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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Alagille Syndrome

Intervention / Treatment
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* Drug: LUM001 (Maralixibat)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 12 months to 18 years of age. Competent to provide informed consent and assent (per institutional review board/Ethics Committee [IRB/EC]), as appropriate. Completed participation in the LUM001-301 protocol. Females of childbearing potential must have a negative urine pregnancy test [beta human chorionic gonadotropin (beta-hCG)] at the Baseline Visit. Sexually active females must be prepared to use an effective method of contraception during the trial. Effective methods of contraception are considered to be: Hormonal (for example, contraceptive pill, patch, intramuscular implant or injection); or Barrier method, for example, (a) condom with spermicide, or (b) diaphragm, with spermicide; or Intrauterine device (IUD). Participants above the age of assent and caregivers and children must be able to read and understand English or Spanish. Caregivers (and age appropriate participants) must have access to phone for scheduled calls from study site. 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. Caregivers (and age appropriate participants) must digitally accept the licensing agreement in the ItchRO electronic diary software at the outset of the study. Eligible participants must be able to adhere to local Ethics Committee or Institutional Review Board (IRB) blood volume limits for laboratory testing. 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. 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. 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. Informed consent and assent (per IRB/EC) as appropriate. Caregivers (and age appropriate participants) must have access to phone for scheduled calls from study site. Caregivers (and age appropriate participants) must be willing to follow the rules of eDiary completion. Exclusion Criteria: 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. 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. History or known presence of gallstones or kidney stones. 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. Unlikely to comply with the study protocol, or unsuitable for any other reason, as judged by the investigator. All above exclusion criteria will apply upon re-entry into the long-term, optional follow-up treatment period 2.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LUM001 (Maralixibat)<br>Participant will receive LUM001 also known as Maralixibat (MRX) administered orally once per day. | Drug: LUM001 (Maralixibat)<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From MRX Baseline to Week 48 in Fasting Serum Bile Acid (sBA) | This primacy efficacy endpoint is the mean change from MRX baseline to week 48 in fasting sBA levels. | Baseline to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From MRX Baseline to Week 216 in Fasting Serum Bile Acid (sBA) | The secondary endpoint of this study was the mean change from MRX baseline to week 216 fasting in sBA levels. | Baseline to week 216 | 
| Change From Baseline to Week 218 in Pruritus | 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. | Baseline to Week 218 | 
| Change From Baseline to Week 216 in Alanine Aminotransferase | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in ALT levels. | Baseline to week 216 | 
| Change From Baseline to End of Treatment in Alkaline Phosphatase | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in ALP levels. | Baseline to Week 216 | 
| Change From MRX Baseline to Week 216 in Aspartate Aminotransferase | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in AST levels. | Baseline to week 216 | 
| Change From MRX Baseline to Week 216 in Clinician Xanthoma Severity Score | 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. | Baseline to week 216 | 
| Change From Baseline to Week 216/LOFC Clinician Scratch Scale (CSS) Score | 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. | Baseline to Week 216 | 
| Change From MRX Baseline to Week 216 in Gamma Glutamyltransferase | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in GGT. | Baseline to Week 216 | 
| Mean Change From MRX Baseline to Week 216 in Total Bilirubin | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in total bilirubin. | Baseline to week 216 | 
| Mean Change From MRX Baseline to Week 216 in Direct Bilirubin | This secondary efficacy endpoint is the mean change from MRX baseline to week 216 in direct bilirubin. | Baseline to week 216 |