A Study to Evaluate the Efficacy and Safety of Maralixibat in Subjects With Progressive Familial Intrahepatic Cholestasis (MARCH-PFIC)
Condition: Progressive Familial Intrahepatic Cholestasis (PFIC)
MeSH terms: Cholestasis; Cholestasis, Intrahepatic
Intervention: Maralixibat; Placebo
Intervention description: Maralixibat oral solution (up to 600 mcg/kg) orally twice daily for 26 weeks.; Placebo matching to maralixibat orally twice daily for 26 weeks.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 93.0
Sex: All
Minimum age: 1 Year
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Cholestasis; Maralixibat; Mutation; PFIC; PFIC2; Bile Duct Diseases; Liver Diseases; Biliary Tract Diseases; Digestive System Diseases; Pediatric

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).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Informed consent and assent (as applicable) per Institutional Review Board/Ethics
             Committee (IRB/EC)

          2. Male or female subjects with a body weight ≥5 kg, who are ≥12 months and <18 years of
             age at time of baseline

          3. Cholestasis as manifested by total sBA ≥3× ULN (applies to primary cohort only)

          4. An average AM ItchRO(Obs) score ≥1.5 during 4 consecutive weeks of the screening
             period, leading to the baseline visit (Visit 1)

          5. 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)

          6. 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.

          7. 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

          8. Access to email or phone for scheduled remote visits

          9. Ability to read and understand the questionnaires (both caregivers and subjects above
             the age of assent)

         10. Access to consistent caregiver(s) during the study

         11. Subject and caregiver willingness to comply with all study visits and requirements.

        Exclusion Criteria:

          1. Predicted complete absence of bile salt excretion pump (BSEP) function based on the
             type of ABCB11 mutation (PFIC2), as determined by a standard of care genotyping
             (applies to primary cohort only). Subjects can enter the study in the Supplemental
             Cohort (under inclusion criteria 6.ii or 6.iii).

          2. Recurrent intrahepatic cholestasis, indicated by a history of sBA levels <3x ULN or
             intermittent pruritus (applies to primary cohort only)

          3. Current or recent history (<1 year) of atopic dermatitis or other non-cholestatic
             diseases associated with pruritus.

          4. History of surgical disruption of the enterohepatic circulation (applies to primary
             cohort only)

          5. 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

          6. Previous or need for imminent liver transplant

          7. Decompensated cirrhosis (international normalized ratio [INR] >1.5, albumin <30 g/L,
             history or presence of clinically significant ascites, variceal hemorrhage, and/or
             encephalopathy)

          8. ALT or total serum bilirubin (TSB) >15× ULN at screening

          9. Presence of other liver disease

         10. 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

         11. Possibly malignant liver mass on imaging, including screening ultrasound

         12. Known diagnosis of human immunodeficiency virus (HIV) infection

         13. Any prior cancer diagnosis (except for in situ carcinoma) within 5 years of the
             screening visit (Visit 0)

         14. Any known history of alcohol or substance abuse

         15. Administration of bile acids or lipid binding resins, or phenylbutyrates during the
             screening period

         16. Criterion has been deleted as of Amendment 3

         17. Administration of any investigational drug, biologic, or medical device during the
             screening period

         18. Previous use of an ileal bile acid transporter inhibitor (IBATi)

         19. History of non-adherence to medical regimens, unreliability, medical condition, mental
             instability or cognitive impairment that, in the opinion of the Investigator or
             Sponsor medical monitor, could compromise the validity of informed consent, compromise
             the safety of the subject, or lead to nonadherence with the study protocol or
             inability to conduct the study procedures

         20. Known hypersensitivity to maralixibat or any of its excipients.