Open Label Study to Evaluate Efficacy and Long Term Safety of LUM001 (Maralixibat) in the Treatment of Cholestatic Liver Disease in Patients With Progressive Familial Intrahepatic Cholestasis

Open Label Study of the Efficacy and Long Term Safety of LUM001 (Maralixibat), an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment of Cholestatic Liver Disease in Pediatric Patients With Progressive Familial Intrahepatic Cholestasis

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02057718

Acronym

INDIGO

Enrollment

Registered

2014-02-07

Start date

2014-03-01

Completion date

2020-05-08

Last updated

2023-10-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Progressive Familial Intrahepatic Cholestasis (PFIC)

Keywords

Bile duct diseases, Intrahepatic Cholestasis, Cholestasis, PFIC, Pruritus, Cholestatic Liver Disease

Brief summary

This is an open label study in children with Progressive Familial Intrahepatic Cholestasis (PFIC) designed to evaluate the safety and efficacy of LUM001, also known as Maralixibat (MRX). Efficacy will be assessed by evaluating the effect of LUM001 on pruritus and the biochemical markers of pruritus associated with PFIC.

Detailed description

The study is divided into 5 parts: a 4-week dose escalation period, a 4-week stable dosing period, a 5-week stable dosing period, a 59-week long-term exposure period, and an optional follow-up treatment period for eligible participants who continue treatment with LUM001. Participants in the optional follow-up treatment period will continue to receive study drug until they are eligible to enter another LUM001 study or until LUM001 is available commercially, whichever occurs first.

Interventions

DRUGLUM001 (Maralixibat)

LUM001 also known as Maralixibat (MRX) oral dose up to twice a day (BID).

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

12 Months to 18 Years

Healthy volunteers

Inclusion criteria

1\. Male or female subjects between the ages of 12 months and 18 years inclusive. 2\. Diagnosis of PFIC based on: 1. Intrahepatic cholestasis manifest by total serum bile acid \>3x upper limit of normal (ULN) for age and, b or c: 2. Two documented mutant alleles in ATP8B1, or ABCB11. 3. Evidence of chronic liver disease, excluding those listed in (see Section 16.3), with one or more of the following criteria: 1. Duration of biochemical or clinical abnormalities of \>6 months, or 2. Pathologic evidence of progressive liver disease, or 3. Sibling of known individual affected by PFIC (predicted to be chronic). 3\. GGTP \<100 IU/L at screening. 4. Females of childbearing potential must have a negative urine or serum pregnancy test \[β human chorionic gonadotropin (β-hCG)\] during screening and a negative urine pregnancy test at the Baseline (Day 0) 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 30 days following the last dose of study drug, must agree and use acceptable contraception during the trial, as described in Section 8.7.1. of the protocol 6. Informed consent and assent (per IRB/EC) as appropriate. 7. Access to phone for scheduled calls from study site. 8. Caregivers and children above the age of assent must have the ability to read and understand one of the following languages: English, Spanish, US Spanish, French, German or Polish. 9\. Subjects expected to have a consistent caregiver(s) for the duration of the first 13 weeks of the study. 10\. Caregivers (and age appropriate subjects) must be willing and able to use an eDiary device as required by the study. To accommodate potential cultural restrictions within the FIC1 affected population a paper version of the ItchRO diary will be made available. 11\. Caregivers (and age appropriate subjects) using the eDiary must digitally accept the licensing agreement in the eDiary software at the outset of the study. 12\. Caregivers (and age appropriate subjects) must complete at least 10 eDiary reports (morning or evening) during each of two consecutive weeks of the screening period, prior to assignment (maximum possible reports = 14 per week). Subjects using a paper diary must complete the same number of reports within the same timeframe

Exclusion criteria

1. Chronic diarrhea requiring specific intravenous fluid or nutritional intervention for the diarrhea and/or its sequelae. 2. Surgical disruption of the enterohepatic circulation at the time at screening. Subjects who have undergone reversal of a prior surgical procedure intended to disrupt enterohepatic circulation and who and have a permanently restored flow of bile acids from the liver to the terminal ileum may be eligible for the study upon consultation with the Medical Monitor. 3. Liver transplant. 4. Decompensated cirrhosis \[international normalized ratio (INR) \> 1.5, albumin \< 30 g/L, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy\]. 5. ALT \>15×ULN at screening. 6. History or presence of other liver disease (see Section 16.3). 7. 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 (e.g., inflammatory bowel disease). 8. Liver mass on imaging. 9. Known diagnosis of human immunodeficiency virus (HIV) infection. 10. Cancers except for in situ carcinoma, or cancers treated at least 5 years prior to screening with no evidence of recurrence. 11. Any female who is pregnant or lactating or who is planning to become pregnant within 20 weeks of assignment. 12. Any known history of alcohol or substance abuse. 13. Administration of bile acid or lipid binding resins within 30 days prior to Baseline / Day 0 and throughout the trial. 14. Administration of sodium phenylbutyrate within 30 days prior to Baseline / Day 0 and throughout the trial. 15. Investigational drug, biologic, or medical device within 30 days prior to screening, or 5 half-lives of the study agent, whichever is longer. 16. History of non-adherence to medical regimens, unreliability, mental instability or incompetence that could compromise the validity of informed consent or lead to non-adherence with the study protocol based on Investigator judgment. 17. Any other conditions or 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

