Safety and Efficacy of BIA 5-1058 in PAH

NCT06009185 | Completed Phase 2 DMC

• 2 other identifiers: BIA-51058-2022018-002796-18
• Study Type: interventional
• Target: 20
• Locations: 6 countries
• Sites: 11

Brief Summary

This study aims 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 Pulmonary Arterial Hypertension (PAH) disease.

Conditions

Pulmonary Arterial Hypertension

Keywords

PAH; BIA 5-1058; Zamicastat; Bial; Bial - Portela & Ca, S.A.; dopamine ß-hydroxylase (DßH) inhibitor; vascular obstruction; pulmonary arteries; right-heart catheterisation (RHC); idiopathic; rare lung disease

Outcome Measures

Primary Outcomes (10)

• Number of participants with adverse events (AEs)

  The number of participants with AEs will be presented. An AE is any untoward medical occurrence in a patient to whom a medicinal product is administered and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease occurring during the course of the study.

  Up to 12 weeks

• Clinically relevant changes in laboratory parameters: coagulation

  Based on coagulation analysis measurements of prothrombin time test (international normalized ratio). The prothrombin time (PT) test measures how long it takes for a clot to form in a blood sample. The International Normalized Ratio is a type of calculation based on PT test results. Baseline values will be obtained from V1/A1 of study BIA-51058-201.

  From baseline to week 6 and week 12, and from day -1 to week 6 and week 12

• Incidence of clinically relevant changes (abnormalities) in laboratory parameters: biochemistry

  Based on biochemistry analysis measurements (mmol/L) of Sodium, Potassium, Chloride, Calcium, Phosphate . Baseline values will be obtained from V1/A1 of study BIA-51058-201.

  From baseline to week 6 and week 12, and from day -1 to week 6 and week 12

• Incidence of clinically relevant changes (abnormalities) in laboratory parameters: haematology

  Based on haematology analysis measurement haemoglobin (g/dL). Baseline values will be obtained from V1/A1 of study BIA-51058-201.

  From baseline to week 6 and week 12, and from day -1 to week 6 and week 12

• Clinically relevant changes in laboratory parameters: urinalysis

  Based on urinalysis analysis measurements of the potential of hydrogen (pH). The pH scale is used to determine the degree of acidity of a substance. The basic pH scale extends from 0 (strong acid) to 7 (neutral, pure water) to 14 (strong caustic). Urine has the widest range of pH compared to other bodily fluids. Baseline values will be obtained from V1/A1 of study BIA-51058-201.

  From baseline to week 6 and week 12, and from day -1 to week 6 and week 12

• Clinically relevant changes in laboratory parameters: arterial blood gas

  Based on arterial blood gas analysis measurements of Fraction of Inspired Oxygen (%). The fraction of inspired oxygen is the concentration or percentage of oxygen in the air that is inhaled by a person. Baseline values will be obtained from V1/A1 of study BIA-51058-201.

  From baseline to week 12, and from day -1 to week 12

• Clinically relevant changes in vital signs: blood pressure

  Systolic and diastolic blood pressure (mmHg) will be measured after the patient has rested for at least 5 minutes in supine position (first measurement) and at least one minute after the first measurement (second measurement). Afterwards, systolic and diastolic blood pressure will be measured again in standing position after the patient has been standing for at least 3 minutes (third measurement). Baseline values will be obtained from V1/A1 of study BIA-51058-201.

  From baseline to week 6 and week 12, and from day -1 to week 6 and week 12

• Clinically relevant changes in vital signs: pulse rate

  Pulse rate (bpm) will be measured after the patient has rested for at least 5 minutes in supine position (first measurement) and at least one minute after the first measurement (second measurement). Afterwards, vital signs will be measured again in standing position after the patient has been standing for at least 3 minutes (third measurement). Baseline values will be obtained from V1/A1 of study BIA-51058-201.

  From baseline to week 6 and week 12, and from day -1 to week 6 and week 12

• Clinically relevant changes in electrocardiogram ECG parameter QT interval

  QT interval measures the time (msec) it takes the heart muscle to contract and then recover. Baseline values will be obtained from V1/A1 of study BIA-51058-201. At Baseline of BIA-51058-201 study and week 12, triplicate 12-lead ECG will be recorded before IMP intake as well as 4 and 8 hours after IMP intake.

  From baseline to week 6 and week 12, and from day -1 to week 6 and week 12

• Clinically relevant changes in electrocardiogram ECG parameter QRS duration

  The QRS duration measures the time (msec) required for a stimulus to spread through the heart ventricles (ventricular depolarization). Baseline values will be obtained from V1/A1 of study BIA-51058-201. At Baseline of BIA-51058-201 study and week 12, triplicate 12-lead ECG will be recorded before IMP intake as well as 4 and 8 hours after IMP intake.

