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: 14.1 Level: PT Classificati
Conditions
Interventions
Product Name: LUM001
Pharmaceutical Form: Powder and solvent for oral solution
INN or Proposed INN: LUM001
Current Sponsor code: LUM001
Concentration unit: µg/kg microgram(s)/kilogram
Concentration ty
Sponsors
Lumena Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female, 2 -18 years of age. 2. Diagnosis of ALGS based on the diagnostic criteria outlined in Section 16.3 of the study protocol. 3. Cholestasis as evidenced by total serum bile acid > 3x upper limit of normal (ULN) for age. 4. Intractable pruritus explainable only by liver disease. 5. 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 randomization. A daily score is the highest score between the morning and evening reports. The average daily score is the sum of all daily scores divided by the number of days the ItchRO was completed. 6. Native liver. 7. Females of childbearing potential must have a negative urine or serum pregnancy test [ß human chorionic gonadotropin (ß-hCG)] during screening and a negative urine pregnancy test at the baseline visit. 8. Sexually active females must be prepared to use an effective method (= 1% failure rate) of contraception during the trial. Effective methods of contraception are considered to be: a. Hormonal (e.g., contraceptive pill, patch, intramuscular implant or injection); or b. Barrier method, i.e., (a) condom (male or female) or (b) diaphragm, with spermicide; or c. Intrauterine device (IUD). 9. The ability to read and understand English (caregivers and children above the age of assent). 10. Subjects expected to have a consistent caregiver(s) for the duration of the study. 11. Informed consent and assent (per EC) as appropriate. 12. Access to phone for scheduled calls from study site 13. Caregivers (and age appropriate subjects) must be willing and able to use an eDiary device daily for a minimum of 20 weeks. 14. Caregivers (and age appropriate subjects) must digitally accept the licensing agreement in the eDiary software at the outset of the study. 15. 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 randomization (maximum possible reports = 14 per week). Are the trial subjects under 18? yes Number of subjects for this age range: 18 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Subjects will be excluded from the study if they meet any of the following criteria: 1. Chronic diarrhoea requiring specific intravenous fluid or nutritional intervention for the diarrhoea and/or its sequelae. 2. Surgical disruption of the enterohepatic circulation. 3. Liver transplant. 4. Decompensated cirrhosis [international normalized ratio (INR) > 1.5 albumen 15 x ULN at screening. 6. History or presence of other concomitant liver disease. 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. Known diagnosis of human immunodeficiency virus (HIV) infection. 9. Cancers except for in situ carcinoma, or cancers treated at least 5 years prior to screening with no evidence of recurrence. 10. Any female who is pregnant or lactating or who is planning to become pregnant within 20 weeks of randomization. 11. Any known history of alcohol or substance abuse. 12. Administration of bile acid or lipid binding resins within 30 days prior to randomization and throughout the trial. 13. Investigational drug, biologic, or medical device within 30 days prior to randomization, or 5 half-lives of the study agent, whichever is longer. 14. 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. 15. 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 |
|---|---|
| Main Objective: To evaluate the safety and tolerability of LUM001 in paediatric subjects with ALGS. To evaluate the effect of LUM001 versus placebo on serum bile acids associated with ALGS. To evaluate the effect of LUM001 versus placebo on liver enzymes associated with ALGS. To evaluate the effect of LUM001 versus placebo on pruritus associated with ALGS. To explore the effect of LUM001 versus placebo on other biochemical markers associated with ALGS.;Secondary Objective: Not applicable.;Primary end point(s): The primary efficacy endpoint is change from baseline to Week 13 in fasting serum bile acids.;Timepoint(s) of evaluation of this end point: Week 0 and week 13. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary efficacy endpoints include change from baseline to Week 13 (compared to placebo) in liver enzymes (ALP, AST, ALT) and pruritus as measured by the average daily score of the ItchRO instrument. The average daily score will be calculated using the 7 days pre-treatment for baseline, and the last 7 days of treatment for Week 13 Exploratory efficacy endpoints include: Change from baseline in fasting serum bile acid level at Weeks 5 and 9. Change from baseline for liver enzymes (ALT, AST, ALP) at Weeks 5 and 9. Change from baseline in pruritus as measured by the average daily ItchRO (Observer ItchRO/patient ItchRO) at Weeks 5 and 9. The average daily score will be calculated using the 7 days prior to each visit. Change from baseline for other biochemical markers of cholestasis (total and conjugated bilirubin, total cholesterol, LDL-C) at Weeks 5, 9 and 13. Responder analysis: pruritus response rates as measured by ItchRO (Observer ItchRO/patient ItchRO) at Weeks 5, 9 and 13. Change from baseline in the clinician administered pruritus scale, at Weeks 2, 5, 9 and 13. Change from baseline in bile acid synthesis [serum 7a-hydroxy-4-cholesten-3-one (7aC4)] at Weeks 5, 9 and 13. Change from baseline for PedsQL at Week 13. Other efficacy endpoints include: Patient Impression of Change (PIC) at Week 13. Caregiver Impression of Change (CIC) at Week 13. Caregiver Global Therapeutic Benefit (CGTB) assessment at Week 13. In addition, the following exploratory evaluations will be conducted if the results of the primary and secondary analyses illustrate a difference between drug and placebo treated subjects: Change from baseline for other biochemical markers [autotaxin and lysophosphatidic acid (LPA)] at Weeks 5, 9 and 13. Change from baseline for urine measures of bile acid at Week 13. Change from baseline for measures of bile acid synthesis (FGF-19 and FGF-21) at Weeks 5, 9 and 13.;Timepoint(s) of evaluation of this | — |
Countries
United Kingdom
Contacts
Public ContactVice President, Operations
Lumena Pharmaceuticals, Inc.
Outcome results
None listed