An Extension Study to Evaluate the Long-Term Safety and Durability of Effect of LUM001 in the Treatment of Cholestatic Liver Disease in Pediatric Subjects With Alagille Syndrome (IMAGINE-II)

• ClinicalTrials.gov Identifier: NCT02117713
• Recruitment Status: Completed
• First Posted: April 21, 2014
• Results First Posted: June 22, 2021
• Last Update Posted: July 1, 2021
• Sponsor: Mirum Pharmaceuticals, Inc.
• Collaborators: Lumena Pharmaceuticals, Inc.; Childhood Liver Disease Research and Education Network
• Information provided by (Responsible Party): Mirum Pharmaceuticals, Inc.

Study Description

Brief Summary:

This is a multicentre, extension study of LUM001 in children diagnosed with Alagille Syndrome who have completed participation in a core LUM001 treatment protocol. The primary objective is to evaluate long-term safety and tolerability of LUM001. Efficacy will be assessed by evaluating the effect of LUM001 on the biochemical markers and pruritus associated with Alagille Syndrome.

Condition or disease	Intervention/treatment	Phase
Alagille Syndrome	Drug: LUM001 (Maralixibat)	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter 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
• Actual Study Start Date: March 16, 2015
• Actual Primary Completion Date: June 1, 2020
• Actual Study Completion Date: June 1, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: LUM001 (Maralixibat); Participant will receive LUM001 also known as Maralixibat (MRX) administered orally once per day.	Drug: LUM001 (Maralixibat); Dosing of LUM001 also known as Maralixibat (MRX) with the objective of achieving optimal control of pruritus at a dose level that is tolerated by the participant and up to a maximum daily dose of 280 micrograms per kilogram (mcg/kg).

Outcome Measures

Primary Outcome Measures :

1. Change From MRX Baseline to Week 48 in Fasting Serum Bile Acid (sBA) [ Time Frame: Baseline to Week 48 ]
   This primacy efficacy endpoint is the mean change from MRX baseline to week 48 in fasting sBA levels.

Secondary Outcome Measures :

1. Change From MRX Baseline to Week 216 in Fasting Serum Bile Acid (sBA) [ Time Frame: Baseline to week 216 ]
   The secondary endpoint of this study was the mean change from MRX baseline to week 216 fasting in sBA levels.
2. Change From Baseline to Week 218 in Pruritus [ Time Frame: Baseline to Week 218 ]
   This secondary efficacy endpoint is the mean change from MRX baseline over time to week 218 in pruritus as measured by ItchRO(Obs) weekly average morning severity score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe). Results reported here are the long-term results.
3. Change From Baseline to Week 216 in Alanine Aminotransferase [ Time Frame: Baseline to week 216 ]
   This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in ALT levels.
4. Change From Baseline to End of Treatment in Alkaline Phosphatase [ Time Frame: Baseline to Week 216 ]
   This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in ALP levels.
5. Change From MRX Baseline to Week 216 in Aspartate Aminotransferase [ Time Frame: Baseline to week 216 ]
   This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in AST levels.
6. Change From MRX Baseline to Week 216 in Clinician Xanthoma Severity Score [ Time Frame: Baseline to week 216 ]
   This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in clinician xanthoma severity scores. It is based on a 0-4 scale to rate the number of lesions present and the degree to which the lesions interfere or limit activities. Clinician xanthoma severity scores range from 0 to 4, with a score of zero representing no evidence of xanthomatosis and a score of 4 representing xanthoma so severe that it is disabling.
7. Change From Baseline to Week 216/LOFC Clinician Scratch Scale (CSS) Score [ Time Frame: Baseline to Week 216 ]
   This secondary efficacy endpoint is the mean change from MRX baseline over time to week 216/LOCF in pruritus as measured by the Clinician Scratch Scale (CSS). The Clinician Scratch Scale uses a 5-point scale, where 0 = none; 1 = rubbing or mild scratching when undistracted; 2 = active scratching without evident skin abrasions; 3 = abrasion evident; 4 = cutaneous mutilation, haemorrhage and scarring evident.
8. Change From MRX Baseline to Week 216 in Gamma Glutamyltransferase [ Time Frame: Baseline to Week 216 ]
   This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in GGT.
9. Mean Change From MRX Baseline to Week 216 in Total Bilirubin [ Time Frame: Baseline to week 216 ]
   This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in total bilirubin.
10. Mean Change From MRX Baseline to Week 216 in Direct Bilirubin [ Time Frame: Baseline to week 216 ]
    This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in direct bilirubin.

