Trientine Tetrahydrochloride (TETA 4HCL) for the Treatment of Wilson's Disease

• ClinicalTrials.gov Identifier: NCT03539952
• Recruitment Status: Completed
• First Posted: May 30, 2018
• Last Update Posted: April 15, 2022
• Sponsor: Orphalan
• Information provided by (Responsible Party): Orphalan

Study Description

Brief Summary:

This is a multicenter, randomized, open-label study with an active standard-of-care comparator (penicillamine)

Condition or disease	Intervention/treatment	Phase
Wilson Disease	Drug: TETA 4HCL; Drug: Penicillamine	Phase 3

Detailed Description:

This is a multicenter, randomized, open label study with an active standard-of-care comparator.

Stable patients who are already considered to be stable on their standard-of-care penicillamine chelation therapy for at least 1 year will enroll in the study and enter a 12-week Penicillamine Baseline Period comprising of 1 month (4 weeks) run-in period followed by a 2 month (8 weeks) evaluation period. During this time all patients will continue to take their current penicillamine under study conditions. At the end of the Penicillamine Baseline Period, patients who fulfill the protocol definition of being adequately controlled and tolerating penicillamine will be randomized in a 1:1 ratio to receive either TETA 4HCl or to continue to receive penicillamine. There is then a 24-week Post-randomization Phase comprising of a 1 month (4 weeks) run-in period for both treatment arms and a 5 month (20 weeks) evaluation period.

Patients who successfully complete the 24-week Post-randomization Phase of the study will have the opportunity to enter an 18 month (72 weeks) Extension Phase. Initially they continue to receive their allocated TETA 4HCl or penicillamine for a further 24 weeks (i.e., up to Week 60 of the study). Thereafter all patients will receive TETA 4HCl for 48 weeks (i.e., between Week 60 and Week 108). Study clinic visits occur every 6 months (24 weeks) for all patients (i.e., at Weeks 60, 84 and 108).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 53 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CHELATE STUDY: Trientine Tetrahydrochloride (TETA 4HCL) for the Treatment of Wilson's Disease
• Actual Study Start Date: June 4, 2018
• Actual Primary Completion Date: August 19, 2020
• Actual Study Completion Date: January 18, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: TETA 4HCL; Active Treatment	Drug: TETA 4HCL; TETA 4HCL; Other Name: trientine tetrahydrochloride; Drug: Penicillamine; Penicillamine
Experimental: Penicillamine; Comparator: Penicillamine	Drug: TETA 4HCL; TETA 4HCL; Other Name: trientine tetrahydrochloride; Drug: Penicillamine; Penicillamine

Outcome Measures

Primary Outcome Measures :

1. Serum NCC concentration [ Time Frame: Week 36 ]
   Serum NCC concentration will be analysed using a validated assay (direct NCC assay).

Secondary Outcome Measures :

1. 24-hour urinary copper excretion [ Time Frame: Week 36 ]
   24-hour urinary copper excretion is to be measured, patients will collect urine for 24-hours. Specific materials for collection of urine and detailed instructions will be provided to patients.
2. Clinical Global Impression of Change (CGIC) rating scale [ Time Frame: Week 36 ]

   The clinician will rate the change in the patients Wilson's disease relative to the prior study clinic visit on a 7-point scale by responding to the following statement: 'Please rate the change in the overall severity of the patients Wilson's disease compared to the previous study clinic visit".

