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| ID | Type | Description | Link |
|---|---|---|---|
| 2018-002448-10 | EudraCT Number |
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This Study evaluates the pharmacokinetic (PK) profile of different zamicastat doses in Pulmonary arterial hypertension (PAH) patients to find the most promising therapeutic dosage range for the treatment of PAH disease
This is an open-label, multi-centre study in patients with PAH who are currently on stable treatment with at least one PAH medication. It is planned to evaluate the PK profile (24 hour profile and trough levels) and the safety, tolerability and efficacy of four different zamicastat doses. Each patient will start treatment with the lowest dose (50 mg zamicastat once daily) and the dose will be up-titrated to the individual highest tolerated dose (HTD) i.e. up to 200 mg zamicastat once daily.
A data safety monitoring board (DSMB) will periodically review the safety data and will issue a recommendation if the doses can be used as planned.
This study will consist of:
A screening period, 5 to 12 days: visit V1
Up to four dose finding periods, 14 days each:
Maintenance period, 42 days: maintenance period visit (MPV)1, MPV2 and MPV3
Follow-up (FU) period, 14 to 28 days: visits FU (down-titration) and FU
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 50 mg zamicastat | Experimental | 50 mg zamicastat once daily |
|
| 100 mg zamicastat once daily | Experimental | 100 mg zamicastat once daily |
|
| 150 mg zamicastat once daily | Experimental | 150 mg zamicastat once daily |
|
| 200 mg zamicastat once daily | Experimental | 200 mg zamicastat once daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Oral zamicastat | Drug | Tablets for oral administration under fed conditions containing 100 mg of zamicastat |
|
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg | This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat | Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after investigational medicinal product (IMP) intake) |
| Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) | 1, 2, 4, 8, 16 and 24 hours after IMP intake |
| Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat | Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after IMP intake) |
| Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) | 1, 2, 4, 8, 16 and 24 hours after IMP intake |
| Time Until Cmax (Tmax) (h) - 50 mg | This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat | Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after IMP intake) |
| Time Until Cmax (Tmax) (h) - HTD | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) |
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Inclusion Criteria:
Male or female patients aged 18 to 70 years.
Able to comprehend and willing to sign an informed consent form.
Diagnosis of PAH (pulmonary arterial hypertension WHO Group 1), documented by right heart catheterisation with a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and a pulmonary vascular resistance (PVR) > 3 wood unit (WU):
World Health Organization (WHO) functional class II or III as judged by the investigator.
Stable treatment with at least one of the following approved PAH therapies for at least 90 days prior to V1: Ambrisentan, Bosentan, Macitentan, Riociguat, Selexipag, Sildenafil, Tadalafil, Epoprostenol intravenous, Iloprost inhaled or Treprostinil intravenous or subcutaneous.
Exclusion Criteria:
Contraindication to zamicastat, i.e. known hypersensitivity to ingredients of zamicastat formulation.
Two or more consecutive measurements of systolic blood pressure (SBP) < 95 mmHg or diastolic blood pressure (DBP) < 50 mmHg.
Uncontrolled diabetes mellitus with HbA1c ≥ 8.5% within the last three months or at screening.
PAH WHO Group 1 due to portal hypertension, human immunodeficiency virus (HIV) infection and schistosomiasis.
Any disease known to cause pulmonary hypertension other than PAH WHO Group 1.
Obstructive lung disease: Forced Expiratory Volume in 1 second/Forced Vital Capacity (FEV1/FVC) < 60% and FEV1 < 60% of predicted value after bronchodilator administration.
Restrictive lung disease: Total Lung Capacity (TLC) < 70% of predicted value.
History of moderate to severe hepatic impairment (Child-Pugh B and C).
Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (measured at V1).
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 dopamine ß-hydroxylase (DβH) e.g. rimiterole, isoprenaline, dopamine, dopexamine or dobutamide or α- and/or β-blockers.
Current or previous (within the past year) alcohol or substance abuse excluding caffeine or nicotine.
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.
For women: Pregnancy or breast-feeding. Women of childbearing potential unable or unwilling to undergo pregnancy tests and practice acceptable contraceptive measures from the time of informed consent until 30 days after last investigational medicinal product (IMP) intake. Acceptable methods for women are surgical intervention (e.g. bilateral tubal occlusion), non-hormonal implantable intrauterine device, double-barrier methods, 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).
Previous participation in any other drug investigational study within the past 30 days (or five half-lives of IMP whichever is longer) prior to V1.
Vulnerable patients according to Section 1.61 of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline for Good Clinical Practice E6.
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ordensklinikum Linz Elisabethinen, Interne 2 - Kardiologie, Angiologie & Interne Intensivmedizin Fadingerstraße 1 | Linz | 4020 | Austria |
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Of 33 patients enrolled in this study, 29 patients started treatment with zamicastat (4 Screening Failures), 28 patients completed the dose finding period and entered the maintenance period (1 premature termination). Patients who had been enrolled and, for whatever reason, discontinued the study after first IMP intake at visit A1 were classified as withdrawals. Patients might withdraw from the study at any time, either on their own request or at the discretion of the investigator.
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| ID | Title | Description |
|---|---|---|
| FG000 | 50 mg Zamicastat | 50 mg zamicastat once daily (half a tablet of 100 mg) Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) |
| FG001 | 100 mg Zamicastat Once Daily | 100 mg zamicastat once daily (one tablet of 100 mg) Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) |
| FG002 | 150 mg Zamicastat Once Daily | 150 mg zamicastat once daily (one and a half tablet of 100 mg) Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) |
| FG003 | 200 mg Zamicastat Once Daily | 200 mg zamicastat once daily (two tablets of 100 mg) Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 50 mg Toleration Period - Dose A |
| |||||||||||||
| 100 mg Toleration Period - Dose B |
| |||||||||||||
| 150 mg Toleration Period - Dose C |
| |||||||||||||
| 200 mg Toleration Period - Dose D |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 50 mg Zamicastat | 50 mg zamicastat once daily (half a tablet of 100 mg) Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) |
| BG001 | 100 mg Zamicastat Once Daily |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg | This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat | Following multiple administrations of the HTD of zamicastat to pulmonary arterial hypertension (PAH) patients at maintenance period visit (MPV)3, pharmacokinetic (PK) concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data. | Posted | Geometric Mean | Standard Deviation | ng.h/mL | Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after investigational medicinal product (IMP) intake) |
|
94,5 days
In the overall population, 23 (79.3%) patients experienced 94 TEAEs during the study. The overall frequency of TEAEs was comparable between patients taking 100mg (15 patients, 53.6%), 150mg (15 patients, 55.6%) and 200mg (11 patients, 52.4%) doses at onset of TEAEs, whereas the lowest frequency (10 patients, 34.5%) was observed for patients receiving 50mg. Most TEAEs (68 out of 94) were assessed as mild in intensity, 26 TEAEs were assessed as moderate in intensity. No severe TEAEs were reported.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 50 mg Zamicastat | 50 mg zamicastat once daily (half a tablet of 100 mg) Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Device breakage | Product Issues | MedDRA version 22.0 | Systematic Assessment | Possible Hickman line fracture |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ventricular extrasystoles | Cardiac disorders | MedDRA version 22.0 | Systematic Assessment | VENTRICULAR EXTRASYSTOLES |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Responsible of Clinical Research & Operations | BIAL - Portela & Ca, SA | +351229866100 | clinical.trials@bial.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 11, 2020 | Jun 5, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 22, 2022 | Jun 16, 2023 | SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jun 18, 2019 | Jun 6, 2023 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D000081029 | Pulmonary Arterial Hypertension |
| ID | Term |
|---|---|
| D006976 | Hypertension, Pulmonary |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| C000630084 | zamicastat |
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|
| 1, 2, 4, 8, 16 and 24 hours after IMP intake |
| Minimum Plasma Concentration at the End of the Dosing Interval (Cmin,SS) (ng/mL/mg) - HTD | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD). Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data. | 1, 2, 4, 8, 16 and 24 hours after IMP intake |
| Universitätsklinikum Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik I, Pneumologie Fetscherstraße 74 | Dresden | 01307 | Germany |
