| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Alagille syndrome is a childhood disease that affects the liver and different parts of the body. These children have buildup of a fluid made by the liver called bile which can cause severe itch. |
|
| 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 |
|
| 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 primary objective is to demonstrate the efficacy of repeated daily doses of 120 μg/kg/day odevixibat in relieving pruritus in patients with ALGS. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the impact of odevixibat on serum bile acid levels in patients with ALGS.
To evaluate the safety and tolerability of odevixibat in patients with ALGS. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. A male or female patient (of any age) with genetically confirmed diagnosis of ALGS. A patient may be randomized based on genetic testing results in the medical record. If genetic testing results are not available, testing will be performed at Screening Visit 1, and the patient may not be randomized until the genetic diagnosis is confirmed
2. Patient must have a history of significant pruritus and a caregiver reported observed scratching or a patient-reported pruritus score at an average of ≥2 (on 0 to 4 scale), as measured by the Albireo ObsRO instrument (for patients <18 years of age) or the PRO instrument (for patients ≥18 years of age) in the 14 days prior to randomization. For each AM and PM weekly assessment a minimum of 4 out of 7 expected scores must be recorded. The mean of the weekly AM and the mean of the weekly PM scores will be averaged to determine the pruritus score as measured by ObsRO or PRO, if the patient is ≥18 years of age.
3.Patient must have an elevated baseline serum bile acid level. Each of the serum bile acid levels obtained at Screening Visit 1 and Screening Visit 2 must be greater than the upper limit of normal (>ULN)
4.Patient and/or legal guardian must sign informed consent (and assent) as appropriate. Patients who turn 18 years of age (or legal age per country) during the study will be required to re-consent in order to remain in the study
5. Caregivers must be willing and able to use an eDiary device as required by the study and patients ≥8 years of age must be willing to use an eDiary if able to do so
6. Sexually active males and females must agree to use a reliable contraceptive method with ≤1% failure rate (such as hormonal contraception, intrauterine device, or complete abstinence) throughout the duration of the study and 90 days thereafter (from signed informed consent through 90 days after last dose of study drug) |
|
| E.4 | Principal exclusion criteria |
1. Patient with past medical history or ongoing presence of other types of liver disease including, but not limited to, the following:
a) Biliary atresia
b) Progressive Familial Intrahepatic Cholestasis (PFIC)
c) Benign recurrent intrahepatic cholestasis
d) Suspected or proven liver cancer or metastasis to the liver on imaging studies
2. Patient with a past medical history or ongoing presence of any other disease or condition known to interfere with the absorption, distribution, metabolism (specifically bile acid metabolism), or excretion of drugs in the intestine, including but not limited to, inflammatory bowel disease
3. Patient with past medical history or ongoing chronic (i.e. >3 months) diarrhea requiring intravenous fluid or nutritional intervention for treatment of the diarrhea and/or its sequelae
4. Patient has a confirmed past diagnosis of infection with human immunodeficiency virus or other present and active, clinically significant chronic infection
5. Recent infection requiring hospitalization or treatment with parenteral anti-infective within 4 weeks of randomization (Study Day 1) or completion of oral anti-infective treatment within 2 weeks prior to start of Screening Period
6. Cancer within the last 5 years except for basal cell carcinoma
7. Cancer >5 years prior to screening except for non-liver cancers with no evidence of recurrence
8. Chronic kidney disease with an impaired renal function and a glomerular filtration rate <70 mL/min/1.73 m2
9. Patient with surgical history of disruption of the enterohepatic circulation (biliary diversion surgery) within 6 months prior to start of Screening Period
10. Patient has had a liver transplant or a liver transplant is planned within 6 months of randomization
11. Decompensated liver disease, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy
12. International normalized ratio (INR) >1.4 (the patient may be treated with Vitamin K intravenously, and if INR is ≤1.4 at resampling the patient may be randomized)
13. Serum alanine aminotransferase (ALT) >10 × ULN at Screening
14. Serum ALT >15 × ULN at any time point during the last 6 months unless an alternate etiology was confirmed for the elevation
15. Total bilirubin >15 × ULN at Screening
16. Patient suffers from uncontrolled, recalcitrant pruritic condition other than ALGS. Examples include, but not limited to, refractory atopic dermatitis or other primary pruritic skin diseases |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in scratching to Month 6 (Weeks 21 to 24) as measured by the Albireo ObsRO caregiver instrument |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change from baseline in scratching to Month 6 (Weeks 21 to 24)
|
|
| E.5.2 | Secondary end point(s) |
| Change in serum bile acid levels from baseline to the average of Week 20 and Week 24 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From baseline to the average of Week 20 and Week 24 |
|
| 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 | No |
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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
| Yes |
| 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 | 17 |
| 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 |
| Canada |
| Israel |
| Malaysia |
| New Zealand |
| United States |
| France |
| Poland |
| Netherlands |
| Germany |
| Italy |
| Belgium |
| Turkey |
| United Kingdom |
|
| 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
|
The end of the study is defined as follows:
• End of study in one country: last patient last visit (LPLV) in the country and sites in the country are closed
• End of study globally: LPLV globally and all study sites closed |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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