   The responses options are (1) very much improved; (2) much improved; (3) minimally improved; (4) no change; (5) minimally worse; (6), much worse; or (7) very much worse.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patient is able to provide, and has provided, written informed consent
2. Written documentation has been obtained in accordance with the relevant country and local privacy requirements, where applicable, including: For US sites: Authorization for Use and Release of Health Research Study Information and for EU sites: Data Protection Consent
3. Male or female, aged ≥ 18 and ≤ 75 years of age at time of consent
4. Patient has a diagnosis of Wilson's disease, as defined by a prior or current Leipzig score of ≥ 4
5. Patient's Wilson's disease is clinically stable, in the opinion of the investigator, and being treated with penicillamine for at least 1 year (52 weeks) prior to the screening/enrolment visit
6. Patient is on a stable dose and regimen of penicillamine for at least 4 months (16 weeks) prior to the screening/enrolment visit (other prescribed treatments for Wilson's disease not permitted during this study)
7. No anticipated need that patient will require additional pharmacological therapies other than study medication, including prescribed zinc therapy, for the management of copper levels during the study
8. Patient must be willing to maintain stable diet throughout the study, and avoid foods with high copper content, including the Penicillamine Baseline Period
9. Patient considered suitable to receive therapy with both TETA 4HCl and penicillamine administered twice a day
10. Negative central laboratory tests for HIV and viral hepatitis (results will be available after start of run-in period)
11. For female patients of childbearing potential, negative urine pregnancy test (at screening/enrolment visit and prior to randomization)
12. For females of childbearing potential, use of a reliable form of contraceptive

13. Patient is considered as able to complete study requirements and attend the study visits, in the opinion of the investigator

    Additional inclusion criteria following receipt of Screening laboratory results

14. Patient is adequately controlled and tolerating penicillamine therapy as defined by fulfilment of all of the following: a. Serum non-ceruloplasmin bound copper (NCC) level between ≥ 25 and ≤ 150 μg/L* b. 24-hour urinary copper excretion of between ≥ 100 and ≤ 900 μg/24 hours* c. Alanine transaminase (ALT) < 2 times upper limit of normal* d. No other laboratory or clinical findings that would prevent continuation of maintenance therapy, in the opinion of the investigator

    * Based on results from screening/enrolment visit samples for which can be taken within ± 7 days of visit. Result should be within the assay limits of quantification for the sample. The ranges in μmol of copper are 0.40 to 2.38 μmol/L for NCC and 1.59 to 14.29 for 24-hour urinary copper excretion (using division by 63 of value in μg per Walshe, 2011). In the event that one or more of the above lab values fall outside the specified range, it can be repeated, including at the Week 4 and Week 8 visits.

    Additional inclusion criteria at Week 12 visit (end of Penicillamine Baseline Period) and prior to randomization

15. Patient is adequately controlled and tolerating penicillamine therapy as defined by fulfilment of all of the following criteria:

    1. Serum non-ceruloplasmin bound copper (NCC) level between ≥ 25 and ≤ 150 μg/L*
    2. 24-hour urinary copper excretion of between ≥ 100 and ≤ 900 μg/24 hours**
    3. Alanine transaminase (ALT) < 2 times upper limit of normal*

    4. No other laboratory or clinical findings that would prevent continuation of maintenance therapy, in the opinion of the investigator

       • Based on lab values from Week 8 visit; ** Based on lab value from Week 4 visit as routinely not performed at Week 8 visit, however can also be based on value at Week 8 visit if a repeat (unscheduled) urinary copper excretion was performed at this visit. Result should be within the assay limits of quantification for the sample. The ranges in μmol of copper are 0.40 to 2.38 μmol/L for NCC and 1.59 to 14.29 for 24-hour urinary copper excretion (using division by 63 of value in μg per Walshe, 2011). In the event that one or more of the above lab values fall outside the specified range, it can be repeated. The repeat value(s) must be available prior to randomization at Week 12 and, if within specified range, the patient can continue to randomization. If a patient fails this additional criterion at the end of the Penicillamine Baseline Period, the patient can return to the start of the run-in period i.e. Day 1 (but only once). A negative urinary pregnancy test is also required prior to randomization for females of childbearing potential.

