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

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ClinicalTrials.gov Identifier: NCT03539952
Recruitment Status : Recruiting
First Posted : May 30, 2018
Last Update Posted : May 16, 2019
Sponsor:
Information provided by (Responsible Party):
GMP-Orphan SAS

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).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 55 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
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : November 2021


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




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.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03539952


Contacts
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Contact: Reema Shah +44(0)7799256260 reema@gmp-o.com

Locations
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United States, Connecticut
Yale University School of Medicine Recruiting
New Haven, Connecticut, United States, 06510
Contact: Michael Schilsky    203-785-2480    michael.schilsky@yale.edu   
United States, Tennessee
Vanderbuilt University Not yet recruiting
Nashville, Tennessee, United States, 37232
Contact: Peter Hedera    615-936-3920    peter.hedera@vanderbuilt.edu   
Belgium
KU Leuven, Department of Clinical and Experimental Medicine Not yet recruiting
Leuven, Belgium
Contact: David Cassiman    32 16 34 46 49    david.cassiman@kuleuven.be   
Principal Investigator: David Cassiman, MD         
Brazil
Hospital Nossa Senhora das Graças (HNSG) Recruiting
Curitiba, Brazil
Contact: Dr. Carlos Twardowschy    55-41-999-798654    carlos.a.tw@gmail.com   
Hospital Geral de Fortaleza Not yet recruiting
Fortaleza, Brazil, 60175-295
Contact: Fernanda Maia    55 85 9922 9544    fernandamaia@unifor.br   
Nucleo de Pesquisa e Desenvolvimento de Medicamentos - Universidade Federal do Ceará - Rodolfo Teófilo Not yet recruiting
Fortaleza, Brazil, 60430-275
Contact: Francisco Gondim    55 85 8587 2363    fernandamaia@unifor.br   
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Not yet recruiting
São Paulo, Brazil
Contact: Dr. Rubens Gisbert Cury    +55 11-2661-0000    rubens.cury@hc.fm.usp.br   
Denmark
Hepato-gastroenterologisk afd Recruiting
Aarhus, Denmark
Contact: Peter Ott       peterott@rm.dk   
France
Hospital mother children Recruiting
Bron, France, 69677
Contact: Dr. Alain Lachaux    + 33 (0)8 25 08 25 69      
Centre National de Référence Wilson, Hôpital Lariboisière Recruiting
Paris, France, 75475
Contact: Aurelia Poujois    +33 (0) 1-49-95-65-09      
Contact: France Woimant    +33 (0) 1-49-95-65-09    france.woimant@aphp.fr   
Germany
Innere Medizin Recruiting
Heidelberg, Germany, 69120
Contact: Andrea Langel    49 6221-56 8388    andrea.langel@med.uni-heidelberg.de   
Contact: Jessica Langel       jessica.langel@med.uni-heidelberg   
Poliklinik Hepatologie/Transplantationsambulanz Not yet recruiting
Munich, Germany, 81377
Contact: Gerald Denk    089 4400 73962    Gerald.Denk@med.uni-muenchen.de   
Italy
A.O. San Paolo Milano Recruiting
Milan, Italy, 20142
Contact: Massimo Zuin    +39-02-81841    massimo.zuin@unimi.it   
U.O.S. Epatologia Pediatrica Dipartimento di Pediatria Not yet recruiting
Napoli, Italy
Contact: Raffaele Iorio    39 081 7464337    riorio@unina.it   
DiSCOG Gastroenterology Unit Recruiting
Padova, Italy, 35128
Contact: Dr. Renata D'Inca    39-0498021995    dinca@unipd.it   
Contact: Giacomo Carlo    +39 049 8211111    gc.sturniolo@unipd.it   
Poland
Institute of Psychiatry and Neurology Recruiting
Warsaw, Poland, 02 957
Contact: Beata Ziółkowska    48 2245 82 609    ziolko275@wp.pl   
Sweden
Department of Medical Sciences, Uppsala Not yet recruiting
Uppsala, Sweden
Contact: Andreas Kindmark    46 18 61 19297    andres.kindmark@medsci.uu.se   
Principal Investigator: Andreas Kindmark, MD         
United Kingdom
Department of Hepatology Addenbrooke's NHS Trust Not yet recruiting
Cambridge, United Kingdom, CB2 0QQ
Contact: William Griffith    44 1223 586891    bill.griffith@addenbrookes.nhs.uk   
Leeds Teaching Hospitals NHS Trust Not yet recruiting
Leeds, United Kingdom, LS9 7TF
Contact: Joanna Moore    44 1132060469    joanna.moore@nhs.net   
University of Surrey, Department of Clinical and Experimental Medicine Not yet recruiting
Surrey, United Kingdom, GU2 7XH
Contact: Aftab Ala    44 01483571122    aftabala@nhs.com   
Principal Investigator: Aftab Ala, MD         
Sponsors and Collaborators
GMP-Orphan SAS

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Responsible Party: GMP-Orphan SAS
ClinicalTrials.gov Identifier: NCT03539952     History of Changes
Other Study ID Numbers: GMPO-131-002
First Posted: May 30, 2018    Key Record Dates
Last Update Posted: May 16, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Additional relevant MeSH terms:
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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
Trientine
Penicillamine
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Antidotes
Protective Agents
Physiological Effects of Drugs
Antirheumatic Agents