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

Phase 1

Completed

Conditions: Wilson's Disease

Interventions: Drug: 900mg TETA 4HCl Once Daily Formulation
Drug: 900mg TETA 4HCl Cuprior®

Registration Number: NCT06128954

Lead Sponsor: Orphalan

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Once Daily Dose Formulation (Treatment A)	900mg TETA 4HCl Once Daily Formulation	1 x 900mg TETA 4HCl, new once daily formulation (3x300mg trientine base tablets as a single AM dose)
Cuprior® comparator (Treatment B)	900mg TETA 4HCl Cuprior®	2 x 450mg TETA 4HCl, Marketed Cuprior® formulation (6 x150mg trientine base tablets in two equally divided doses (450mg doses 8 hours apart)

Primary Outcome Measures

Name	Time	Method
Plasma Concentrations (AUC) of TETA 4HCL Following Administration of Two TETA 4HCL Tablet Formulations.	Up to 48 hours post first dose initiation.	PK parameters derived by non-compartmental methods including: AUC 24 and AUCinf. PK sampling was done pre-first dose and then post-first dose for Treatment A (hours): 0.5, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48. Post-first dose for Treatment B (hours): 0.5, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8 (before 2nd dose), 8.5, 9, 9.25, 9.5, 10, 11, 12, 13, 14, 16, 20, 24, 36, 48.
Pharmacokinetic Parameters (Concentration) of TETA in Plasma	Up to 48 hours post first dose initiation.	PK parameters derived by non-compartmental methods including: Clast and Cmax.
Pharmacokinetic Parameters (Time) of MAT in Plasma	Up to 48 hours post first dose initiation	PK parameters derived by non-compartmental methods including: Thalf and Tmax..
Plasma Concentrations (AUC) of N1-acetyltriethylenetetramine (MAT) Following Administration of Two TETA 4HCL Tablet Formulations.	Up to 48 hours post first dose initiation.	PK parameters derived by non-compartmental methods including: AUC 24 and AUCinf. PK sampling was done pre-first dose and then post-first dose for Treatment A (hours): 0.5, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48. Post-first dose for Treatment B (hours): 0.5, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8 (before 2nd dose), 8.5, 9, 9.25, 9.5, 10, 11, 12, 13, 14, 16, 20, 24, 36, 48.
Plasma Concentrations (AUC) of N1, N10-diacetyltriethylenetetramine (DAT) Following Administration of Two TETA 4HCL Tablet Formulations.	Up to 48 hours post first dose initiation.	PK parameters derived by non-compartmental methods including: AUC 24 and AUCinf. PK sampling was done pre-first dose and then post-first dose for Treatment A (hours): 0.5, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48. Post-first dose for Treatment B (hours): 0.5, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8 (before 2nd dose), 8.5, 9, 9.25, 9.5, 10, 11, 12, 13, 14, 16, 20, 24, 36, 48.
Pharmacokinetic Parameters (AUC) of TETA in Plasma	Up to 48 hours post first dose initiation.	PK parameters derived by non-compartmental methods including: AUCinf and AUC 24. PK sampling was done pre-first dose and then post-first dose for Treatment A (hours): 0.5, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48. Post-first dose for Treatment B (hours): 0.5, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8 (before 2nd dose), 8.5, 9, 9.25, 9.5, 10, 11, 12, 13, 14, 16, 20, 24, 36, 48.
Plasma Concentrations (Cmax) of TETA 4HCL Following Administration of Two TETA 4HCL Tablet Formulations.	Up to 48 hours post first dose initiation.	PK parameters derived by non-compartmental methods including: Cmax.
Pharmacokinetic Parameters (Time) of TETA in Plasma	Up to 48 hours post first dose initiation.	PK parameters derived by non-compartmental methods including: Thalf and Tmax.
Pharmacokinetic Parameters (AUC) of MAT in Plasma	Up to 48 hours post first dose initiation	PK parameters derived by non-compartmental methods including: AUCinf and AUC 24. PK sampling was done pre-first dose and then post-first dose for Treatment A (hours): 0.5, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48. Post-first dose for Treatment B (hours): 0.5, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8 (before 2nd dose), 8.5, 9, 9.25, 9.5, 10, 11, 12, 13, 14, 16, 20, 24, 36, 48.
Plasma Concentrations (Cmax) of N1-acetyltriethylenetetramine (MAT) Following Administration of Two TETA 4HCL Tablet Formulations.	Up to 48 hours post first dose initiation.	PK parameters derived by non-compartmental methods including: Cmax.
Pharmacokinetic Parameters (Concentration) of MAT in Plasma	Up to 48 hours post first dose initiation	PK parameters derived by non-compartmental methods including: Clast and Cmax..
Pharmacokinetic Parameters (AUC) of DAT in Plasma	Up to 48 hours post first dose initiation.	PK parameters derived by non-compartmental methods including: AUCinf and AUC 24. PK sampling was done pre-first dose and then post-first dose for Treatment A (hours): 0.5, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48. Post-first dose for Treatment B (hours): 0.5, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8 (before 2nd dose), 8.5, 9, 9.25, 9.5, 10, 11, 12, 13, 14, 16, 20, 24, 36, 48.
Plasma Concentrations (Cmax) of N1, N10-diacetyltriethylenetetramine (DAT) Following Administration of Two TETA 4HCL Tablet Formulations.	Up to 48 hours post first dose initiation.	PK parameters derived by non-compartmental methods including: Cmax.
Pharmacokinetic Parameters (Time) of DAT in Plasma	Up to 48 hours post first dose initiation.	PK parameters derived by non-compartmental methods including: Thalf and Tmax.
Pharmacokinetic Parameters (Concentration) of DAT in Plasma	Up to 48 hours post first dose initiation.	PK parameters derived by non-compartmental methods including: Clast and Cmax.

Secondary Outcome Measures

Name	Time	Method
To Compare the Safety and Tolerability of the Two TETA 4HCL Tablet Formulations.	Adverse events were collected from the patient signing the ICF until the end of study/follow-up (EOS/FU) visit. The Mean (Min, Max) number of days between signing ICF and the EOS/FU visit in the study was 20.2 (16, 25). All patients completed the study.	The incidence, severity, and relationship of Treatment-Emergent Adverse Events (TEAEs).