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male or female, 12 months to 18 years of age.
2. Competent to provide informed consent and assent (per institutional review board/Ethics Committee [IRB/EC]), as appropriate.
3. Completed participation in the LUM001-301 protocol.
4. Females of childbearing potential must have a negative urine pregnancy test [beta human chorionic gonadotropin (beta-hCG)] at the Baseline Visit.

5. Sexually active females must be prepared to use an effective method of contraception during the trial.

   Effective methods of contraception are considered to be:

   1. Hormonal (for example, contraceptive pill, patch, intramuscular implant or injection); or
   2. Barrier method, for example, (a) condom with spermicide, or (b) diaphragm, with spermicide; or
   3. Intrauterine device (IUD).
6. Participants above the age of assent and caregivers and children must be able to read and understand English or Spanish.
7. Caregivers (and age appropriate participants) must have access to phone for scheduled calls from study site.
8. Caregivers (and age appropriate participants) 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.
9. Caregivers (and age appropriate participants) must digitally accept the licensing agreement in the ItchRO electronic diary software at the outset of the study.
10. Eligible participants must be able to adhere to local Ethics Committee or Institutional Review Board (IRB) blood volume limits for laboratory testing.
11. The participant has completed the protocol either through Week 144, or the End of Trial visit, or has received permission from the sponsor and the Premier Medical monitor to re-enter the study in the long-term, optional follow-up treatment period 2.
12. Females of child-bearing potential must have a negative urine or serum pregnancy test (beta-HCG]) at the time of entry into the long-term optional follow-up treatment period 2.
13. Male and female participants of child-bearing potential who are sexually active, or are not currently sexually active, but become sexually active during the study or for 30 days following the last dose of study drug, must agree to use acceptable contraception during the study.
14. Informed consent and assent (per IRB/EC) as appropriate.
15. Caregivers (and age appropriate participants) must have access to phone for scheduled calls from study site.
16. Caregivers (and age appropriate participants) must be willing to follow the rules of eDiary completion.

Exclusion Criteria:

1. Experienced an adverse event or serious adverse event (SAE) related to the study drug during the LUM001-301 protocol that led to the discontinuation of the participant from the core study.
2. Any conditions or abnormalities (including laboratory abnormalities) which in the opinion of the Investigator, Medical Monitor or ChiLDReN Protocol Chair, may compromise the safety of the participant, or interfere with the participant participating in or completing the study.
3. History or known presence of gallstones or kidney stones.
4. History of non-adherence during the participant's participation in the LUM001-301 protocol. Non-adherence is defined by dosing compliance (dosing compliance is calculated by [the total number of doses that were actually taken by the participant] divided by [the total number of doses that should have been taken by the participant] multiplied by 100) of less than 80% in the LUM001-301 protocol.
5. Unlikely to comply with the study protocol, or unsuitable for any other reason, as judged by the investigator.
6. All above exclusion criteria will apply upon re-entry into the long-term, optional follow-up treatment period 2.

Contacts and Locations

Locations

United States, California

Children's Hospital Los Angeles

Los Angeles, California, United States, 90027

University of California at San Francisco Children's Hospital

San Francisco, California, United States, 94143

United States, Colorado

Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Indiana

Riley Hospital for Children

Indianapolis, Indiana, United States, 46202

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

United States, Pennsylvania

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19147

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States, 15224

United States, Texas

Baylor College of Medicine/Texas Children's Hospital

Houston, Texas, United States, 77030

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84113

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98105

Canada, Ontario

The Hospital for Sick Children

Toronto, Ontario, Canada, M5G 1X8

Sponsors and Collaborators

Mirum Pharmaceuticals, Inc.

Lumena Pharmaceuticals, Inc.

Childhood Liver Disease Research and Education Network

Investigators

• Study Director: Study Director; Mirum

  Study Documents (Full-Text)

Documents provided by Mirum Pharmaceuticals, Inc.:

Study Protocol  [PDF] May 13, 2019

Statistical Analysis Plan  [PDF] April 9, 2020

More Information

• Responsible Party: Mirum Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02117713
• Other Study ID Numbers: LUM001-305; SHP625-305 ( Other Identifier: Shire )
• First Posted: April 21, 2014
• Results First Posted: June 22, 2021
• Last Update Posted: July 1, 2021
• Last Verified: June 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Liver Diseases; Alagille Syndrome; Syndrome; Disease; Pathologic Processes; Digestive System Diseases; Cholestasis, Intrahepatic; Cholestasis; Bile Duct Diseases; Biliary Tract Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Abnormalities, Multiple; Congenital Abnormalities; Genetic Diseases, Inborn