  From baseline to week 6 and week 12, and from day -1 to week 6 and week 12

Secondary Outcomes (13)

• Changes in haemodynamic parameters: pulmonary vascular resistance (PVR)

  From Baseline to week 12, and from Day -1 to week 12

• Changes in haemodynamic parameters: right atrial pressure (RAP)

  From Baseline to week 12, and from Day -1 to week 12

• Changes in haemodynamic parameters: mean pulmonary artery pressure (mPAP)

  From Baseline to week 12, and from Day -1 to week 12

• Changes in haemodynamic parameters: Cardiac index (CI)

  From Baseline to week 12, and from Day -1 to week 12

• Changes in haemodynamic parameters: mixed venous oxygen saturation (SvO2)

  From Baseline to week 12, and from Day -1 to week 12

Study Arms (2)

HTD < 200 mg zamicastat

EXPERIMENTAL

Tablets for oral administration under fed conditions. Zamicastat has to be taken in the morning after breakfast. Each patient will continue treatment with the individual highest tolerated dose (HTD) he/she was taking at MPV3 of the study BIA-51058-201 and will take this dose until visit V5.

Drug: Oral zamicastat

HTD 200 mg zamicastat

EXPERIMENTAL

Tablets for oral administration under fed conditions containing 100 mg of zamicastat (two tablets of 100 mg). Zamicastat has to be taken in the morning after breakfast. Each patient will continue treatment with the individual highest tolerated dose (HTD) he/she was taking at MPV3 of the study BIA-51058-201 and will take this dose until visit V5.

Drug: Oral zamicastat

Interventions

Oral zamicastat DRUG

Tablets for oral administration under fed conditions containing 100 mg of zamicastat. Zamicastat has to be taken in the morning after breakfast.

HTD 200 mg zamicastat; HTD < 200 mg zamicastat

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have performed MPV3 of the preceding study BIA-51058-201.
• Able to comprehend and willing to sign an informed consent form (ICF).
• For women: Agreed not to donate ova from the time of informed consent until 30 days after the last IMP intake.
• For men: Agreed not to donate sperm from the time of informed consent until 90 days after the last IMP intake

You may not qualify if:

• Patients were to be excluded for any one of the following reasons:
• Significant non-compliance with the protocol during the preceding study BIA-51058-201 which may have an impact on this extension study.
• WHO functional class IV as judged by the investigator (reference 1)
• Two or more consecutive measurements of systolic blood pressure (SBP) \< 95 mmHg or diastolic blood pressure (DBP) \< 50 mmHg measured at visit V1.
• Uncontrolled diabetes mellitus with HbA1c ≥ 8.5% within the last three months or at visit V1.
• Occurrence of an AE during the preceding study which is judged by the investigator as contraindicative to further participation in the extension study.
• 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, 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.
• 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.
• 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 Maintenance period visit 1 (MPV1) of study BIA-51058-201).
• 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.
• 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 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).

Sponsors & Collaborators

• Bial - Portela C S.A.: lead

Study Sites (11)

Ordensklinikum Linz Elisabethinen, Interne 2 - Kardiologie, Angiologie & Interne Intensivmedizin Fadingerstraße 1

Linz, 4020, Austria

Location

Universitätsklinikum Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik I, Pneumologie Fetscherstraße 74

Dresden, 01307, Germany

Location

ASST di Monza-Ospedale San Gerardo -Dipartimento di Pneumologia via Pergolesi 33

Monza, 20900, Italy

Location

AOU di Roma-Policlinico Umberto I-Unità Dipartimentale Malattie del Circolo Polmonare Viale del Policlinico 155

Roma, 00161, Italy

Location

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

Location

Hospital Clinic de Barcelona Calle Villarroel, 170

Barcelona, 08036, Spain

Location

Hospital Universitario "12 de Octubre" Avda. de Córdoba, s/n

Madrid, 28041, Spain

Location

Complejo Asistencial Universitario de Salamanca Pº. San Vicente, 58

Salamanca, 37007, Spain

Location

Hospital Universitario Marques de Valdecilla Avenida Valdecilla, 25

Santander, 39008, Spain

Location

Golden Jubilee National Hospital Golden Jubilee National Hospital Agamemnon St, Scottish Pulmonary Vascular Unit Golden Jubilee National Hospital

Clydebank, G81 4DY, United Kingdom

Location

Royal Free Hospital Pond Street

London, NW3 2QG, United Kingdom

Location

Related Publications (2)

• Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015 Oct;46(4):903-75. doi: 10.1183/13993003.01032-2015. Epub 2015 Aug 29.

  PMID: 26318161 BACKGROUND

• Holland AE, Spruit MA, Troosters T, Puhan MA, Pepin V, Saey D, McCormack MC, Carlin BW, Sciurba FC, Pitta F, Wanger J, MacIntyre N, Kaminsky DA, Culver BH, Revill SM, Hernandes NA, Andrianopoulos V, Camillo CA, Mitchell KE, Lee AL, Hill CJ, Singh SJ. An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respir J. 2014 Dec;44(6):1428-46. doi: 10.1183/09031936.00150314. Epub 2014 Oct 30.

  PMID: 25359355 BACKGROUND

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

zamicastat

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2023
• First Posted: August 24, 2023
• Study Start: June 26, 2019
• Primary Completion: February 17, 2022
• Study Completion: February 17, 2022
• Last Updated: September 1, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1); DE (1); PT (1); ES (4); GB (2); IT (2)