E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary arterial hypertension |
Ipertensione arteriosa polmonare |
|
E.1.1.1 | Medical condition in easily understood language |
Pulmonary arterial hypertension |
Ipertensione arteriosa polmonare |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10038738 |
E.1.2 | Term | Respiratory, thoracic and mediastinal disorders |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the safety and tolerability of the individual highest tolerated zamicastat doses, achieved in the study BIA-51058-201, during long-term treatment in PAH disease. |
Valutare la sicurezza e la tollerabilità delle dosi più elevate tollerate individuali di zamicastat, raggiunte nello studio BIA-51058-201, durante il trattamento a lungo termine dell'IAP. |
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E.2.2 | Secondary objectives of the trial |
To assess further efficacy, safety and tolerability parameters of the individual highest tolerated zamicastat doses in long-term treatment of PAH. |
Valutare ulteriori parametri di efficacia, sicurezza e tollerabilità delle dosi più elevate tollerate individuali di zamicastat nel trattamento a lungo termine dell'IAP. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have performed MPV3 of the preceding study BIA-51058-201. 2. Able to comprehend and willing to sign an informed consent form. 3. For women: Agree not to donate ova from the time of informed consent until 30 days after the last IMP intake. For men: Agree not to donate sperm from the time of informed consent until 90 days after the last IMP intake. |
1. Avere effettuato la visita MPV3 dello studio BIA-51058-201 precedente. 2. Essere in grado di comprendere e disposti a firmare un modulo di consenso informato. 3. Per le donne: essere d’accordo a non donare ovuli dal momento del consenso informato fino a 30 giorni dopo l’ultima assunzione dell’ IMP. Per gli uomini: essere d’accordo a non donare sperma dal momento del consenso informato fino a 90 giorni dopo l’ultima assunzione dell’ IMP. |
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E.4 | Principal exclusion criteria |
1. Significant non-compliance with the protocol during the preceding study BIA-51058-201 which may have an impact on this extension study. 2. WHO functional class IV as judged by the investigator. 3. Two or more consecutive measurements of systolic blood pressure (SBP) < 95 mmHg or diastolic blood pressure (DBP) < 50 mmHg, measured at visit V1. 4. Uncontrolled diabetes mellitus with HbA1c = 8.5% within the last three months or at visit V1. 5. Occurrence of an AE during the preceding study which is judged by the investigator as contraindicative to further participation in the extension study. 6. Any disease known to cause pulmonary hypertension other than PAH WHO Group 1. 7. Obstructive lung disease: Forced Expiratory Volume in 1 second/Forced Vital Capacity (FEV1/FVC) < 60% and FEV1 < 60% of predicted value after bronchodilator administration, as demonstrated and documented by previous spirometry data which, in the opinion of the investigator, represent the clinical state of the patient at the time of visit V1. 8. Restrictive lung disease: Total Lung Capacity (TLC) < 70% of predicted value, as demonstrated and documented by previous spirometry data which, in the opinion of the investigator, represent the clinical state of the patient at the time of visit V1. 9. History of moderate to severe hepatic impairment (Child-Pugh B and C). 10. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (measured at MPV1 of study BIA-51058-201). 11. Use of the following prohibited medication or treatments during study participation: calcium channel blockers (CCBs) if used for the treatment of PAH in vasoreactive patients; drugs containing a catechol group that is metabolised by DßH (e.g. rimiterole, isoprenaline, dopamine, dopexamine or dobutamide) or a- and/or ß-blockers. 12. Presence of any other significant or progressive/unstable medical condition that, in the opinion of the investigator, would compromise evaluation of the study treatment or may jeopardise the patient’s safety, compliance or adherence to protocol requirements. 13. For women: Pregnancy or breast-feeding. Women of childbearing potential unable or unwilling to undergo pregnancy tests and practice highly effective contraceptive measures in combination with a barrier method e.g. condom, occlusive cap (diaphragm or cervical/vault caps) with spermicidal gel/film/cream/suppository from the time of informed consent until 30 days after the last IMP intake. Highly effective methods for women are surgical intervention (e.g. bilateral tubal occlusion), non-hormonal implantable intrauterine device, true sexual abstinence (i.e. when this is in line with the preferred and usual lifestyle of the patient) and vasectomised partner (provided that the partner is the sole sexual partner of the patient and the partner has received medical assessment of the surgical success). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), hormonal contraceptives and withdrawal are not acceptable methods of contraception. For men: Male patients who are sexually active with a partner of childbearing potential must use, with their partner, a condom plus an approved acceptable contraceptive measure from the time of informed consent until 90 days after the last IMP intake. The following methods are acceptable methods of contraception: partner’s use of combined (oestrogen and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); partner’s use of progestogenonly hormonal contraception (oral, injectable/implantable, intrauterine hormonereleasing system); partner’s use of implantable intrauterine device; surgical sterilisation (for example, vasectomy or bilateral tubal occlusion). 14. Concurrent participation in any other drug investigational study, except BIA-51058-201. 15. Vulnerable patients according to Section 1.61 of the ICH guideline for Good Clinical Practice E6. |
1. Importante non conformità con il protocollo durante lo studio BIA-51058-201 precedente che potrebbe avere un impatto su questo studio di estensione. 2. Classe funzionale IV dell'OMS, a giudizio dello sperimentatore. 3. Due o più misurazioni consecutive della pressione arteriosa sistolica (SBP) < 95 mmHg o pressione arteriosa diastolica (DBP) < 50 mmHg, misurate alla V1 4. Diabete mellito non controllato con HbA1c = 8.5% negli ultimi tre mesi o alla visita V1. 5. Comparsa di un evento avverso (AE) durante lo studio precedente giudicato dallo sperimentatore come controindicazione alla partecipazione allo studio di estensione. 6. Qualsiasi patologia nota per causare ipertensione polmonare diversa da IAP Gruppo 1 dell’OMS. 7. Malattia polmonare ostruttiva: Volume Espiratorio Massimo ad 1 secondo/Capacità Vitale Forzata (FEV1/FVC) < 60% e FEV1 < 60% del valore predetto in seguito a somministrazione di un broncodilatatore, come dimostrato e documentato da precedenti dati spirometrici che, secondo il giudizio dello sperimentatore, rappresentano lo stato clinico del paziente al momento della visita V1. 8. Malattia polmonare restrittiva: Capacità Polmonare Totale (TLC) < 70% del valore predetto, come dimostrato e documentato da precedenti dati spirometrici che, secondo il giudizio dello sperimentatore, rappresentano lo stato clinico del paziente al momento della visita V1. 9. Anamnesi positiva per compromissione epatica da moderata a grave (Child-Pugh B e C). 10. Velocità di filtrazione glomerulare stimata (eGFR) < 30 ml/min/1,73 m2 (misurata alla MPV1 dello studio BIA-51058-201). 11. Uso dei seguenti farmaci o trattamenti vietati durante la partecipazione allo studio: bloccanti dei canali del calcio (CCB) se impiegati per il trattamento dell’IAP in pazienti vasoreattivi; farmaci contenenti un gruppo catecolico metabolizzato da DßH (ad es. rimiterolo, isoprenalina, dopamina, dopexamina o dobutamide) o a- e/o ß-bloccanti. 12. Presenza di qualsiasi altra condizione clinica significativa o progressiva/instabile che, a parere dello sperimentatore, comprometterebbe la valutazione del trattamento sperimentale o potrebbe mettere a rischio la sicurezza del paziente, la conformità o l'aderenza ai requisiti del protocollo. 13. Per le donne: Gravidanza o allattamento. Donne potenzialmente fertili non in grado o non disposte a sottoporsi ai test di gravidanza e ad adottare misure contraccettive altamente efficaci in combinazione con un metodo di barriera ad es.preservativo, cappuccio occlusivo (diaframma o cappucci cervicali) con gel/film/crema/supposta spermicida dal momento del consenso informato fino a 30 giorni dopo l’ultima somministrazione dell’IMP. Metodi altamente efficaci per le donne sono intervento chirurgico (ad es. occlusione tubarica bilaterale), dispositivo intrauterino impiantabile non ormonale, reale astinenza sessuale (se ciò è in linea con lo stile di vita preferito e abituale della paziente) e partner vasectomizzato (a condizione che il partner sia l'unico partner sessuale del paziente e che il partner abbia ricevuto una valutazione medica del successo chirurgico). L'astinenza periodica (ad es. metodi del calendario, dell'ovulazione, sintotermico, post-ovulazione), contraccettivi ormonalie il coito interrotto non sono metodi di contraccezione accettabili. 