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    Summary
    EudraCT Number:2016-003876-29
    Sponsor's Protocol Code Number:GMPO-131-002
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-04-10
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedAustria - BASG
    A.2EudraCT number2016-003876-29
    A.3Full title of the trial
    CHELATE STUDY: Trientine tetrahydrochloride (TETA 4HCl) for the treatment of Wilson’s disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Chelate Study: Trientine for the treatment of Wilson's disease
    A.4.1Sponsor's protocol code numberGMPO-131-002
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of Sponsorgmp-orphan SA
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportgmp-orphan SA
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationgmp-orphan SA
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street AddressPépinière Paris Santé Cochin, 27-29 rue Faubourg Saint-Jacques
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75014
    B.5.3.4CountryFrance
    B.5.4Telephone number33142 49 82 64
    B.5.6E-mailNaseem@gmp-o.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/15/1471
    D.3 Description of the IMP
    D.3.1Product nameTETA 4HCl
    D.3.2Product code TETA 4HCl
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTrientine tetrahydrochloride
    D.3.9.1CAS number 4961-40-4
    D.3.9.2Current sponsor codeTETA 4HCl
    D.3.9.3Other descriptive nameTETA 4HCl
    D.3.9.4EV Substance CodeSUB77343
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationAustria
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpenicillamine
    D.3.9.1CAS number 52-67-5
    D.3.9.3Other descriptive namepenicillamine
    D.3.9.4EV Substance CodeSUB09667MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationAustria
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNpenicillamine
    D.3.9.1CAS number 52-67-5
    D.3.9.3Other descriptive namepenicillamine
    D.3.9.4EV Substance CodeSUB09667MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Wilson's disease (WD) is a life-threatening inborn error of copper metabolism leading to an excessive copper accumulation, mainly in the liver or brain, causing hepatic and neurologic severe symptoms.
    E.1.1.1Medical condition in easily understood language
    Excessive copper accumulation
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10047988
    E.1.2Term Wilson's disease
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of TETA 4HCl compared to penicillamine.
    E.2.2Secondary objectives of the trial
    The safety of TETA 4HCl compared to penicillamine will also be evaluated.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 EU sites, Data Protection Consent
    3. Male or female, aged ≥ 18 and ≤ 75 years old 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 period)
    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 he opinion of the investigator
    E.4Principal 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:
    a. Modified Nazer score of > 4 (result may not be available until after start of run-in period since based on lab results*)
    b. decompensated cirrhosis
    c. acute hemolytic anemia
    d. acute hepatitis
    e. hepatic malignancy
    f. 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

    *In the event that lab value is above the specified threshold, it can be repeated. If repeat value is within specified range, patient can continue
    in the study, otherwise the patient will be a screen failure. Note: if it is not possible to obtain a repeat value prior to the Week 4 clinic visit, then
    the Week 4 value will serve as the repeat lab value(s).
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint variable of this study will be the absolute value of serum NCC, measured at Screening/enrolment, Weeks 4, 8, 12, 16, 20, 28, 28, 32 and 36.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Measured at Screening/Enrolment, Weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36
    E.5.2Secondary end point(s)
    The secondary efficacy measures are:
    * 24-hour urinary copper excretion
    * CGIC score
    Other efficacy measures are:
    *Unified Wilson´s Disease Rating Scale (UWDRS), neurological scale
    *Serum total copper and serum ceruloplasmin
    Significant test will be performed at the a = 0.05 significance level for two-tailed tests and at a = 0.025 for one-tailed tests.
    Safety measures:
    *Adverse events and serious adverse events
    *Clinically significant laboratory abnormalities and significant changes in neurological signs / symptoms will be reported as AEs
    *Hematology, biochemistry and coagulation analysis
    *Urinanalysis
    *Neurological signs and symptoms (using the relevant UWDRS items)
    *Cognitive assessment using the semantic verbal fluency test
    *Modified Nazer score
    *vital signs (hear rate, blood pressure, respiration rate, body temperature)
    *Urine Pregnancy test (for females of childbearing potential)
    Pharmacokinetic measures:
    Plasma samples for subsequent pharmacokinetic (PK) evaluation will be collected at steady state. This will be done at designated sites for
    patients who received TETA 4HCL. Details will provided in a separate PK manual.
    The following plasma concentrations will be assessed:
    *The parent compound, trientine
    *The two metabolites, N1-acetyltriethylenetetramine (MAT) and N1, N10-diacetyltriethylenetetramine (DAT).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary efficacy:
    The secondary variable of 24-hour urinary copper excretion absolute values, measured at Screening/enrolment Weeks 4, 12, 16, 24 and 36 will be analyzed in the same way as the serum NCC.
    The secondary variable of CGIC score measured at Weeks 4,12, 16, 25 and 36 will be summarized and the difference between the randomized
    groups will be tested using the Cochran-Mantel-Haenszel test with ridit scores.
    For the UWDRS neurological scale, summary statistics for change versus baseline will be presented for score
    Safety measured at Screening Weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36 PK measures at Weeks 24 and 36.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Brazil
    Denmark
    France
    Germany
    Italy
    Poland
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of the study: The study ends with the last visit of the last patient participating in the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months25
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months25
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 55
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    All patients who end their participation in the study will continue to be monitored by their respective physicians, using standard of care.
    No special procedure or extra medical care is needed after the trial that would not be otherwise used in patients who have not participated in the trial.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-04-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-04-10
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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