Pharmacokinetic and Pharmacodynamic Characterization of Trientine Dihydrochloride in Wilson's Disease: A Multicenter, Open-Label, Prospective Study

Trial ID: 2024-516431-27-00
Protocol: TR-004
Sponsor: Univar Solutions B.V.

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Diseases & Conditions

Hepato-lenticular degeneration

Objectives

The primary objective of this study is to characterize the **Cufence** dose-exposure-copper markers relationships through population pharmacokinetic-pharmacodynamic (PKPD) modeling in patients with **Wilson's Disease**. This involves evaluating the influence of patient characteristics on relevant model parameters, such as apparent clearance, apparent volume of distribution, and drug potency. Understanding these relationships is clinically relevant as it aids in optimizing dosing regimens to improve therapeutic outcomes and minimize adverse effects in patients with Wilson's Disease.

Secondary objectives include:

Investigating the contribution of trientine, N(1)-acetyltriethylenetetramine (MAT), and N(1),N(10)-diacetyltriethylenetetramine (DAT) to the exposure and copper markers in patients with Wilson's Disease.
Exploring the relationship between Cufence exposure and clinical efficacy measures, such as changes in neurological disease, psychiatric symptoms, and hepatic disease.
Examining the relationships between copper markers (24-hour urinary copper excretion, total serum copper, ceruloplasmin, non-ceruloplasmin bound copper) and clinical efficacy measures in patients with Wilson's Disease.
Assessing the safety and tolerability of Cufence in patients with Wilson's Disease.

Participants

The clinical trial involves a total of **5 participants** diagnosed with **Wilson's Disease**, a rare genetic disorder characterized by excessive copper accumulation in the body. The study population includes both male and female subjects, with an age range starting from 5 years and above. Participants have previously been treated with D-penicillamine or zinc, depending on their age, as part of their standard care for Wilson's Disease. The trial population was selected based on a confirmed diagnosis using a Leipzig score of 4 or higher, ensuring that all participants meet the necessary criteria for inclusion. The study considers lifestyle factors such as the use of effective birth control methods for female participants of childbearing potential. The trial includes a vulnerable population, indicating that special considerations are in place to protect the participants' welfare throughout the study.

Plans and Procedures

The clinical trial is designed to evaluate the **pharmacokinetics** and **pharmacodynamics** of Cufence (trientine dihydrochloride) in patients with **Wilson's Disease**. This is a prospective, open-label, multicenter study aimed at characterizing the dose-exposure-copper markers relationship through population pharmacokinetic-pharmacodynamic modeling. The trial will assess the influence of patient characteristics on model parameters such as apparent clearance, volume of distribution, and drug potency. The study is expected to run from September 2021 to September 2025, with a maximum treatment period of 24 months for each participant.

Participants will be required to attend several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, prior treatment history, and a diagnosis of Wilson's Disease with a Leipzig score of 4 or higher. Female participants of childbearing potential must have a negative pregnancy test at both the screening and baseline visits and use a highly effective method of birth control throughout the study. The study will include follow-up visits to monitor the concentration of trientine in plasma, trientine clearance, and various copper markers, including 24-hour urinary copper excretion, serum copper, and ceruloplasmin levels. Secondary endpoints will evaluate changes in neurological and psychiatric symptoms, as well as hepatic disease status.

The expected length of participant involvement is up to 24 months, with conditions for early termination including adverse events leading to discontinuation of treatment or inability to comply with study requirements. The trial is not categorized as low intervention and is classified as a Phase 4 study. The study will not involve any pediatric formulations, and the administration of Cufence will be oral, with a maximum daily dose of 1600 mg. Participants will be monitored for adverse events, and any significant changes in health status will be documented and analyzed as part of the study's safety evaluation.

Treatment

The clinical trial involves the administration of **Cufence 200 mg hard capsules**, which contain the active substance **trientine dihydrochloride**. This experimental medication is provided in the form of hard capsules and is intended for oral administration. The maximum daily dose of Cufence is 1600 mg, with a total maximum dose of 1168000 mg over the course of the study. The treatment period is set to a maximum of 24 months. The primary objective of the trial is to characterize the dose-exposure-copper markers relationship in patients with Wilson's disease through population pharmacokinetic-pharmacodynamic modeling. The study will also evaluate the influence of patient characteristics on relevant model parameters, such as apparent clearance, apparent volume of distribution, and drug potency.

In addition to the experimental treatment, participants may receive non-experimental treatments, which include various alimentary tract and metabolism products. These treatments are considered standard-of-care therapy and are not the primary focus of the study. The administration of these non-experimental treatments will be monitored to ensure compliance and to assess any potential interactions with the experimental medication. Participant compliance with the dosing schedule will be closely monitored throughout the study to ensure accurate data collection and to maintain the integrity of the trial results.

Efficacy

The efficacy of Cufence (Trientine Dihydrochloride) in patients with Wilson's Disease will be assessed through a series of primary and secondary endpoints. Primary endpoints include the concentration of **trientine** in plasma, trientine clearance (CL/F), volume(s) of distribution (V/F), and several copper markers such as 24-hour urinary copper excretion (UCE), non-ceruloplasmin bound copper (NCC), serum copper, and serum ceruloplasmin. Additionally, patient characteristics will be evaluated for covariates.

Secondary endpoints will focus on the concentration of MAT and DAT in plasma, as well as pharmacokinetic parameters such as AUC0-t, Cmax, and Ctrough for trientine and its metabolites. Changes in neurological disease status will be measured using the Unified Wilson’s Disease Rating Scale (UWDRS), while psychiatric symptoms will be assessed with tools like SCID-5, MMSE, EQ-5D-3L, PHQ-9, PHQ-9-A, and CBCL. Hepatic disease changes will be evaluated through a full liver panel to determine scores such as APRI, Child-Pugh, FIB4, and the New Wilson Index (Dhawan Index), along with Fibroscan results. The number of adverse events (AEs), including those leading to discontinuation of treatment, will also be recorded.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient (or a representative) must provide written, informed consent before the start of any study procedures.
Male and female patient aged ≥ 5 years at time of consent.
Diagnosis of WD previously determined by the physician based on a Leipzig score ≥ 4.
Patient (≥ 18 years) has previously been treated with D-penicillamine for WD.
Patient (< 18 years) has previously been treated with D-penicillamine or zinc for WD.
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).
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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Exclusion Criteria

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
Uncontrolled neurological disease according to the judgement of the physician.
Patient has severe anaemia defined as hemoglobin of < 9 g/dL.
Patient has a known intolerance, allergy or sensitivity to trientine dihydrochloride, including any component of the study medication.
Female patient is pregnant or lactating.
Any patients who lack the capacity to consent, including the parent(s) of a paediatric patient.