| Ospedale Generale Regionale Miulli-Cardiologia e UTIC Strada Prov. 127 Acquaviva - Santeramo Km. 4,100 | Acquaviva delle Fonti | 70021 | Italy |
| ASST di Monza-Ospedale San Gerardo -Dipartimento di Pneumologia via Pergolesi 33 | Monza | 20900 | Italy |
| AOU di Roma-Policlinico Umberto I-Unità Dipartimentale Malattie del Circolo Polmonare Viale del Policlinico 155 | Roma | 00161 | Italy |
| Centro Hospitalar Lisboa Norte, E.P.E. - Hospital Pulido Valente Consulta Externa de Hipertensão Pulmonar Alameda das Linhas de Torres, 117 | Lisbon | 1769-001 | Portugal |
| Hospital Clinic de Barcelona Calle Villarroel, 170 | Barcelona | 08036 | Spain |
| Hospital Universitario "12 de Octubre" Avda. de Córdoba, s/n | Madrid | 28041 | Spain |
| Complejo Asistencial Universitario de Salamanca Pº. San Vicente, 58 | Salamanca | 37007 | Spain |
| Hospital Universitario Marques de Valdecilla Avenida Valdecilla, 25 | Santander | 39008 | Spain |
| State Institution ""National Scientific Centre "M.D. Strazhesko Institute of Cardiology" of NAMS of Ukraine", Department of symptomatic arterial hypertensions Narodnogo opolcheniya 5 | Kyiv | 03151 | Ukraine |
| Golden Jubilee National Hospital Golden Jubilee National Hospital Agamemnon St, Scottish Pulmonary Vascular Unit Golden Jubilee National Hospital | Clydebank | G81 4DY | United Kingdom |
| Royal Free Hospital Pond Street | London | NW3 2QG | United Kingdom |
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
|
| NOT COMPLETED |
|
100 mg zamicastat once daily (one tablet of 100 mg)
Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058)
| BG002 | 150 mg Zamicastat Once Daily | 150 mg zamicastat once daily (one and a half tablet of 100 mg) Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) |
| BG003 | 200 mg Zamicastat Once Daily | 200 mg zamicastat once daily (two tablets of 100 mg) Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Height (cm) | Category title defined according Median presented in Table 15.1.6.2.2 Baseline Characteristics - Full Analysis Set | Count of Participants | Participants |
|
| Weight (kg) | Category title defined according Median presented in Table 15.1.6.2.2 Baseline Characteristics - Full Analysis Set | Count of Participants | Participants |
|
| BMI (kg/m2) | Category title defined according Median presented in Table 15.1.6.2.2 Baseline Characteristics - Full Analysis Set | Count of Participants | Participants |
|
| Childbearing Potential | Count of Participants | Participants |
|
| OG001 | 100 mg Zamicastat Once Daily | 100 mg zamicastat once daily Oral zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat |
| OG002 | 150 mg Zamicastat Once Daily | 150 mg zamicastat once daily Oral zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat |
| OG003 | 200 mg Zamicastat Once Daily | 200 mg zamicastat once daily Oral zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat |
|
|
| Primary | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) | Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data. | Posted | Geometric Mean | Standard Deviation | ng.h/mL/mg | 1, 2, 4, 8, 16 and 24 hours after IMP intake |
|
|
|
| Primary | Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat | Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data. | Posted | Geometric Mean | Standard Deviation | ng/mL | Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after IMP intake) |
|
|
|
| Primary | Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) | Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data. | Posted | Geometric Mean | Standard Deviation | ng/mL/mg | 1, 2, 4, 8, 16 and 24 hours after IMP intake |
|
|
|
| Primary | Time Until Cmax (Tmax) (h) - 50 mg | This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat | Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data. | Posted | Geometric Mean | Standard Deviation | h | Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after IMP intake) |
|
|
|
| Primary | Time Until Cmax (Tmax) (h) - HTD | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) | Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data. | Posted | Geometric Mean | Standard Deviation | h | 1, 2, 4, 8, 16 and 24 hours after IMP intake |
|
|
|
| Primary | Minimum Plasma Concentration at the End of the Dosing Interval (Cmin,SS) (ng/mL/mg) - HTD | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD). Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data. | Non-numerical values reported in the plasma concentration data (i.e. values that are below the limit of quantification), will be treated as missing for the determination of summary statistics. This also applies to any concentrations that are defined as PK parameters (e.g. Cmin). Where less than 3 patients receive the same dose at MPV3 or there are less than 3 quantifiable concentrations at a time point or parameter, summary statistics will not be produced for this dose/visits or time point. | Posted | Geometric Mean | Standard Deviation | ng/mL/mg | 1, 2, 4, 8, 16 and 24 hours after IMP intake |
|
|
|
| 0 |
| 29 |
| 0 |
| 29 |
| 10 |
| 29 |
| EG001 | 100 mg Zamicastat Once Daily | 100 mg zamicastat once daily (one tablet of 100 mg) Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) | 0 | 28 | 2 | 28 | 15 | 28 |
| EG002 | 150 mg Zamicastat Once Daily | 150 mg zamicastat once daily (one and a half tablet of 100 mg) Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) | 0 | 27 | 0 | 27 | 15 | 27 |
| EG003 | 200 mg Zamicastat Once Daily | 200 mg zamicastat once daily (two tablets of 100 mg) Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) | 0 | 21 | 0 | 21 | 11 | 21 |
|
| Pulmonary arterial hypertension | Respiratory, thoracic and mediastinal disorders | MedDRA version 22.0 | Systematic Assessment | Clinical worsening of PAH |
|
|
| Sinus arrhythmia | Cardiac disorders | MedDRA version 22.0 | Systematic Assessment | RESPIRATORY ARRHYTHMIA |
|
| Nausea | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment | NAUSEA |
|
| Fatigue | General disorders | MedDRA version 22.0 | Systematic Assessment | FATIGUE |
|
| Feeling abnormal | General disorders | MedDRA version 22.0 | Systematic Assessment | FOGGY-HEADEDNESS |
|
| Pain in jaw | Musculoskeletal and connective tissue disorders | MedDRA version 22.0 | Systematic Assessment | JAW PAIN |
|
| Syncope | Nervous system disorders | MedDRA version 22.0 | Systematic Assessment | SYNCOPE |
|
| Dermatitis allergic | Skin and subcutaneous tissue disorders | MedDRA version 22.0 | Systematic Assessment | CUTANEOUS HYPERSENSITIVITY |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA version 22.0 | Systematic Assessment | EXANTHEMA |
|
| Hypotension | Vascular disorders | MedDRA version 22.0 | Systematic Assessment | HYPOTENSION |
|
| Orthostatic hypotension | Vascular disorders | MedDRA version 22.0 | Systematic Assessment | ORTHOSTATIC HYPOTENSION |
|
| Nasopharyngitis | Infections and infestations | MedDRA version 22.0 | Systematic Assessment | COLD |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA version 22.0 | Systematic Assessment | UPPER RESPIRATORY TRACT INFECTION |
|
| Tonsillitis | Infections and infestations | MedDRA version 22.0 | Systematic Assessment | TONSILLITIS |
|
| Headache | Nervous system disorders | MedDRA version 22.0 | Systematic Assessment | HEADACHE |
|
| Herpes simplex | Infections and infestations | MedDRA version 22.0 | Systematic Assessment | HERPES SIMPLEX |
|
| Gastrointestinal infection | Infections and infestations | MedDRA version 22.0 | Systematic Assessment | GASTROINTESTINAL INFECTION |
|
| Viral infection | Infections and infestations | MedDRA version 22.0 | Systematic Assessment | VIROSIS |
|
| Dizziness | Nervous system disorders | MedDRA version 22.0 | Systematic Assessment | DIZZINESS WORSENING LIGHTHEADEDNESS |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment | ABDOMINAL PAIN |
|
| Pyrexia | General disorders | MedDRA version 22.0 | Systematic Assessment | FEVER |
|
| Cardiovascular disorder | Cardiac disorders | MedDRA version 22.0 | Systematic Assessment | CIRCULATORY DYSREGULATION |
|
| Temporomandibular joint syndrome | Musculoskeletal and connective tissue disorders | MedDRA version 22.0 | Systematic Assessment | TEMPOROMANDIBULAR PAIN |
|
| Dysmenorrhoea | Reproductive system and breast disorders | MedDRA version 22.0 | Systematic Assessment | DYSMENORRHEA |
|
| Presyncope | Nervous system disorders | MedDRA version 22.0 | Systematic Assessment | PRE-SYNCOPE |
|
| Sleep deficit | Nervous system disorders | MedDRA version 22.0 | Systematic Assessment | LACK OF SLEEP |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment | DIARRHOEA |
|
| Diverticulum | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment | WORSENING OF DIVERTICULOSIS |
|
| Alanine aminotransferase increased | Investigations | MedDRA version 22.0 | Systematic Assessment | ALT INCREASE |
|
| Gamma-glutamyltransferase increased | Investigations | MedDRA version 22.0 | Systematic Assessment | GAMMA-GLUTAMYLTRANSFERASE INCREASE |