Exclusion Criteria:

1. Patient is in 'de-coppering' phase of treatment for Wilson's disease, in the opinion of the investigator

2. Patient evidence of uncontrolled liver disease, including but not limited to:

   1. Modified Nazer score of > 4 (result may not be available until after start of run in period since based on lab results*)
   2. decompensated cirrhosis
   3. acute hemolytic anemia
   4. acute hepatitis
   5. hepatic malignancy
   6. evidence of acute liver failure
3. Cause of patient's liver disease is due to another condition, in the investigator's opinion
4. Patient has severe anemia defined as hemoglobin of ≤ 9 g/dL (result will be available after start of run-in period*)
5. Patient has experienced a gastrointestinal bleed within 6 months (24 weeks) prior to screening/enrolment visit
6. Patient has renal impairment defined as creatinine clearance of ≤ 30 mL/min (result may not be available until after start of run-in period*), or patient has nephritis or nephrotic syndrome, in the opinion of the investigator
7. Patient has neurological disease that prevents swallowing of study medication (e.g., requires a nasogastric feeding tube) or requires intensive in-patient medical care
8. Patient is currently taking medication containing trientine for management of Wilson's disease or has taken it within 4 months (16 weeks) of screening/enrolment visit
9. Patient is currently receiving prescribed zinc therapy for management of Wilson's disease or has taken it within 4 months (16 weeks) of screening/enrolment visit
10. Patient is taking any of the following concomitant therapies: gold therapy, antimalarial therapy, cytotoxic drugs, oxyphenbutazone, phenyl butazone
11. Patient has a known intolerance, allergy or sensitivity to penicillamine (that is uncontrolled) or to TETA 4HCl, including any component of the study medication
12. For female patients of childbearing potential, planning a pregnancy during study period or currently nursing
13. For female patients of childbearing potential, unable or unwilling to use a reliable form of contraceptive throughout the study
14. Patient is currently participating in another therapeutic study, or has previously participated in a therapeutic study within 30 days of screening/enrolment visit (or longer, if local requirements specify this)
15. Patient has any condition or in any situation which, in the investigator's opinion, puts the patient at significant risk, could confound study results, or may interfere significantly with the patient's participation in the study

Contacts and Locations

Locations

United States, Connecticut

Yale University School of Medicine

New Haven, Connecticut, United States, 06510

Belgium

KU Leuven, Department of Clinical and Experimental Medicine

Leuven, Belgium

Brazil

Hospital Nossa Senhora das Graças (HNSG)

Curitiba, Brazil

Nucleo de Pesquisa e Desenvolvimento de Medicamentos - Universidade Federal do Ceará - Rodolfo Teófilo

Fortaleza, Brazil, 60430-275

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

São Paulo, Brazil

Denmark

Hepato-gastroenterologisk afd

Aarhus, Denmark

France

Hospital mother children

Bron, France, 69677

Centre National de Référence Wilson, Hôpital Lariboisière

Paris, France, 75475

Germany

Innere Medizin

Heidelberg, Germany, 69120

Poliklinik Hepatologie/Transplantationsambulanz

Munich, Germany, 81377

Italy

A.O. San Paolo Milano

Milan, Italy, 20142

DiSCOG Gastroenterology Unit

Padova, Italy, 35128

Poland

Institute of Psychiatry and Neurology

Warsaw, Poland, 02 957

United Kingdom

University of Surrey, Department of Clinical and Experimental Medicine

Guildford, Surrey, United Kingdom, GU2 7XH

Leeds Teaching Hospitals NHS Trust

Leeds, United Kingdom, LS9 7TF

Sponsors and Collaborators

Orphalan

More Information

• Responsible Party: Orphalan
• ClinicalTrials.gov Identifier: NCT03539952
• Other Study ID Numbers: GMPO-131-002
• First Posted: May 30, 2018
• Last Update Posted: April 15, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hepatolenticular Degeneration; Liver Diseases; Digestive System Diseases; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Metal Metabolism, Inborn Errors; Metabolic Diseases; Penicillamine; Trientine; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action; Antidotes; Protective Agents; Physiological Effects of Drugs; Antirheumatic Agents