Pharmacokinetics, Safety and Efficacy of BIA 5-1058 in PAH (Zamicastat)

NCT04316143 | Completed Phase 2 Results DMC

• 2 other identifiers: BIA-51058-2012018-002448-10
• Study Type: interventional
• Target: 33
• Locations: 7 countries
• Sites: 13

Brief Summary

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

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 (7)

• 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)

  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

Study Arms (4)

50 mg zamicastat

EXPERIMENTAL

50 mg zamicastat once daily

Drug: Oral zamicastat

100 mg zamicastat once daily

EXPERIMENTAL

100 mg zamicastat once daily

Drug: Oral zamicastat

150 mg zamicastat once daily

EXPERIMENTAL

150 mg zamicastat once daily

Drug: Oral zamicastat

200 mg zamicastat once daily

EXPERIMENTAL

200 mg zamicastat once daily

Drug: Oral zamicastat

Interventions

Oral zamicastat DRUG

Tablets for oral administration under fed conditions containing 100 mg of zamicastat

Also known as: BIA 5-1058

100 mg zamicastat once daily; 150 mg zamicastat once daily; 200 mg zamicastat once daily; 50 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:

• 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):
• Idiopathic, in non-vasoreactive patients
• Heritable: Bone morphogenetic protein receptor type II (BMPR2) mutation and other mutations, in non-vasoreactive patients
• Drugs and toxin induced, in non-vasoreactive patients
• Associated with connective tissue disease
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Bial - Portela C S.A.: lead

Study Sites (13)

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

Ospedale Generale Regionale Miulli-Cardiologia e UTIC Strada Prov. 127 Acquaviva - Santeramo Km. 4,100

Acquaviva delle Fonti, 70021, Italy

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

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

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

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

zamicastat

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Responsible of Clinical Research & Operations
• Organization: BIAL - Portela & Ca, SA

clinical.trials@bial.com

+351229866100

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: March 18, 2020
• First Posted: March 20, 2020
• Study Start: June 3, 2019
• Primary Completion: October 20, 2021
• Study Completion: October 20, 2021
• Last Updated: October 15, 2024
• Results First Posted: October 15, 2024

Record last verified: 2024-09

Locations

ES (4); PT (1); IT (3); UA (1); GB (2); AU (1); DE (1)