A MULTICENTRE CLINICAL STUDY TO EVALUATE THE SAFETY AND EFFICACY OF LUM001, AN AGENT THAT INHIBITS BILE ACID REUPTAKE FROM THE INTESTINE, IN THE TREATMENT OF CHOLESTATIC LIVER DISEASE IN PAEDIATRIC PATIENTS WITH ALAGILLE SYNDROME

• Register: EUCTR
• Last refreshed on: 13 October 2020
• Main ID: EUCTR2013-003832-54-GB
• Date of registration: 09/12/2013
• Prospective Registration: No
• Primary sponsor: Mirum Pharmaceuticals, Inc.
• Public title: A MULTICENTRE CLINICAL STUDY TO EVALUATE THE SAFETY AND EFFICACY OF LUM001, AN AGENT THAT INHIBITS BILE ACID REUPTAKE FROM THE INTESTINE, IN THE TREATMENT OF CHOLESTATIC LIVER DISEASE IN PAEDIATRIC PATIENTS WITH ALAGILLE SYNDROME
• Scientific title: A MULTICENTRE EXTENSION STUDY TO EVALUATE THE LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS WITH ALAGILLE SYNDROME - IMAGINE STUDY
• Date of first enrolment: 28/11/2013
• Target sample size: 18
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-003832-54
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: Open: Single blind: Double blind: Parallel group: Cross over: Other: If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

United Kingdom

Contacts

• Name: Chief Scientific Officer
• Affiliation: Mirum Pharmaceuticals, Inc.

• Name: Chief Scientific Officer
• Affiliation: Mirum Pharmaceuticals, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
To participate in this study, subjects must meet all of the following criteria:
1. Male or female, 12 months to 18 years of age.
2. Competent to provide informed consent and assent (per IRB/EC), as appropriate.
3. Completed participation in protocol LUM001-302.
4. Females of childbearing potential must have a negative urine pregnancy test [ß human chorionic gonadotropin (ß-hCG)] at the Baseline Visit.
5. 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 for 30 days following the last dose of study drug, must agree to use acceptable contraception during the study. Effective methods of contraception are considered to be:
a. Hormonal (e.g., contraceptive pill, patch, intramuscular implant or
injection); or
b. Barrier method, e.g., (a) condom with spermicide, or (b) diaphragm, with spermicide; or
c. Intrauterine device (IUD).
d. A sexual partner who is surgically sterilized.
6. Subjects are expected to have consistent caregiver(s) for the duration of the study.
7.Caregiver (and age appropriate subjects) must be able to read and understand English.
8. Caregivers (and age appropriate subjects) must have access to phone for scheduled calls from study site.
9. Caregivers (and age appropriate subjects) must be willing and able to complete a daily electronic diary (ItchRO) during the first consecutive 12 weeks of the study and then for 4 consecutive weeks following the Week 24 and Week 44 visits.
10. Caregivers (and age appropriate subjects) must digitally accept the licensing agreement in the ItchRO electronic diary software at the outset of the study.

Eligible subjects for the 52-week optional follow-up treatment period:
Subjects will be considered eligible for the 52-week optional follow-up treatment period if they have completed the protocol through the Week 72 visit with no safety concerns. Subjects who were discontinued due to safety reasons can be re-challenged if blood tests are back to relatively normal values for this patient population and subject 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. Subjects who have undergone a surgical disruption of the enterohepatic circulation will not be eligible to enter into the follow-up treatment period. Subjects who were discontinued for other reasons will be considered on an individual basis.

Protocol Amendment 5: Eligible subjects for the long-term optional follow-up treatment period
Subjects will be considered eligible for the long-term optional follow-up treatment period if they meet the following criteria:
1. The subject has either:
a. Completed the protocol through either the Week 124 or the ET visit with no major safety concerns.
OR
b. 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 subject 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. Subjects who were discontinued for other reasons will be considered on an individual basis.
2. Females of childbearing potential must have a negative urine or serum pregnancy test (ß- human chorionic gonadotropin [ß-hCG]) at the time of entry into the
Exclusion criteria:
Subjects will be excluded from the study if they meet any of the following criteria:

1. Experienced an adverse event or serious adverse event (SAE) related to the study drug during the LUM001-302 study that led to the discontinuation of the subject from the LUM001-302 study.
2. Any conditions or abnormalities (including laboratory abnormalities) which, in the opinion of the Investigator or Medical Monitor, may compromise the safety of the subject, or interfere with the subject participating in or completing the study.
3. History or presence of gallstones or kidney stones.
4. History of non-adherence during the subject’s participation in the LUM001-302 study. Non-adherence is defined by dosing compliance of less than 80% in the LUM001-302 study, or earlier in the LUM001-303 study.
5. Unlikely to comply with the study protocol, or unsuitable for any other reason, as judged by the investigator.

