E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Wilson Disease |
Wilsons sygdom |
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E.1.1.1 | Medical condition in easily understood language |
Wilson's disease is a rare inherited disorder that causes copper to accumulate in the liver, brain and other vital organs. If left untreated this can lead to significant damage and even death. |
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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 | 22.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019819 |
E.1.2 | Term | Hepato-lenticular degeneration |
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 principle objective for this study is to provide more data on possible pharmacokinetic (PK) and pharmacodynamic (PD), further evaluate the efficacy and safety and find out the optimal treatment dose in adult and paediatric patients. |
At karakterisere dosiseksponering for Cufence – og forholdene mellem kobbermarkører (24-timers udskillelse af kobber i urinen (UCE)), total serumkobber (Cu), ceruloplasminbundet kobber, non-ceruloplasminbundet kobber (NCC) gennem populationsfarmakokinetisk/farmakodynamisk (PKPD) modellering hos patienter med Wilsons sygdom og at evaluere påvirkningen af patientegenskaber på relevante modelparametre, såsom tilsyneladende clearance, tilsyneladende distributionsvolumen og lægemiddelstyrke. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are as follows: 1. to investigate the contribution of Cufence to the exposure and copper markers in patients with Wilson Disease. 2. To investigate the relationship between Cufence exposure and clinical efficacy measures in patients with Wilson Disease. 3. To investigate the relationship between copper markers and clinical efficacy measures in patients with Wilson Disease. |
• At undersøge bidraget af trientin, N(1)-acetyltriethylentetramin (MAT) og N(1),N(10)-diacetyltriethylentetramin (DAT) på eksponeringen og kobbermarkører* (eksponeringsrespons) hos patienter med Wilsons sygdom. • At undersøge forholdet mellem Cufence' eksponering (systemisk trientin, MAT og DAT) og kliniske virkningsmål (ændringer i neurologisk sygdom, ændringer af psykiske symptomer og ændringer af leversygdom) hos patienter med Wilsons sygdom. • At undersøge forholdet mellem kobbermarkører (24-timers UCE, total serum Cu, ceruloplasminbundet kobber, NCC) og kliniske virkningsmål (ændringer i neurologisk sygdom, ændringer i psykiske symptomer og ændringer i leversygdom) hos patienter med Wilsons sygdom. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The following criteria must be met by all patients considered for study participation: 1. Patient (or a representative) must provide written, informed consent before the start of any study procedures. 2. Male and female patient aged ≥ 5 years at time of consent. 3. Diagnosis of WD previously determined by the physician based on a Leipzig score ≥ 4. 4. Patient (≥ 18 years) has previously been treated with D-penicillamine for WD. 5. Patient (< 18 years) has previously been treated with D-penicillamine or zinc for WD. 6. For female patients of childbearing potential, a negative pregnancy test at the Screening visit and the Baseline visit is required. In addition, a highly effective method (failure rate <1%) of birth control must be used during the study which includes (but is not limited to) the following: - vasectomized partner (at least 6 months prior to dosing); - oral, patch, or injected contraceptives, or vaginal hormonal device (i.e. NuvaRing®), in use for at least 3 consecutive months prior to study dosing and throughout the study duration; - implanted or intrauterine contraceptives in use for at least 6 consecutive months prior to study dosing and throughout the study duration; - abstinence (must agree to use a highly effective method if they become sexually active during the study). 7. Patient is considered to be able to complete study requirements and attend the study visits, in the opinion of the investigator. |
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E.4 | Principal exclusion criteria |
Patients will be excluded if they meet any of the following criteria: 1. Patient has evidence of uncontrolled liver disease, including but not limited to: a. New Wilson index (Dhawan Index) > 10 b. Alanine aminotransferase (ALT) > 5x upper limit of normal (ULN) c. Aspartate aminotransferase (AST) > 5x ULN d. MELD score > 13 (only applicable for patients that are ≥ 12 years of age) e. Acute liver failure f. Hepatic malignancy 2. Uncontrolled neurological disease according to the judgement of the physician. 3. Patient has severe anaemia defined as hemoglobin of < 9 g/dL. 4. Patient has a known intolerance, allergy or sensitivity to trientine dihydrochloride, including any component of the study medication. 5. Female patient is pregnant or lactating. 6. Any patients who lack the capacity to consent including the parent(s) of a paediatric patient.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Concentration of trientine in plasma • Trientine clearance (CL/F) and volume(s) of distribution (V/F) • 24-h UCE (copper marker) • NCC* (copper marker) • Serum copper (copper marker) • Serum ceruloplasmin (copper marker) • Patient characteristics for covariates
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• Koncentration af trientin i plasma • Trientinclearance (CL/F) og distributionsvolumen(er) (V/F) • 24-timers UCE (kobbermarkør) • NCC* (kobbermarkør) • Serumkobber (kobbermarkør) • Serumceruloplasmin (kobbermarkør) • Patientegenskaber for kovariater |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Concentration of trientine in plasma at Visit 2- Visit 10 • Trientine clearance (CL/F) and volume(s) of distribution (V/F) at Visit 2- Visit 10 except Visit 5 • 24-h UCE (copper marker)at Visit 2- Visit 10 except Visit 5 • NCC* (copper marker) at Visit 2- Visit 10 except Visit 5 • Serum copper (copper marker)- Visit 2- Visit 10 except Visit 5
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E.5.2 | Secondary end point(s) |
• Concentration of MAT in plasma • Concentration of DAT in plasma • AUC0-tau, Cmax and Cmin for trientine and metabolites (by NCA) • Number of AEs including number of AEs leading to discontinuation of treatment with Cufence • Changes in neurological disease status (Unified Wilson's Disease Rating Scale (UWDRS)) • Changes in psychiatric symptoms (SCID-5, MMSE, EQ-5D-3L, PHQ-9, PHQ-9-A, CBCL) • Changes in hepatic disease (full liver panel to determine the APRI, the Child-Pugh score, the FIB4 index and the New Wilson Index (Dhawan Index), and Fibroscan) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Concentration of MAT in plasma at Visit 2- Visit 10 • Concentration of DAT in plasma at Visit 2- Visit 10 • AUC0-tau, Cmax and Cmin for trientine and metabolites (by NCA) at Visit 2- Visit 10 except Visit 5 • Number of AEs including number of AEs leading to discontinuation of treatment with Cufence at all visits • Changes in neurological disease status (Unified Wilson's Disease Rating Scale (UWDRS)) at Visit 2,4 and Visit 6-10 • Changes in psychiatric symptoms (SCID-5, MMSE, EQ-5D-3L, PHQ-9, PHQ-9-A, CBCL)-various timepoint for each assessment • Changes in hepatic disease (full liver panel to determine the APRI, the Child-Pugh score, the FIB4 index and the New Wilson Index (Dhawan Index), and Fibroscan) |
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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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Cufence (Trientine Dihydrochloride)- fixed dose as per SmPc |
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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 | 11 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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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Follow up call 28 days after LVLS. |
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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 | 9 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 1 |