|
| International normalised ratio abnormal | Investigations | MedDRA version 22.0 | Systematic Assessment | ALTERED INR |
|
| Pallor | Vascular disorders | MedDRA version 22.0 | Systematic Assessment | PALLOR |
|
| Insomnia | Psychiatric disorders | MedDRA version 22.0 | Systematic Assessment | INSOMNIA |
|
| Depression | Psychiatric disorders | MedDRA version 22.0 | Systematic Assessment | WORSENING OF THE DEPRESSIVE SYNDROME |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA version 22.0 | Systematic Assessment | THROMBOCYTOPENIA |
|
| Hyperkalaemia | Metabolism and nutrition disorders | MedDRA version 22.0 | Systematic Assessment | HYPERKALAEMIA |
|
| Hypertriglyceridaemia | Metabolism and nutrition disorders | MedDRA version 22.0 | Systematic Assessment | HYPERTRIGLYCERIDEMIA |
|
| Pulmonary arterial hypertension | Respiratory, thoracic and mediastinal disorders | MedDRA version 22.0 | Systematic Assessment | CLINICAL WORSENING OF PAH |
|
| Pulmonary hypertension | Respiratory, thoracic and mediastinal disorders | MedDRA version 22.0 | Systematic Assessment | PAH WORSENING |
|
| Device breakage | Product Issues | MedDRA version 22.0 | Systematic Assessment | POSSIBLE HICKMAN LINE FRACTURE |
|
| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment | WORSENING GASTROESOPHAGEAL REFLUX DISEASE |
|
| Vomiting | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment | VOMITING |
|
| Aspartate aminotransferase increased | Investigations | MedDRA version 22.0 | Systematic Assessment | AST INCREASE |
|
| Blood glucose increased | Investigations | MedDRA version 22.0 | Systematic Assessment | INCREASING OF GLUCOSE |
|
| Blood iron decreased | Investigations | MedDRA version 22.0 | Systematic Assessment | FERROPENIA |
|
| Rash papular | Skin and subcutaneous tissue disorders | MedDRA version 22.0 | Systematic Assessment | PAPULAR RASH |
|
| Arrhythmia supraventricular | Cardiac disorders | MedDRA version 22.0 | Systematic Assessment | LOW ATRIAL RHYTHM |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA version 22.0 | Systematic Assessment | BACK PAIN |
|
| Eosinophilia | Blood and lymphatic system disorders | MedDRA version 22.0 | Systematic Assessment | HYPEREOSINOPHILIA |
|
| Lymphopenia | Blood and lymphatic system disorders | MedDRA version 22.0 | Systematic Assessment | LYMPHOCYTIC LEUKOPENIA |
|
| Haematuria | Renal and urinary disorders | MedDRA version 22.0 | Systematic Assessment | INTERMITTENT MICROSCOPIC HAEMATURIA |
|
| Renal impairment | Renal and urinary disorders | MedDRA version 22.0 | Systematic Assessment | RENAL DYSFUNCTION |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment | EPIGASTRIC PAIN |
|
| Irritable bowel syndrome | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment | IRRITABLE COLON WORSENING |
|
| Toothache | Gastrointestinal disorders | MedDRA version 22.0 | Systematic Assessment | TOOTH PAIN |
|
| C-reactive protein increased | Investigations | MedDRA version 22.0 | Systematic Assessment | CRP VALUE INCREASE |
|
| Haematoma | Vascular disorders | MedDRA version 22.0 | Systematic Assessment | FACE HEMATOMA |
|
| Anxiety | Psychiatric disorders | MedDRA version 22.0 | Systematic Assessment | ANXIETY |
|
| Skin lesion | Skin and subcutaneous tissue disorders | MedDRA version 22.0 | Systematic Assessment | SKIN LESIONS |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA version 22.0 | Systematic Assessment | LOWER LIMB MUSCULAR PAIN WHILE WALKING |
|
| Diabetes mellitus | Metabolism and nutrition disorders | MedDRA version 22.0 | Systematic Assessment | WORSENING OF DIABETES MELLITUS |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA version 22.0 | Systematic Assessment | WORSENING SHORTNESS OF BREATH |
|
| Gallbladder polyp | Hepatobiliary disorders | MedDRA version 22.0 | Systematic Assessment | GALLBLADDER POLYPS |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA version 22.0 | Systematic Assessment | SWEATING |
|
Not provided
| Title | Measurements |
|---|---|
|
| Title | Measurements |
|---|---|
|
| Title | Measurements |
|---|---|
|
|
| BIA 5-453_1 |
|
|
| BIA 5-453_2 |
|
|
| BIA 5-961_1 |
|
|
| BIA 5-961_2 |
|
|
|
| 5-453 |
|
|
| BIA 5-961_1 |
|
|
| BIA 5-961_2 |
|
|
|
| BIA 5-453 |
|
|
| BIA 5-961_1 |
|
|
| BIA 5-961_2 |
|
|
|
| BIA 5-453 |
|
|
| BIA 5-961 |
|
|
|
| BIA 5-453 |
|
|
| BIA 5-961 |
|
|
|
| BIA 5-453_1 |
|
|
| BIA 5-453_2 |
|
|
| BIA 5-961 |
|
|