholestatic liver disease with pruritus that has been refractory to other therapies, and who have no other treatment options.
Detailed description
This study will be conducted in multiple sites in North America, Europe, Middle East and South America.
Interventions
DRUGMaralixibat
Maralixibat will be provided as an oral solution along with 0.5-, 1.0-, and 3.0-mL sized dosing dispensers. During the double-blind dose escalation period (4 weeks), the study drug (maralixibat) will be administered once daily for 1 week and then twice daily (BID; morning and evening). During the double-blind stable dosing period (16 weeks), participants will be treated with 300 μg/kg BID or the maximum tolerated dose (determined during the double-blind dose-escalation period) of maralixibat. During the open-label dose escalation period (4 weeks), all participants will receive maralixibat treatment once daily for 1 week and then twice daily (BID; morning and evening). During the open-label stable dosing period (at least 16 weeks), participants will be treated with 300 μg/kg BID or the maximum tolerated dose (determined during the open-label dose-escalation period) of maralixibat.
OTHERPlacebo
Placebo matched to maralixibat will be provided as an oral solution along with 0.5-, 1.0-, and 3.0-mL sized dosing dispensers. During the double-blind dose escalation period (4 weeks), study drug will be administered once daily for 1 week and then twice daily (BID; morning and evening). During the double-blind stable dosing period (16 weeks), participants will be treated with 300 μg/kg BID or the maximum tolerated dose (determined during the double-blind dose-escalation period) of study drug. During the open-label dose escalation period (4 weeks), all participants will receive maralixibat treatment once daily for 1 week and then twice daily (BID; morning and evening). During the open-label stable dosing period (16 weeks), participants will be treated with 300 μg/kg BID or the maximum tolerated dose (determined during the open-label dose-escalation period) of maralixibat.
Sponsors
Mirum Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Months to No maximum
Healthy volunteers
No
Inclusion criteria
1. Informed consent and assent (as applicable) 2. Age ≥6 months at time of baseline visit 3. Diagnosis of a rare cholestatic liver disease with cholestatic pruritus based on the following: 1. Chronic liver biochemical abnormalities (\>90 days) and/or pathological evidence of progressive liver disease. Total sBA \>2× ULN is required. 2. Persistent pruritus (\>90 days). An average worst-daily (morning and evening) ItchRO(Obs)/ItchRO(Pt) score ≥1.5 during the 2 consecutive weeks of the screening period leading to the baseline visit. If both instruments are administered, a score ≥1.5 is required only for ItchRO(Obs). Participants with the following rare diseases will be enrolled in the study: Any rare cholestatic liver disease associated with persistent cholestatic pruritus, including but not limited to the following: alpha-1 antitrypsin deficiency, ARC syndrome, BA, Caroli's disease, ciliopathies, hepatic sarcoidosis, idiopathic amyloidosis, IgG4-related sclerosing cholangitis, ischemic cholangiopathy, metabolic or genetic cholestatic liver diseases (e.g., bile acid synthesis defects, defects of bile acid transport or disorders such as transaldolase deficiency, where chronic cholestasis and pruritus are present), secondary sclerosing cholangitis. 4. Completion of at least 10 valid daily (morning and evening) ItchRO(Obs)/ItchRO(Pt) entries during 2 consecutive weeks of the screening period, leading to the baseline visit. Each week should have at least 4 valid daily (morning and evening) entries. If both instruments are administered, the completion criterion is required only for ItchRO(Obs). 5. If taking antipruritics or ursodeoxycholic acid, the participant has to be on a stable dosing regimen (i.e., same dose and frequency in the 30 days prior to the screening visit and will continue this dosing regimen up to Week 40 \[adjustment for body weight is allowed\]). 6. Non-pregnant, non-lactating females of childbearing potential who are sexually active must agree to use at least an acceptable effective method of contraception during the study. Females of childbearing potential must have a negative pregnancy test result. 7. Access to email or telephone for scheduled participant contacts and access to smart phone or tablet for PROs (Exception: Participants who do not use a smart phone or tablet because of cultural restrictions will complete the PROs on paper.) 8. Ability to read and/or understand the questionnaires (both caregivers and participants ≥9 years of age) 9. For participants ≤18 years of age: Access to consistent caregiver(s) during the study 10. Willingness (participant or caregiver) to comply with all study visits and requirements through the end of the study
Exclusion criteria
Those who meet any of the following criteria are NOT eligible to participate in the study: Patient Characteristics 1. Diagnosis of ALGS, ICP, PBC, PFIC, or PSC 2. 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 3. 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. 4. Suspected or proven cholangiocarcinoma or hepatocellular carcinoma 5. 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. 6. Laboratory results during the screening visit as follows: 1. Platelet count \<70,000/mm3 . Patients with any condition that further increases bleeding risk (e.g., recent clinically relevant bleeding event \[6 months\], recent major surgery \[12 weeks\], anticoagulant use, platelet function disorders) are excluded. 2. Albumin \<30 g/L 3. INR ≥1.5 (after intravenous or subcutaneous supplementation of vitamin K) 4. Total bilirubin: For participants \<18 years of age: total bilirubin \>10 mg/dL For participants ≥18 years of age: total bilirubin ≥3× ULN 5. ALT: For participants \<18 years of age: ALT \>10× ULN For participants ≥18 years of age: ALT \>5× ULN 7. 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 8. History of liver transplant Prior/Concomitant Therapy 9. Use of an IBAT inhibitor within 8 weeks prior to the screening visit 10. Use of any other investigational medication within 30 days or 5 times the half-life, whichever is greater, prior to the screening visit Other Exclusions 11. Pregnant or nursing 12. Known intolerance/hypersensitivity to maralixibat or its excipients 13. History of nonadherence to medical regimens, unreliability, medical condition, mental instability, or cognitive impairment that, in the opinion of the investigator, could compromise the validity of informed consent, compromise the safety of the participant, or lead to nonadherence with the study protocol or inability to conduct the study procedures 14. Clinically relevant alcohol use disorder or drug abuse within 12 weeks of screening: 1. Moderate alcohol consumption as defined for this study by \>1 and \>2 standard drinks on average per day for women and men, respectively, within 12 weeks prior to the screening visit. A standard drink is defined as 44 mL (1.5 oz, one shot) of liquor, 148 mL (5 oz) of nonfortified wine, or 355 mL (12 oz) of beer (1 oz=29.57 mL; NIAAA) 2. Drug abuse within the 12 weeks prior to, or a positive drug screening result at, the screening visit unless it can be explained by a drug prescription. A positive drug screen will exclude participants if the investigator deems the result to be reflective of a pattern of behavior that might impair the participant's ability to participate in the study. 3. Use of cannabinoids (legal, prescribed, or otherwise) is allowed, provided use is stable (including as-needed use without need for increased frequency of use) for ≥12 weeks prior to the screening visit and throughout the entire study duration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean change in the ItchRO(Obs) severity score | From baseline to average of week 13 to week 20 | 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. |
Secondary
| Measure | Time frame |
|---|---|
| Mean change in total sBA (serum bile acid) level | From baseline to average of week 12 and week 20 |
Countries
Brazil, Canada, France, Germany, Italy, Lebanon, Poland, Spain, United Kingdom, United States
Outcome results
None listed