14. Partecipazione concomitante a qualsiasi altra sperimentazione farmacologica, eccetto lo studio BIA-51058-201. 15. Pazienti vulnerabili, secondo la sezione 1.61 delle linee guida ICH di buona pratica clinica E6. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The safety and tolerability of the used zamicastat doses will be evaluated by: 1. Adverse events 2. Clinically relevant changes in laboratory parameters (haematology, biochemistry, coagulation, urinalysis, arterial blood gas analysis) 3. Clinically relevant changes in vital signs 4. Clinically relevant changes in ECG parameters 5. Number of digital scars (only in patients with scleroderma) 6. Skin score (only in patients with scleroderma) |
La sicurezza e la tollerabilità delle dosi di zamicastat utilizzate saranno valutate in base a: 1. Eventi avversi 2. Variazioni clinicamente rilevanti dei parametri di laboratorio (ematologici, biochimici, coagulazione, analisi delle urine, emogasanalisi) 3. Variazioni clinicamente rilevanti dei parametri vitali 4. Variazioni clinicamente rilevanti dei parametri dell’ECG 5. Numero di cicatrici digitali (solo in pazienti affetti da sclerodermia) 6. Punteggio cutaneo (solo in pazienti affetti da sclerodermia) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
As soon as the last subject has completed the last visit and all data have been locked, the results will be analysed and described in a Clinical Study Report. |
Non appena l'ultimo soggetto avrà completato l'ultima visita e tutti i dati saranno stati bloccati, i risultati verranno analizzati e descritti nel Clinical Study Report. |
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E.5.2 | Secondary end point(s) |
Change from baseline* to V5 (if applicable) and from V1 to V5 (if applicable) for the following parameters: 1. Pulmonary vascular resistance (PVR), right atrial pressure (RAP), mean pulmonary artery pressure (mPAP), cardiac index (CI) and mixed venous oxygen saturation (SvO2). Further haemodynamic parameters may also be calculated if considered appropriate. Change from baseline* to V3 and to V5/EDV and from V1 to V5/EDV for the following parameters: 2. WHO functional class 3. 6-minute walk test (6-MWT), including Borg dyspnoea score 4. Biomarker (N-terminal pro brain natriuretic peptide [NT-proBNP]) 5. Echocardiogram parameters: • Tricuspid regurgitation, classified as absent, mild, moderate or severe • Right ventricular contractility, measured via tricuspid annular plane systolic excursion (TAPSE) • Pericardial effusion, classified as absent, traces or present • Right atrial area (end-systolic), right ventricular end-diastolic area 6. Quality of life (SF-36v2) |
Variazioni dal basale* alla visita V5 (se applicabile) e dalla visita V1 alla visita V5 (se applicabile) per i seguenti parametri: 1. Resistenza vascolare polmonare (PVR), pressione atriale destra (RAP), pressione arteriosa polmonare media (PAPm), indice cardiaco (IC) e saturazione di ossigeno venosa mista (SvO2). Se ritenuto opportuno, è inoltre possibile calcolare ulteriori parametri emodinamici. Variazioni dal basale* alla visita V3 e alla visita V5/EDV e dalla visita V1 alla visita V5/EDV per i seguenti parametri: 2. Classe funzionale dell’OMS 3. Test del cammino dei 6 minuti (6-MWT), compreso il punteggio della dispnea secondo Borg 4. Biomaracatore (N-terminale del propeptide natriuretico cerebrale [NT-proBNP]) 5. Parametri ecocardiografici: • Rigurgito tricuspidale, classificato come assente, lieve, moderato o severo • Contrattilità ventricolare destra, misurata mediante escursione sistolica dell'anello tricuspidale (TAPSE) • Versamento pericardico, classificato come assente, in tracce o presente • Area atriale destra (telesistolica), area ventricolare destra telediastolica 6. Qualità della vita (SF-36v2) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
As soon as the last subject has completed the last visit and all data have been locked, the results will be analysed and described in a Clinical Study Report. |
Non appena l'ultimo soggetto avrà completato l'ultima visita e tutti i dati saranno stati bloccati, i risultati verranno analizzati e descritti nel Clinical Study Report. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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 |
Ukraine |
Austria |
Germany |
Italy |
Portugal |
Spain |
United Kingdom |
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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
|
LVLS |
Ultima visita dell'ultimo soggetto |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |