Prospective Study to Characterize the Pharmacokinetics and Pharmacodynamics of Cufence (Trientine Dihydrochloride) in Wilson Disease Patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Univar Solutions B.V.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

23 Feb 2021 → 20 Sep 2025

Decision date (initial)

2024-09-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-516431-27-00

EudraCT number

2020-004604-33

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacodynamic, Pharmacokinetic, Efficacy

To characterize the Cufence dose – exposure – copper markers (24-hr urinary copper excretion (UCE), total serum copper (Cu), ceruloplasmin, non-ceruloplasmin bound copper (NCC)) relationships through population pharmacokinetic-pharmacodynamic (PKPD) modelling in Wilson’s disease patients and to evaluate the influence of patient characteristics on relevant model parameters, such as apparent clearance, apparent volume of distribution and drug potency.

Secondary objectives 4

1. To investigate the contribution of trientine, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT) to the exposure and copper markers* (exposure-response) in patients with Wilson’s disease.
2. To investigate the relationship between Cufence exposure (systemic trientine, MAT and DAT) and clinical efficacy measures (changes in neurological disease, changes in psychiatric symptoms and changes in hepatic disease) in patients with Wilson’s disease.
3. To investigate the relationships between copper markers (24-hr UCE, total serum Cu, ceruloplasmin, NCC) and clinical efficacy measures (changes in neurological disease, changes in psychiatric symptoms and changes in hepatic disease) in patients with Wilson’s disease.
4. To investigate the safety and tolerability of Cufence in patients with Wilson’s disease.

Conditions and MedDRA coding

Wilson’s Disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

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.

Exclusion criteria 6

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. Model for End-Stage Liver Disease (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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. Concentration of trientine in plasma
2. Trientine clearance (CL/F) and volume(s) of distribution (V/F)
3. 24-hr UCE (copper marker)
4. NCC (copper marker)
5. Serum copper (copper marker)
6. Serum ceruloplasmin (copper marker)
7. Patient characteristics for covariates

Secondary endpoints 7

1. Concentration of MAT in plasma
2. Concentration of DAT in plasma
3. AUC0-t, Cmax and Ctrough for trientine and metabolites. (As secondary endpoint, pre-dose concentrations are reported and summarized using NCA. While the pre-dose PK samples are collected shortly prior to the next dose, the pre-dose concentration is assumed to approximate the Ctrough.)
4. Number of AEs including number of AEs leading to discontinuation of treatment with Cufence
5. Changes in neurological disease status (Unified Wilson’s Disease Rating Scale (UWDRS))
6. Changes in psychiatric symptoms (SCID-5, MMSE, EQ-5D-3L, PHQ-9, PHQ-9-A, CBCL)
7. 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)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Univar Solutions B.V.

Sponsor organisation

Univar Solutions B.V.

Address

Schouwburgplein 30

City

Rotterdam

Postcode

3012 CL

Country

Netherlands

Scientific contact point

Organisation

Univar Solutions B.V.

Contact name

Carlot Kruse

Public contact point

Organisation

Univar Solutions B.V.

Contact name

Carlot Kruse

Third parties 1

Locations

4 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 56 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications