Safety and Efficacy Study of LUM001 (Maralixibat) With a Drug Withdrawal Period in Participants With Alagille Syndrome (ALGS)
Condition: Alagille Syndrome
MeSH terms: Alagille Syndrome; Syndrome; Substance Withdrawal Syndrome
Intervention: LUM001 (Maralixibat); Placebo
Intervention description: LUM001, also known as Maralixibat (MRX) will be administered orally Once Daily (OD). To be administered Twice Daily (BID) for patients who are eligible.; Placebo will be administered orally once daily during randomized withdrawal period
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Open-label single arm study with a randomized placebo-controlled parallel group period
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 31.0
Sex: All
Minimum age: 12 Months
Maximum age: 18 Years
Healthy volunteers: No

Summary:

      This is a long-term, open-label study with a double-blind, placebo-controlled, randomized
      drug withdrawal period in children with Alagille Syndrome (ALGS) designed to evaluate the
      safety and efficacy of LUM001 (Also known as maralixibat or MRX).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female between the ages of 12 months and 18 years inclusive.

          -  Diagnosis of ALGS.

          -  Evidence of cholestasis (one or more of the following):

               1. Total serum bile acid > 3x ULN for age.

               2. Conjugated bilirubin > 1 mg/dL.

               3. Fat soluble vitamin deficiency otherwise unexplainable.

               4. GGT > 3x ULN for age.

               5. Intractable pruritus explainable only by liver disease.

          -  Females of childbearing potential must have a negative serum pregnancy test during
             Screening.

          -  Males and females of child-bearing potential who are sexually active, or are not
             currently sexually active during the study, but become sexually active during the
             period of the study and 30 days following the last dose of study drug, must agree and
             use acceptable contraception during the trial.

          -  Participant is expected to have a consistent caregiver(s) for the duration of the
             study.

          -  Informed consent and assent (per IRB/IEC) as appropriate.

          -  Access to phone for scheduled calls from study site.

          -  Caregivers (and age-appropriate participants) must be willing and able to use an
             eDiary device during the study.

          -  Caregivers (and age-appropriate participants) must digitally accept the licensing
             agreement in the eDiary software.

          -  Caregivers (and age-appropriate participants) must complete at least 10 eDiary reports
             (morning or evening) during each of two consecutive weeks of the screening period
             (maximum possible reports = 14 per week).

          -  Average daily score >2 on the Itch Reported Outcome (ItchRO™) questionnaire (maximum
             possible daily score of 4) for two consecutive weeks in the screening period, prior to
             dosing. A daily score is the higher of the scores for the morning and evening ItchRO.
             The average daily score is the sum of all daily scores divided by the number of days
             the ItchRO was completed.

        Inclusion Criteria for participants to be eligible for the 52-week optional follow-up
        treatment period:

          -  Completed the protocol through the Week 48 visit with no safety concerns. Participants
             who were discontinued due to safety reasons can be rechallenged if blood tests are
             back to relatively normal values for this patient population and participant does not
             meet any of the protocol's stopping rules. The decision will be made by the
             investigator in consultation with the sponsor medical monitor.

          -  Participants who have undergone a surgical disruption of the enterohepatic circulation
             will not be eligible to enter into the follow up treatment period.

          -  Participants who were discontinued for other reasons will be considered for the
             52-week optional follow-up treatment period on an individual basis. The decision will
             be made by the investigator in consultation with the sponsor medical monitor.

        Inclusion Criteria for participants with LUM001dosing interruption <7 days, or >=7 days:

          -  The Participant has either: completed the protocol through the Week 48 visit with no
             major safety concerns OR discontinued due to safety reasons judged unrelated to the
             study drug, and laboratory results have returned to levels acceptable for this patient
             population or individual and participant does not meet any of the protocol's stopping
             rules at the time of entry into the follow-up period. The decision will be made by the
             investigator in consultation with the sponsor medical monitor. [Participants who were
             discontinued for other reasons will be considered on an individual basis.]

          -  Females of childbearing potential must have a negative urine or serum pregnancy test
             (beta- human chorionic gonadotropin [β-hCG]) at the time of entry into the long-term
             optional follow-up treatment period.

          -  Males and females of child-bearing potential who are sexually active, or are not
             currently sexually active during the study, but become sexually active during the
             period of the study and 30 days following the last dose of study drug, must agree and
             use acceptable contraception during the trial.

          -  Informed consent and assent (per IRB/EC) as appropriate.

          -  Access to phone for scheduled calls from study site.

          -  Caregivers (and age-appropriate participants) must be willing and able to use an
             eDiary device during the study.

        Exclusion Criteria:

          -  Chronic diarrhea requiring ongoing intravenous fluid or nutritional intervention.

          -  Surgical interruption of the enterohepatic circulation.

          -  Previous liver transplant

          -  Decompensated cirrhosis (ALT >15 x ULN, INR >1.5 [unresponsive to vitamin K therapy],
             albumin <3.0 g/dL, history or presence of clinically significant ascites, variceal
             hemorrhage, and/or encephalopathy).

          -  History or presence of other concomitant 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 (eg, inflammatory bowel disease).

          -  History or presence of gallstones or kidney stones.

          -  Known diagnosis of human immunodeficiency virus (HIV) infection.

          -  Cancers, except for in situ carcinoma, or cancers treated at least 5 years prior to
             Screening with no evidence of recurrence.

          -  Recent medical history or current status that suggests that the participant may be
             unable to complete the study.

          -  Any female who is pregnant or lactating or who is planning to become pregnant during
             the study period.

          -  Known history of alcohol or substance abuse.

          -  Administration of bile acid or lipid binding resins within 28 days prior to screening
             and throughout the trial.

          -  Known hypersensitivity to LUM001 or any of its components.

          -  Receipt of investigational drug, biologic, or medical device within 28 days prior to
             screening, or 5 half-lives of the study agent, whichever is longer.

          -  History of non-adherence to medical regimens, unreliability, mental instability or
             incompetence that could compromise the validity of informed consent or lead to
             nonadherence with the study protocol based upon investigator judgment.

          -  Any other conditions or abnormalities which, in the opinion of the investigator or
             sponsor medical monitor, may compromise the safety of the participant, or interfere
             with the participant participating in or completing the study.

          -  Participants weighing over 50 kg at screening.

        Exclusion Criteria for participants with LUM001 dosing interruption >=7 days:

        - All exclusion criteria mentioned above apply upon entry into the long-term optional
        follow-up period, with the exception of participants weighing over 50 kg at screening.