Protocol Amendment 5: Eligible subjects for the long-term optional follow-up treatment period.

All exclusion criteria mentioned for the original study LUM001-303 apply upon re-entry into the long-term optional follow-up treatment period.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Alagille syndrome (ALGS). This is an example of cholestatic liver disease in children. In patients with Alagille syndrome, impairment of the egress of bile acids from the liver leads to cholestasis, hepatocellular injury and damage, and progressive liver disease that may ultimately lead to the need for liver transplantation. Itch is the archetypal symptom of cholestasis, occurring at all stages of cholestatic liver disease, with or without jaundice.
MedDRA version: 20.0 Level: PT Classification code 10053870 Term: Alagille syndrome System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Intervention(s)

Product Name: LUM001
Pharmaceutical Form: Powder and solvent for oral solution
INN or Proposed INN: maralixibat chloride
CAS Number: 228113-66-4
Current Sponsor code: LUM001
Concentration unit: µg/kg microgram(s)/kilogram
Concentration type: up to
Concentration number: 280-

Primary Outcome(s)

Primary end point(s): The primary evaluation will be the mean change from Baseline (Day 0) to Week 48 in:

Fasting serum bile acid level.

Timepoint(s) of evaluation of this end point: 0, 2, 4, 8, 12, 16, 24, 36 and 48 weeks.

Main Objective: The primary objective of the study (up to and including week 72) is to:

1. Evaluate the long-term safety and tolerability of LUM001 in pediatric subjects with
ALGS.

Secondary Objective: Secondary objectives of the study (up to and including week 72) are to:
•Evaluate the long-term effect of LUM001 on serum bile acid levels associated with ALGS.
•Evaluate the long-term effect of LUM001 on pruritus associated with ALGS.
•Explore the long-term effect of LUM001 on other biochemical markers of cholestasis and liver disease.
•Evaluate the long-term effect of LUM001 on xanthomas associated with ALGS.
• Explore an expanded dosing range to identify the doses necessary to achieve the optimal benefit-to-risk ratio for this patient population.

Objectives of the long-term optional follow-up treatment period for subjects who are eligible for PA5:
•To explore twice a day (BID) dosing regimen and higher daily dosing of LUM001.
•To obtain safety and efficacy data in subjects treated long term on LUM001.
•To assess the level of alpha-fetoprotein (AFP), a marker of hepatocellular carcinoma.
•To assess palatability of the LUM001 formulation.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Time points for evaluation of each exploratory endpoint are reported in the Schedule of Procedures (Section 16.1)

Secondary end point(s): Secondary evaluations will be the mean change from Baseline (Day 0) to Week 48 and the change from Week 12 to Week 48 in:

1. Biochemical markers of cholestasis and liver disease [ALT, GGT and total bilirubin].
2. Pruritus as measured by the ItchRO instruments (ItchRO(Obs)TM, caregiver instrument/ItchRO(Pt) TM patient instrument).
-During the first 12 weeks of the study, the electronic diary (ItchRO) will be completed twice daily (AM & PM). During the stable dosing period (Weeks 13-
48), twice daily completion of the electronic diary (ItchRO) for 4 consecutive weeks will be required following the Week 24 and Week 44 clinic visits. For
subjects who continue in the follow-up treatment period, twice daily completion of the electronic diary (ItchRO) for 2 consecutive weeks will be required following the Week 84, 96, 108, and 120 clinic visits.
3. Xanthomas as measured by clinician xanthoma scale.

Change from Week 12 to Week 48 in fasting serum bile acid will also be examined.
Efficacy variables will be presented for each time point at which they are measured. Additional exploration, including behavior during the dose escalation and optimization phases, will be specified in the SAP.

Secondary ID(s)

LUM001-303

NCT02047318

Source(s) of Monetary Support

Mirum Pharmaceuticals, Inc.

Ethics review

Status: Approved
Approval date: 28/11/2013
Contact: