E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Alagille syndrome (ALGS) is an autosomal dominant with variable penetration genetic multisystem disorder. The clinical diagnosis is based on the presence of intrahepatic bile duct paucity on liver biopsy in association with at least three of the major clinical features: chronic cholestasis, cardiac disease, skeletal abnormalities, ocular abnormalities and characteristic facial features. |
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E.1.1.1 | Medical condition in easily understood language |
Alagille syndrome is a genetic disorder that can affect the liver, heart, and other parts of the body. One of the major features of ALGS is liver damage caused by abnormalities in the bile ducts. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053870 |
E.1.2 | Term | Alagille syndrome |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objectives are to evaluate: 1. The long-term safety and tolerability of LUM001 in children with ALGS. 2. The effect of LUM001 on serum bile acid levels in children with ALGS. 3. The effect of LUM001 on biochemical markers of cholestasis and liver disease in children with ALGS. 4. The effect of LUM001 on pruritus in children with ALGS. 5. The long-term effect of LUM001 in children with ALGS 48 weeks of treatment.
Additional objectives for the Optional Follow-up Treatment Period are: 1. To explore twice a day (BID) dosing regimen and higher daily dosing of LUM001; 2. Assessment of alpha-fetoprotein (AFP) levels, a marker of hepatocellular carcinoma; 3. Assessment of the palatability of the LUM001 formulation in all subjects, by-proxy in subjects <4 years old and by patient questionnaire in children ≥4 years old. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To participate in this study subjects must meet all of the following criteria: 1. Male or female between the ages of 12 months and 18 years inclusive. 2. Diagnosis of ALGS based on the diagnostic criteria. 3. Evidence of cholestasis (one or more of the following): a. Total serum bile acid >3x ULN for age. b. Conjugated bilirubin >1 mg/dL. c. Fat soluble vitamin deficiency otherwise unexplainable. d. GGT >3x ULN for age. e. Intractable pruritus explainable only by liver disease. 4. Females of childbearing potential must have a negative serum pregnancy test during Screening. 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 for 30 days following the last dose of study drug, must agree to use acceptable contraception during the trial. 6. Subject is expected to have a consistent caregiver(s) for the duration of the study. 7. Informed consent and assent (per IRB/IEC) as appropriate. 8. Access to phone for scheduled calls from study site. 9. Caregivers (and age appropriate subjects) must be willing and able to use an eDiary device during the study. 10. Caregivers (and age appropriate subjects) must digitally accept the licensing agreement in the eDiary software. 11. 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 (maximum possible reports = 14 per week). 12. 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 subjects with LUM001 dosing interruption <7 days, or ≥7 days are: Subjects will be considered eligible for the long-term optional follow-up treatment period if they meet the following criteria: 1. The subject has either: a. completed the protocol through the Week 48 visit with no major safety concerns OR b. 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 subject 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. [Subjects who were discontinued for other reasons will be considered on an individual basis.] 2. Females of childbearing potential must have a negative urine or serum pregnancy test (β-human chorionic gonadotropin [β-hCG]) at the time of entry into the long term optional follow-up treatment period. 3. 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. 4. Informed consent and assent (per IRB/EC) as appropriate. 5. Access to phone for scheduled calls from study site. 6. Caregivers (and age appropriate subjects) must be willing and able to use an eDiary device during the study. |
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E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if they meet any of the following criteria: 1. Chronic diarrhea requiring ongoing intravenous fluid or nutritional intervention. 2. Surgical interruption of the enterohepatic circulation. 3. Previous liver transplant. 4. 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). 5. History or presence of other concomitant liver disease. 6. 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). 7. History or presence of gallstones or kidney stones. 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. Recent medical history or current status that suggests that the subject may be unable to complete the study. 11. Any female who is pregnant or lactating or who is planning to become pregnant during the study period. 12. Known history of alcohol or substance abuse. 13. Administration of bile acid or lipid binding resins within 28 days prior to screening and throughout the trial. 14. Known hypersensitivity to LUM001or any of its components. 15. 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. 16. 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. 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. 18. Subjects weighing over 50 kg at screening
Exclusion Criteria for Subjects with LUM001 dosing interruption≥7 days are: All exclusion criteria mentioned for the core study apply upon entry into the long-term optional follow-up period, with the exception of exclusion criterion #18 (subjects weighing over 50 kg at screening). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoints will be the mean change from Week 18 to 22 of fasting serum bile acid levels in subjects who previously responded to LUM001 treatment, as defined by a reduction in sBA ≥50% from baseline to Week 12 or Week 18. A sensitivity analysis will also be conducted using subjects who experienced a reduction from baseline in serum bile acids of ≥50% at the Week 48 measurement. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Serum bile acid levels are measured at baseline, 12, 18, 22 and 48 weeks |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include mean change from Week 18 to Week 22 in liver enzymes (ALP, ALT, and bilirubin [total and direct]) and pruritus as measured by ItchRO (Observer ItchRO/patient ItchRO), in subjects who previously responded to LUM001 treatment, as defined by a reduction in ItchRO scale >1 point from baseline to Week 12 or Week 18. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
These are measured throughout the trial by means of the subject eDiary and clinician scales and questionnaires. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
This trial also contains a double blind, placebo-controlled, randomized drug withdrawal period |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |