| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical 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. |
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| E.1.1.1 | Medical condition in easily understood language |
| Excessive copper accumulation |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10047988 |
| E.1.2 | Term | Wilson's disease |
| E.1.2 | System Organ Class | 100000004850 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy of TETA 4HCl compared to penicillamine.
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|
| E.2.2 | Secondary objectives of the trial |
| The safety of TETA 4HCl compared to penicillamine will also be evaluated. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is able to provide and has provided written informed consent has been obtained
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
The Clinical Adjudication Committee will be responsible for reviewing clinical study data provided by the sites to confirm that the penicillamine-treated Wilson’s disease patients enrolled into the Penicillamine Baseline Period are well-controlled, clinically stable, and are suitable for randomisation into the study at Week 12 visit. Information associated with the Inclusion and Exclusion criteria demonstrating that patients are adequately controlled and tolerating penicillamine defined by serum NCC, 24-hour urinary copper excretion, ALT and any other laboratory or clinical findings per protocol will be used for this assessment prior to the Week 12 visit. Patient and site identification will be anonymized to the adjudicators and additionally for the evaluations post-randomisation the adjudicators will be blinded to the treatment allocation.
Three adjudication members will review the data independently according to the protocol criteria. A majority assessment of two or more will determine the decision. The recommendation by the Clinical Adjudication Committee on whether or not to include (randomise) the patient will be final.
The details of the process and communication with the Investigator will be detailed in a Charter for the Clinical Adjudication Committee
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|
| E.4 | Principal 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 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 moderate or severe renal impairment defined as creatinine clearance of ≤ 30 mL/min (result will 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
*Samples for screening/enrolment labs can be taken within ± 7 days of visit. In the event that lab value is above the specified threshold, it can be repeated including at the Week 4 and Week 8 visits, with the result available prior to randomization at Week 12. |
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| E.5 End points |
| E.5.1 | Primary 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, 24, 28, 32 and 36. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Measured at Screening/Enrolment, Weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36 |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy measures are:
• 24-hour urinary copper excretion
• Clinical stability assessment by independent Adjudication Committee
• CGIC score
Other efficacy measures are:
• Unified Wilson’s Disease Rating Scale (UWDRS), neurological scale
• Serum total copper and serum ceruloplasmin
Significance tests will be performed at the α = 0.05 significance level for two-tailed tests and at α = 0.025 for one-tailed tests.
Safety measures:
• Adverse events and serious adverse events
o Clinically significant laboratory abnormalities and significant changes in neurological signs/symptoms will be reported as AEs
• Hematology, biochemistry and coagulation analysis
• Urinalysis
• Neurological signs and symptoms (using the relevant UWDRS items)
• Cognitive assessment using the semantic verbal fluency test
• Modified Nazer score
• Vital signs (heart 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.
The aim is to collect 2 separate samples (one at Week 24 and one at Week 36) from each patient that represents trough values at steady state. Therefore, the sample should be taken just prior to the patient’s next dose of study drug i.e. before the morning dose or before the evening dose
Details for the collection and storage of the PK samples is included in the Laboratory Manual.
The following plasma concentrations will be assessed:
• The parent compound, trientine
• The two metabolites, N1-acetyltriethylenetetramine (MAT) and N1, N10-diacetyltriethylenetetramine (DAT).
The outcome of the adjudication will state whether patients are well controlled and clinically stable. The proportion of clinically stable patients at Week 36 and at Week 60 will be computed and reported with their 95% confidence intervals.
Clinical stability assessment by independent Adjudication Committee
The adjudication committee will review data up to and including Week 36 and Week 60 to confirm patients are well controlled and clinically stable post randomisation. Patient and site identification will be anonymized to the adjudicators and additionally for the
evaluations post-randomisation the adjudicators will be blinded to the treatment allocation. The details of the process and communication with the Investigator will be detailed in a Charter for the Clinical Adjudication Committee.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The sec variable of 24h urinary copper excretion absolute values, measured at Scree/enrol, Wks4,12,16,24, and 36 will be analyzed in the same way as the serum NCC.The sec variable on the outcome of the adjudication at Wks 36 and Wks 60 will state whether patients are well controlled and clinically stable. The proportion of clinically stable patients at Wk36 and at Wk60 will be computed and reported with their 95% confidence intervals. The sec variable of CGIC score measured at Wks4,12,16,24and36 will be summarized and the difference between the randomized groups will be tested using a Cochran-Mantel-Haenszel testwith ridit scores For the UWDRS neurological scale, summary statistics for change vs baseline will be presented for score.Safety measured at Screening,Wks4,8,12,16,20,24,28,32and36 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Brazil |
| United States |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Poland |
| Sweden |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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