E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10047988 |
E.1.2 | Term | Wilson's disease |
E.1.2 | System Organ Class | 100000004850 |
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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 |
To evaluate change in liver copper (Cu) concentration following treatment with ALXN1840 at Week 48 in patients with Wilson disease (WD) |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to: - To assess change in liver histopathology following treatment with ALXN1840 - To evaluate the safety of ALXN1840 in patients with WD - To evaluate pharmacokinetics (PK) of ALXN1840 - To evaluate the effects of ALXN1840 on clinical symptoms please see study protocol for more details. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients must be ≥ 18 years of age at the time of signing the informed consent. 2. Diagnosis of WD by Leipzig Criteria >4 documented by testing as outlined in the 2012 European Association for the Study of Liver (EASL) WD Clinical Practice Guidelines (Ferenci, 2003; EASL, 2012) 3. Continuous treatment for WD with penicillamine, trientine or zinc for at least 1 year in duration prior to screening 4. Adequate venous access to allow collection of required blood samples 5. Able to swallow intact ALXN1840 tablets 6. Body mass index < 30 kg/m2 7. Able to cooperate a percutaneous liver biopsy, including having the ability to lie flat and still throughout the procedure, and tolerate mild sedation, if required 8. Adequately visualized landmarks on screening ultrasound without evidence of significant ascites, hemangiomas, or other findings that would put the patient at unnecessarily high risk of complications 9. Male and female patients of reproductive potential must agree to remain abstinent or use an effective method of contraception throughout the duration of the study 10. Capable of giving signed informed consent |
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E.4 | Principal exclusion criteria |
1. Decompensated cirrhosis or MELD score >13 2. Modified Nazer score > 7 (Dhawan, 2005) 3. Clinically significant gastrointestinal bleed within past 3 months 4. Alanine aminotransferase > 2 × upper limit of normal (ULN) 5. History of bleeding abnormality or known coagulopathy, including platelet count < 100,000, and international normalized ratio for prothrombin time (PT-INR) ≥ 1.5; coagulopathy or bleeding risk due to medication is acceptable if medication can be safety discontinued for biopsy 6. Patient unwilling to accept blood products 7. Marked neurological disease requiring either nasogastric feeding tube or intensive inpatient medical care 8. Hemoglobin less than lower limit of the reference range for age and sex 9. Systemic disease or other illness, any disability acquired from trauma or another illness, or any deviation in laboratory values that are confirmed on re-examination to be clinically significant by the Investigator 10. Patients in renal failure, defined as in end-stage renal disease on dialysis (chronic kidney disease [CKD] 5) or creatinine clearance < 30 mL/min 11. Known sensitivity to ALXN1840, ALXN1840 excipients or any of the ingredients contained in ALXN1840 12. History or presence of/significant history of or current cardiovascular, respiratory, renal, gastrointestinal, endocrinological, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs 13. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years 14. Current or chronic history of liver disease not associated with WD, or known hepatic or biliary abnormalities (with the exception of asymptomatic gallstones) 15. Use of nonprescription/ over-the-counter medications, including herbal remedies, nutritional supplements, or mineral supplements containing Cu, zinc, iron or Mo after dosing on Day 1 through the end of the study. 16. In the opinion of the Investigator, the patient and/or their legal guardian is likely to be non-compliant or uncooperative during the study 17. Participation in any other interventional study during the study. 18. Presence of hepatitis B surface antigen or positive hepatitis C antibody or RNA test result at screening or within 3 months prior to first dose of study drug. NOTE: Patients with positive Hepatitis C antibody due to prior resolved disease can be enrolled if a confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtained. NOTE: The RNA test is optional and patients with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing 19. Positive human immunodeficiency virus (HIV) antibody test 20. Regular alcohol consumption within 6 months prior to the study defined as > 14 units for males or > 7 units for females per week. One unit is equivalent to 8 g of alcohol: a half pint (approx. 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. 21. Abuse of illicit or prescribed drugs 22. Sensitivity to any drug or other allergy that, in the opinion of the Investigator or Alexion Medical Monitor, contraindicates participation in the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline to Week 48 in liver Cu concentration |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary endpoints include the following: - Change from baseline to Week 48 in steatosis, inflammation, and fibrosis - Adverse events (AEs), vital signs, ECGs, clinical laboratory data, and physical examination data - ALXN1840 PK profiles in plasma at Week 6 (Day 43) and Week 36 (Day 253), of which ALXN1840 PK are measured as total molybdenum (Mo) and plasma ultrafiltrate (PUF) Mo - Pre-dose trough ALXN1840 concentrations in plasma at each study site visit - ALXN1840 concentrations in the liver biopsy specimen. - Change from baseline in Clinical Global Impression-Improvement (CGI-I) Scale and the Clinical Global Impression-Severity (CGI-S) Scale |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | 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 | No |
E.8.1.1 | Randomised | No |
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 |
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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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 |
Australia |
Austria |
Belgium |
Canada |
Denmark |
France |
Germany |
Korea, Republic of |
New Zealand |
Poland |
Russian Federation |
Serbia |
Singapore |
Spain |
Sweden |
Turkey |
United Kingdom |
United States |
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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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LPLV of the 48-week extension period |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |