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 the efficacy of ALXN1840 administered for 48 weeks, compared to SoC, on copper control in participants with WD aged 3 to < 18 years of age at the time of enrollment |
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E.2.2 | Secondary objectives of the trial |
- Evaluate the safety and tolerability of ALXN1840 administered for up to 48 weeks. - Evaluate PD and biomarkers of ALXN1840 vs SoC administered for 48 weeks. - Evaluate the effects of ALXN1840 and SoC on the NCC responder rate. - Evaluate the effects of ALXN1840 and SoC on participant reported disability status. - Evaluate the effects of ALXN1840 and SoC on rater-blinded neurological status. - Evaluate PK of ALXN1840 administered for 48 weeks. - Evaluate the effects of ALXN1840 and SoC on global clinical symptoms as assessed by the Investigator. - Evaluate the effects of ALXN1840 and SoC on hepatic status.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply: Age 1. Participants must be aged 3 to <18 years at time of signing the informed consent/assent. Type of Participants and Disease Characteristics 2. Established diagnosis of WD by Leipzig-Score ≥ 4 documented by testing as outlined in the 2012 European Association for the Study of Liver WD Clinical Practice Guidelines (Ferenci, 2003; EASL, 2012). Note: Historical test results for WD, including some or all of the following: presence of KF rings, neurologic symptoms, serum ceruloplasmin below the reference range, Coombs-negative hemolytic anemia, elevated liver or urinary copper, presence of mutations in the ATP7B gene, or other, as considered appropriate, may be used instead to confirm the diagnosis of Wilson disease. 3. Participant's parent/proxy must be willing and able to give written informed consent and the participant must be willing to give written informed assent (if applicable as determined by the central or local Institutional Review Board [IRB]/Institutional [or Independent] Ethics Committee [IEC]). If allowable per local regulations, a participant’s Legally Acceptable Representative (LAR) may provide informed consent if a participant is unable to do so. 4. Adequate venous access to allow collection of required blood samples. 5. Able to swallow intact ALXN1840 tablets or mini-tablets. Participants who require gastrostomy devices for feeding or medications may be enrolled if the inner diameter of the tube can accommodate an intact tablet or minitablet without obstruction. 6. Willing to avoid intake of foods and drinks with high contents of copper throughout the study duration Sex 7. Female participants of childbearing potential and male participants must follow protocol-specified contraception guidance as described in Section 10.4 of the protocol. Informed Consent 8. Capable of giving signed informed consent or assent as described in Section 10.1.3 of the protocol, which includes compliance with the requirements and restrictions listed in the informed consent or assent form and in this protocol. |
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E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply: Medical Conditions 1. Decompensated hepatic cirrhosis. 2. MELD score > 13 (ages 12 to <18) or PELD score > 13 (ages 3 to < 12). 3. Modified Nazer score > 7. 4. Clinically significant gastrointestinal (GI) bleed within past 3 months 5. Alanine aminotransferase (ALT) > 2 × upper limit of normal (ULN) for participants treated for > 28 days with WD therapy (Cohort 1). 6. ALT > 5 × ULN for treatment naïve participants or participants who have been treated for ≤ 28 days (Cohort 2) 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. History of seizure activity within 6 months prior to informed consent/assent. Prior/Concomitant Therapy 10. Previous use of ALXN1840 or ammonium tetrathiomolybdate. 11. The use of an investigational drug within 30 days before initiation of the first dose of study intervention. Diagnostic assessments 12. Participants in renal failure, defined as in end-stage renal disease on dialysis (chronic kidney disease stage 5 [CKD 5]) or estimated glomerular filtration rate < 30 mL/min/1.73m2. 13. Active infection with hepatitis B virus (positive hepatitis B surface antigen) or C virus (participants with positive hepatitis C antibody result would require confirmation of active disease with a positive hepatitis C polymerase chain reaction test), or seropositivity for HIV. 14. Any disability acquired from trauma or another illness that, in the opinion of the Investigator, could interfere with evaluation of disability due to WD. 15. Systemic disease or other illness, or any deviation in laboratory values that are confirmed on re-examination to be clinically significant by the Investigator that would, in the opinion of the Investigator, compromise participant safety or interfere with the collection or interpretation of study results. Other Exclusions 16. Pregnant (or females who are planning to become pregnant) or breastfeeding females. 17. Known sensitivity to ALXN1840, ALXN1840 excipients (anhydrous di-calcium phosphate, anhydrous sodium carbonate), or any of the ingredients contained in ALXN1840 or related compounds. 18. 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 14 g of alcohol: a half pint (approx. 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. 19. Abuse of illicit or prescribed drugs. 20. In the opinion of the Investigator, the participant and/or their parent/proxy is likely to be non-compliant or uncooperative during the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Percentage change from baseline (Day 1) to 48 weeks in NCC in plasma. For ALXN1840-treated participants, the NCC in plasma will be corrected for the amount of copper bound to the ALXN1840 TPC (NCCcorrected) |
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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) |
• Incidence of adverse AEs/SAEs, AESIs, tolerability, clinical laboratory test data (including liver function tests), neurological and physical examination findings, 12-lead ECG data, and vital signs. • AUEC for NCC • AUEC for plasma total copper • Biomarkers: observed, absolute and percentage changes of ceruloplasmin-bound copper and ceruloplasmin • NCC responder rate • Change from baseline to Week 48 in the UWDRS Part II total score • Change from baseline in UWDRS Part III total score or individual items/subscales, as appropriate • PK: Cmax, tmax, Ctrough and AUCtau on Day 1, Day 43 (Week 6), and Day 337 (Week 48) for plasma total molybdenum and plasma ultrafiltrate molybdenum concentrations, accumulation ratio of Day 43 to Day 1 and Day 337 to Day 1 based on Cmax, Ctrough and AUCtau • Derived secondary PK parameters such as apparent total body clearance (CL/F) and apparent volume of distribution (Vd/F) (as appropriate) • CGI-I • Change from Baseline to Week 48 in CGI-S • Change from Baseline to Week 48 in MELD score (ages 12 years and older) or PELD score (ages 3 to < 12 years) • Change from Baseline to Week 48 in Modified Nazer score |
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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) | 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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard of Care (Penicillamine, Trientine, and Zinc) |
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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 | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 |
Japan |
Korea, Republic of |
France |
Germany |
Poland |
Spain |
United Kingdom |
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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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The end of the study is defined as the date the last participant completes the last visit shown in the Schedule of Activities (SoA) of Period 2. |
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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 | 2 |
E.8.9.1 | In the Member State concerned days | 10 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 11 |