Study Comparing Once Daily Dose of 900mg of TETA 4HCL Against Cuprior® (450mg Trientine Base, Twice Daily).

Study Overview
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Brief Summary
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A randomised, open-label study evaluating the pharmacokinetics, safety, and tolerability of a new once daily dose of 900mg of TETA 4HCL by comparing it against the current marketed Cuprior® formulation (450mg trientine base, twice daily) in healthy male and female participants.

Detailed Description
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This is a single centre, phase I, randomized, controlled trial with a crossover design to evaluate the pharmacokinetics (PK), safety, and tolerability of a new once daily TETA 4HCL formulation (300mg) (3x300mg trientine base tablets, OD) compared to the current marketed Cuprior® formulation (150mg) (3x150mg trientine base tablets, BD) in adult healthy male and female participants. Participants: 26 healthy participants will be enrolled to ensure 24 participants complete the study, with a balanced gender split. Treatment: Participants will be randomized to receive either the new or the current formulation of the drug, and then switch to the other formulation after a period of time (see study flow chart below). To remain in line with current EU SmPC and US PIL, being: EU daily dose range of 450-975 mg of trientine base US daily dose range of 150-1500mg trientine base the following treatments will be administered according to the treatment allocation schedule below: A: 900mg TETA 4HCl once a day / new formulation = 3 tablets of 300mg trientine base as a single dose B: 900mg TETA 4HCl marketed Cuprior formulation = 6 tablets of 150mg trientine base in two equally divided doses Patients will be randomised in a 1:1 ratio to either one of the following sequences: Treatment Sequence Period 1 Period 2 Sequence 1 Treatment A Treatment B Sequence 2 Treatment B Treatment A Assessments: Participants will be assessed for eligibility criteria and will be monitored closely throughout the study. Assessments will be performed during the study and at the end of the study follow-up visit. Duration: The duration of the study will be up to approximately 7 weeks, from screening to follow-up: Screening will take place between days -28 and -2 In-house period from D-1 to D3 with dosing on D1 of each treatment period Follow-up will take place on D7 of Treatment Period 2 At least 5 days and a maximum of 10 days between treatment period study drug administration Objective: To evaluate the PK, safety, and tolerability of the new once daily TETA 4HCL formulation compared to the current marketed Cuprior® formulation.

Official Title
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A Phase I, Single Centre, Randomised, Interventional, Open-Label, Cross-Over Study to Evaluate the Pharmacokinetics (PK) and the Safety and Tolerability of a Total Daily Dose of 900mg of TETA 4HCL, Comparing a New Once Daily TETA 4HCL Formulation (300mg) (3x300mg Trientine Base Tablets, OD) With the Current Marketed Cuprior® Formulation (150mg) (3x150mg Trientine Base Tablets, BD) in Adult Healthy Male and Female Participants

Conditions
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Wilson's Disease

Intervention / Treatment
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* Drug: 900mg TETA 4HCl Once Daily Formulation
* Drug: 900mg TETA 4HCl Cuprior®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18 to 40 years Body weight: ≥ 50 kg BMI: 18.0 to 25.0 kg/m2 Health: Generally healthy, with no clinically significant illnesses or surgeries in the past 12 weeks Willingness to comply with trial procedures and restrictions Exclusion Criteria: Significant current or recurrent disease Acute significant disease or illness within 7 days before the start of the trial Clinically significant deviations in blood tests An estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73m2 Positive test for alcohol, drugs of abuse, hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) Pregnant or breastfeeding women History or regular use of tobacco or other nicotine-containing products within 6 months before the start of the trial Treatment with an investigational drug within 90 days or 5 half-lives (whichever is longer) or exposure to more than 3 investigational drugs within 12 months of first study drug administration Use of prescription medication (excluding female hormonal contraception or hormone replacement therapy)within 30 days or 5 half lives (whichever is longer) prior to first study drug administration, or use of over-the-counter (OTC) medication (including multivitamin, herbal, or homeopathic preparations; Paracetamol use ≤2g per day is permitted) during the 14 days or 5 half-lives of the drug (whichever is longer) before first study drug administration History of sensitivity/allergy to the study medications or components thereof (mannitol, colloidal anhydrous silica, glycerol dibehenate or magnesium-stearate) Donation or loss of 450 mL or more of blood or plasma within 16 weeks prior to first trial medication administration or intention to donate blood in the 16 weeks after completing the trial An inability to follow a standardised diet and meal schedule or inability to fast, as required during the trial Participants deemed to have difficult veins for cannulation/blood draws

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Once Daily Dose Formulation (Treatment A)<br>1 x 900mg TETA 4HCl, new once daily formulation (3x300mg trientine base tablets as a single AM dose) | Drug: 900mg TETA 4HCl Once Daily Formulation<br>* 3x300mg trientine base tablets as a single AM dose<br>|
| Active Comparator: Cuprior® comparator (Treatment B)<br>2 x 450mg TETA 4HCl, Marketed Cuprior® formulation (6 x150mg trientine base tablets in two equally divided doses (450mg doses 8 hours apart) | Drug: 900mg TETA 4HCl Cuprior®<br>* 6 x150mg trientine base tablets in two equally divided doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of TETA 4HCL and two main metabolites (N1-acetyltriethylenetetramine (MAT) and N1, N10-diacetyltriethylenetetramine (DAT)) following administration of two TETA 4HCL tablet formulations. | PK parameters derived by non-compartmental methods including: area under the plasma concentration-time curve from time zero to last detectable plasma concentration (AUC0-t), area under the plasma concentration-time curve from time zero to 24 hours plasma concentration (AUC0-24), area under the plasma concentration-time curve from time zero extrapolated to infinite (AUC0-¥), maximum observed plasma concentration (Cmax), time to reach maximum plasma concentration (tmax), apparent total plasma clearance (CL/F), apparent volume of distribution during the terminal phase (Vz/F), terminal elimination rate constant (λz), and terminal elimination half-life (t1/2). | Plasma concentrations will be listed and summarised by time point and the PK parameters will be listed for each participant. For comparability of the two products the geometric means, confidence intervals and coefficient of variation will be summarised. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the safety and tolerability of the two TETA 4HCL tablet formulations. | The incidence, severity, and relationship of Treatment-Emergent Adverse Events (TEAEs). | Adverse Events (AE), Serious Adverse Events (SAEs) summarised using descriptive statistics. |