Design outcomes

Primary

Measure	Time frame
Change From Baseline to Endpoint (Week 13) in Fasting sBA Level	Baseline (Day 0) to Week 13

Secondary

Measure	Time frame	Description
Change From Baseline to Week 13/ET in Pruritus as Measured by ItchRO(Obs)	Baseline (Day 0) to Week 13	This secondary efficacy endpoint is the change from baseline to Week 13 in pruritus as measured by ItchRO(Obs) weekly average morning score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe).
Change From Baseline to Week 13/ET in Pruritus as Measured by ItchRO(Pt)	Baseline (Day 0) to Week 13	This secondary efficacy endpoint is the change from baseline to Week 13 in pruritus as measured by ItchRO(Pt) weekly average morning score. ItchRO scores range from 0 to 4; the higher score indicates increasing itch severity (0 = none; 4 = very severe).
Change From Baseline to Week 13/ET in ALT	Baseline (Day 0) to Week 13	—
Change From Baseline to Week 13/ET in Total Bilirubin	Baseline (Day 0) to Week 13	—
Change From Baseline to Week 13/ET in Direct Bilirubin	Baseline (Day 0) to Week 13	—

Countries

France, Poland, United Kingdom, United States

Participant flow

Recruitment details

A total of 33 participants were enrolled at 11 sites in 4 countries (US, UK, France, Poland). Participants included 19 females and 14 males ranging from 1 to 13 years of age. Screening, treatment and safety follow-up, was approximately 76 weeks after which participants had the option of continuing in the additional follow-up treatment period up to 287 weeks.

Pre-assignment details

A total of 37 PFIC patients were screened for the study. Four of these patients were screen failures under the original protocol. A total of 33 participants were enrolled and subsequently had genotyping performed. Of the 33 participants, 8 were PFIC1 and 25 were PFIC2. Two pairs of siblings (all with PFIC2) from 2 families were enrolled. Only a single sibling from each pair was considered for the primary analysis.

Participants by arm

Arm	Count
PFIC1 Sub-group analysis of enrolled subjects with PFIC1 subtype	8
PFIC2 (Overall) Sub-group analysis of overall PFIC2 subtype to include PFIC2 phenotype: - non-truncating (mild to moderate phenotype with residual BSEP \[liver-specific transporter\] function) - truncating (severe phenotype without residual BSEP function or complete absence of BSEP)	25
Total	33

Withdrawals & dropouts

Period	Reason	FG000	FG001
Completed Study Treatment Through Wk. 72	Adverse Event	0	3
Completed Study Treatment Through Wk. 72	Consent withdrawn by caregiver	1	1
Completed Study Treatment Through Wk. 72	Consent withdrawn by subject	0	1
Completed Study Treatment Through Wk. 72	Liver Transplant	0	1
Completed Study Treatment Through Wk. 72	Non-compliance with study drug	0	1
Completed Study Treatment Through Wk. 72	Physician Decision	1	0
Completed Study Treatment Through Wk. 72	Progressive disease	0	2
Optional Follow-up Treatment Period	Adverse Event	1	2
Optional Follow-up Treatment Period	Did not consent to protocol amendment	1	3
Optional Follow-up Treatment Period	Liver Transplant	0	2
Optional Follow-up Treatment Period	Progressive disease	0	1

Baseline characteristics

Characteristic	Total	PFIC1	PFIC2 (Overall)
Age, Customized 13 to 18 years	1 Subjects	0 Subjects	1 Subjects
Age, Customized 2 to 4 years	15 Subjects	5 Subjects	10 Subjects
Age, Customized <2 years	7 Subjects	1 Subjects	6 Subjects
Age, Customized 5 to 8 years	6 Subjects	2 Subjects	4 Subjects
Age, Customized 9 to 12 years	4 Subjects	0 Subjects	4 Subjects
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	29 Participants	8 Participants	21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants	0 Participants	3 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	3 Participants	2 Participants	1 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants	0 Participants	3 Participants
Race (NIH/OMB) White	26 Participants	6 Participants	20 Participants
Region of Enrollment France	3 participants	0 participants	3 participants
Region of Enrollment Poland	1 participants	0 participants	1 participants
Region of Enrollment United Kingdom	14 participants	3 participants	11 participants
Region of Enrollment United States	15 participants	5 participants	10 participants
Sex: Female, Male Female	19 Participants	2 Participants	17 Participants
Sex: Female, Male Male	14 Participants	6 Participants	8 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 33
other Total, other adverse events	33 / 33
serious Total, serious adverse events	15 / 33