E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Arterial Hypertension |
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E.1.1.1 | Medical condition in easily understood language |
Increased Blood Pressure within the Pulmonary artery |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
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 check how safe and how well patients can tolerate the Zamicastat dose during long term treatment in Pulmonary Arterial Hypertension. This dose used will be the best dose found in the BIA-51058-201 study. |
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E.2.2 | Secondary objectives of the trial |
1. To see how effective the best Zamicastat dose, found in the BIA-51058-201 study, is in long term treatment of Pulmonary Arterial Hypertension.
2. To check how much Zamicastat is in the body at the end of Zamicastat treatment.
3. To see how long term treatment, of the best dose of Zamicastat - found in the BIA-51058-201 study, affects chemicals in your body that make your heart beat.
4. How long term treatment, at the best Zamicastat dose - found in the BIA-51058-201 study, affects the levels of hormones in your urine. |
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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. |
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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 DβH (e.g. rimiterole, isoprenaline, dopamine, dopexamine or dobutamide) or α- and/or β-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 (without spermicidal foam/gel/film/cream/suppository or fat- or oil-containing lubricants), 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 progestogen-only hormonal contraception (oral, injectable/implantable, intrauterine hormone-releasing 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
To assess the safety and tolerability of the maximum tolerated zamicastat doses, achieved in the study BIA-51058-201, during long-term treatment in PAH disease |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
A maximum of 14 weeks of treatment |
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E.5.2 | Secondary end point(s) |
1. To investigate the efficacy of the maximum tolerated zamicastat doses, achieved in the study BIA-51058-201, during long-term treatment in PAH disease.
2. To assess the minimum plasma concentration (Cmin) of zamicastat and its metabolites at the end of the dosing interval.
3. To investigate the effect of the maximum tolerated zamicastat doses, achieved in the study BIA-51058-201, on plasma dopamine β-hydroxylase (DβH) activity during longterm treatment in PAH disease.
4. To investigate the effect of the maximum tolerated zamicastat doses, achieved in the study BIA-51058-201, on urinary catecholamine levels (norepinephrine and dopamine) during long-term treatment in PAH disease. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
A maximum of 14 weeks of treatment |
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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.8.3 |
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 | 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 | 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 |
Austria |
Belgium |
Germany |
Netherlands |
Portugal |
Spain |
Ukraine |
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
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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 |