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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02160782




Registration number
NCT02160782
Ethics application status
Date submitted
9/06/2014
Date registered
11/06/2014
Date last updated
14/07/2021

Titles & IDs
Public title
Safety and Efficacy Study of LUM001 (Maralixibat) With a Drug Withdrawal Period in Participants With Alagille Syndrome (ALGS)
Scientific title
Long-Term, Open-Label Study With a Double-Blind, Placebo-Controlled, Randomized Drug Withdrawal Period of LUM001 (Maralixibat), an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in Patients With Alagille Syndrome
Secondary ID [1] 0 0
2013-005373-43
Secondary ID [2] 0 0
LUM001-304
Universal Trial Number (UTN)
Trial acronym
ICONIC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alagille Syndrome 0 0
Condition category
Condition code
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cardiovascular 0 0 0 0
Other cardiovascular diseases
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above
Mental Health 0 0 0 0
Addiction

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - LUM001 (Maralixibat)
Treatment: Drugs - Placebo

Experimental: LUM001 (Maralixibat) - LUM001, also known as Maralixibat (MRX) will be administered orally once a day (QD) up to 400 microgram per kilogram per day (mcg/kg/day) up to Week 52, followed by an increase in dose orally twice a day (BID) during long-term follow-up based on efficacy (serum bile acid \[sBA\] level and ItchRO\[Obs\] score) and safety assessment.

Note: 400 mcg/kg maralixibat chloride is equivalent to 380 mcg/kg free maralixibat.

Placebo comparator: Placebo - Placebo will be administered orally once a day during randomized withdrawal period (Week 19 to Week 22)


Treatment: Drugs: LUM001 (Maralixibat)
LUM001, also known as Maralixibat (MRX) will be administered orally Once Daily (OD). To be administered Twice Daily (BID) for patients who are eligible.

Treatment: Drugs: Placebo
Placebo will be administered orally once daily during randomized withdrawal period
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change From Week 18 to Week 22 in Fasting sBA Levels in Participants Who Had a Reduction in sBA =50% From Baseline to Week 12 or Week 18
Timepoint [1] 0 0
Week 18 to Week 22
Secondary outcome [1] 0 0
Change From Baseline to Week 18 in Fasting sBA Levels
Timepoint [1] 0 0
Baseline to Week 18
Secondary outcome [2] 0 0
Change From Baseline to Week 18 in Pruritus as Measured by ItchRO (Obs)
Timepoint [2] 0 0
Baseline to Week 18
Secondary outcome [3] 0 0
Change From Baseline to Week 18 in Pruritus as Measured by ItchRO (Pt)
Timepoint [3] 0 0
Baseline to Week 18
Secondary outcome [4] 0 0
Change From Week 18 to Week 22 in Pruritus as Measured by ItchRO(Obs)
Timepoint [4] 0 0
Week 18 to Week 22
Secondary outcome [5] 0 0
Change From Week 18 to Week 22 in Pruritus as Measured by ItchRO(Pt)
Timepoint [5] 0 0
Week 18 to Week 22
Secondary outcome [6] 0 0
Change From Baseline to Week 18 in Alkaline Phosphatase
Timepoint [6] 0 0
Baseline to Week 18
Secondary outcome [7] 0 0
Change From Week 18 to Week 22 in Alkaline Phosphatase
Timepoint [7] 0 0
Week 18 to Week 22
Secondary outcome [8] 0 0
Change From Baseline to Week 18 in Alanine Aminotransferase
Timepoint [8] 0 0
Baseline to Week 18
Secondary outcome [9] 0 0
Change From Week 18 to Week 22 in Alanine Aminotransferase
Timepoint [9] 0 0
Week 18 to Week 22
Secondary outcome [10] 0 0
Change From Baseline to Week 18 in Total Bilirubin
Timepoint [10] 0 0
Baseline to Week 18
Secondary outcome [11] 0 0
Change From Week 18 to Week 22 in Total Bilirubin
Timepoint [11] 0 0
Week 18 to Week 22
Secondary outcome [12] 0 0
Change From Baseline to Week 18 in Direct Bilirubin
Timepoint [12] 0 0
Baseline to Week 18
Secondary outcome [13] 0 0
Change From Week 18 to Week 22 in Direct Bilirubin
Timepoint [13] 0 0
Week 18 to Week 22

Eligibility
Key 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 [ß-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.
Minimum age
12 Months
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
28/10/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
28/05/2020
Sample size
Target
Accrual to date
Final
31
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Children's Hospital Westmead - Westmead
Recruitment hospital [2] 0 0
The Royal Children's Hospital Melbourne - Parkville
Recruitment postcode(s) [1] 0 0
2145 - Westmead
Recruitment postcode(s) [2] 0 0
3052 - Parkville
Recruitment outside Australia
Country [1] 0 0
Belgium
State/province [1] 0 0
Brussels
Country [2] 0 0
France
State/province [2] 0 0
Bron
Country [3] 0 0
France
State/province [3] 0 0
Paris
Country [4] 0 0
Poland
State/province [4] 0 0
Warsaw
Country [5] 0 0
Spain
State/province [5] 0 0
Madrid
Country [6] 0 0
United Kingdom
State/province [6] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Mirum Pharmaceuticals, Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief 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).
Trial website
https://clinicaltrials.gov/study/NCT02160782
Trial related presentations / publications
Kamath BM, Goldstein A, Howard R, Garner W, Vig P, Marden JR, Billmyer E, Anderson A, Kirson N, Jacquemin E, Gonzales E. Maralixibat Treatment Response in Alagille Syndrome is Associated with Improved Health-Related Quality of Life. J Pediatr. 2023 Jan;252:68-75.e5. doi: 10.1016/j.jpeds.2022.09.001. Epub 2022 Sep 10.
Gonzales E, Hardikar W, Stormon M, Baker A, Hierro L, Gliwicz D, Lacaille F, Lachaux A, Sturm E, Setchell KDR, Kennedy C, Dorenbaum A, Steinmetz J, Desai NK, Wardle AJ, Garner W, Vig P, Jaecklin T, Sokal EM, Jacquemin E. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study. Lancet. 2021 Oct 30;398(10311):1581-1592. doi: 10.1016/S0140-6736(21)01256-3. Epub 2021 Oct 28.
Public notes

Contacts
Principal investigator
Name 0 0
Study Director
Address 0 0
Mirum
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT02160782