| 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. |
| La Malattia di Wilson (WD) è una malattia genetica, autosomica recessiva, le cui manifestazioni cliniche dipendono dall'accumulo di rame principalmente a livello del fegato e del cervello. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Excessive copper accumulation |
| Accumulo eccessivo di rame |
|
| 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 |
|
| 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.
|
| Valutare l'efficacia di TETA 4HCI confrontata a penicillamina |
|
| E.2.2 | Secondary objectives of the trial |
| The safety of TETA 4HCl compared to penicillamine will also be evaluated. |
| Sarà valutata la sicurezza di TETA 4HCI confrontata a penicillamina |
|
| 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 visit
6. Patient is on a stable dose and regimen of penicillamine for at least 4 months (16 weeks) prior to the screening 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 screening 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 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 |
1.Il paziente è in grado di fornire,e ha fornito, un consenso informato scritto.
2.È stata ottenuta la documentazione scritta in conformità ai requisiti nazionali e locali in materia di tutela della privacy, laddove pertinente, tra cui per i centri europei: Consenso in materia di protezione dei dati
3.Pazienti di ambo i sessi, di età ≥ 18 e ≤ 75 anni al momento del consenso
4.Al paziente è stata diagnosticata la malattia di Wilson, definita da un punteggio di Leipzig precedente o attuale ≥ 4
5.La malattia di Wilson del paziente è clinicamente stabile, secondo il giudizio dello sperimentatore, ed è trattata con penicillamina da almeno 1 anno (52 settimane) al momento della visita di screening
6.Il paziente segue un regime a base di penicillamina a dosaggio stabile da almeno 4 mesi (16 settimane) al momento della visita di screening (in questo periodo non sono consentiti altri trattamenti prescritti per la malattia di Wilson)
7. Non si prevede la necessità di somministrare al paziente altre terapie farmacologiche oltre al farmaco dello studio, compresa terapia a base di zinco prescritta, per la gestione dei livelli di rame nel corso dello studio
8.Il paziente deve essere disposto a mantenere una dieta stabile per l’intera durata dello studio e a evitare alimenti a elevato contenuto di rame, anche durante il periodo di screening
9.Il paziente è ritenuto idoneo a ricevere una terapia sia con TETA 4 HCl sia con penicillamina somministrata due volte al giorno
10.I risultati delle analisi del laboratorio centrale relative a HIV ed epatite virale sono negativi (i risultati saranno disponibili dopo l’inizio del periodo di run-in)
11.Per le pazienti in età fertile, risultato negativo del test di gravidanza sulle urine (eseguito alla visita di screening e prima della randomizzazione)
12.Per le pazienti in età fertile, utilizzo di un metodo contraccettivo affidabile
13.Il paziente è ritenuto in grado, secondo il giudizio dello sperimentatore, di completare le procedure dello studio e di sottoporsi alle visite previste dallo studio
|
|
| 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 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 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 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 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. If repeat value 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). |
1.Il paziente si trova, secondo il giudizio dello sperimentatore, nella fase di trattamento per la malattia di Wilson di riduzione dei livelli di rame
2.Segni e sintomi di una malattia epatica non controllata, inclusi a titolo esemplificativo e non esaustivo i seguenti:
a.Punteggio di Nazer modificato ≥ 4 (il risultato potrebbe non essere disponibile fino a dopo l’inizio del periodo di run-in perché è basato sui risultati degli esami di laboratorio*)
b.Cirrosi scompensata
c.Anemia emolitica acuta
d.Epatite acuta
e.Neoplasia epatica maligna
f.Evidenza d’insufficienza epatica acuta
3.Secondo il giudizio dello sperimentatore, la causa della malattia epatica è da ricercarsi in un’altra patologia
4.Il paziente presenta anemia grave, definita da livelli di emoglobina ≤ 9 g/dl (i risultati saranno disponibili dopo l’inizio del periodo di run-in*)
5.Il paziente ha manifestato un sanguinamento gastrointestinale nei 6 mesi (24 settimane) precedenti la visita di screening
6.Il paziente ha una funzione renale compromessa, definita da una clearance della creatinina ≤ 30 ml/min (i risultati potrebbero non essere disponibili fino a dopo l’inizio del periodo di run-in*) oppure soffre, a giudizio del sperimentatore, di nefrite o di sindrome nefrosica
7.Il paziente è affetto da una malattia neurologica che gli impedisce di ingerire il farmaco dello studio (ad es. necessita di un sondino nasogastrico) oppure ha bisogno di cure mediche intensive in regime di ricovero ospedaliero
8.Il paziente è attualmente in trattamento con un farmaco contenente trientina per la gestione della malattia di Wilson o è stato in trattamento con tale farmaco nei 4 mesi (16 settimane) precedenti la visita di screening
9.Il paziente è attualmente in terapia con zinco prescritta per la gestione della malattia di Wilson o l’ha assunta nei 4 mesi (16 settimane) precedenti la visita di screening
10.Il paziente è attualmente in trattamento con una delle seguenti terapie concomitanti: oro terapia, terapia antimalarica, farmaci citotossici, ossifenbutazone, fenilbutazone
11.Il paziente presenta una nota intolleranza, allergia o sensibilità alla penicillamina (non controllata) o al TETA 4 HCl, incluso qualsiasi componente del farmaco dello studio
12.Per le pazienti di sesso femminile, gravidanza programmata durante il periodo dello studio o attuale allattamento al seno
13.Per le pazienti di sesso femminile in età fertile, incapacità o riluttanza a utilizzare un metodo contraccettivo affidabile durante l’intero studio
14.Attuale partecipazione a un altro studio terapeutico oppure partecipazione a uno studio terapeutico nei 30 giorni precedenti la visita di screening (o un periodo più lungo, se specificato dai requisiti locali)
15.Il paziente presenta, a giudizio del sperimentatore, una condizione o una situazione che comporta un rischio significativo, potrebbe confondere i risultati dello studio o potrebbe interferire in maniera significativa con la sua partecipazione allo studio
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To evaluate the efficacy of TETA 4HCl compared to penicillamine:
The primary hypothesis is that the efficacy of TETA 4HCl, as assessed by serum NCC levels, is not inferior to the efficacy of penicillamine, at 36 weeks of treatment.
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 (used to derive non-ceruloplasmin bound copper).
Significance tests will be performed at the α = 0.05 significance level for two-tailed tests at a= 0.025 for one tailed test |
|
| 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 safety of TETA 4HCl compared to penicillamine will also be evaluated
Safety will be evaluated by assessing treatment emergent AEs (TEAEs), and other safety measures (vital signs, hematology, biochemistry, coagulation analysis, urinalysis, modified Nazer score, and urine pregnancy test). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Measured at Screening, Weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36 |
|
| 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 | No |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 | Information not present in EudraCT |
| 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 |
| Austria |
| Brazil |
| Denmark |
| France |
| Germany |
| Italy |
| Micronesia, Federated States of |
| Poland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial 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. |
| Fine dello studio: Lo studio finisce con l'ultima visita dell'ultimo paziente partecipante nello studio |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 32 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 32 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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