Clinical trial NCT06009185: Safety and Efficacy of BIA 5-1058 in PAH
Official title: An Open-label, Multicentre Study to Evaluate the Safety and Efficacy of Zamicastat as Adjunctive Therapy in Long-term Treatment of Pulmonary Arterial Hypertension (PAH) Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: Bial - Portela C S.A.
Sponsor class: INDUSTRY
First posted: 2023-08-24
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: This is an extension study with Pulmonary Arterial Hypertension (PAH) patients who are under treatment with zamicastat as adjunctive therapy in the study BIA-51058-201.

For patients participating in this extension study, visit "Maintenance Period Visit 3" (MPV3) of the study BIA-51058-201 will also be the first visit (V1) of this extension study (BIA-51058-202). Their treatment with zamicastat will be continued at their individual highest tolerated dose (HTD) for an additional 12 weeks (50 mg, 100 mg, 150 mg or 200 mg).

Further visits will be performed 20 ±3 days (V2, telephone), 41 ±3 days (V3, on-site), 62 ±3 days (V4, telephone) and 83 ±3 days (V5, on-site) after V1. At V5, patients will have the opportunity to continue treatment with zamicastat in a compassionate use program. Patients who will not participate in this compassionate use program will come to the following follow-up visit(s):

* Follow-up (FU) down-titration (telephone, 14 ±2 days after V5); only applicable in patients taking 150 mg or 200 mg zamicastat
* FU visit (on-site, 14 ±2 days after last investigational medicinal product (IMP) intake).

The data and safety monitoring board (DSMB) will periodically review the safety data and will issue a recommendation if the study can be continued as planned.

Eligibility criteria: Inclusion Criteria:

For inclusion in the extension study, patients had to fulfil all of the following criteria at visit V1 (Day 1, start of the extension study):

* 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

Exclusion Criteria:

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).
* Concurrent participation in any other drug investigational study except BIA-51058-201.
* 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.

Primary outcomes:
measure: Number of participants with adverse events (AEs)
timeFrame: Up to 12 weeks
measure: Clinically relevant changes in laboratory parameters: coagulation
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 6 and week 12
measure: Incidence of clinically relevant changes (abnormalities) in laboratory parameters: biochemistry
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 6 and week 12
measure: Incidence of clinically relevant changes (abnormalities) in laboratory parameters: haematology
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 6 and week 12
measure: Clinically relevant changes in laboratory parameters: urinalysis
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 6 and week 12
measure: Clinically relevant changes in laboratory parameters: arterial blood gas
timeFrame: From baseline to week 12, and from day -1 to week 12
measure: Clinically relevant changes in vital signs: blood pressure
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 6 and week 12
measure: Clinically relevant changes in vital signs: pulse rate
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 6 and week 12
measure: Clinically relevant changes in electrocardiogram ECG parameter QT interval
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 6 and week 12
measure: Clinically relevant changes in electrocardiogram ECG parameter QRS duration
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 6 and week 12
Secondary outcomes:
measure: Changes in haemodynamic parameters: pulmonary vascular resistance (PVR)
timeFrame: From Baseline to week 12, and from Day -1 to week 12
measure: Changes in haemodynamic parameters: right atrial pressure (RAP)
timeFrame: From Baseline to week 12, and from Day -1 to week 12
measure: Changes in haemodynamic parameters: mean pulmonary artery pressure (mPAP)
timeFrame: From Baseline to week 12, and from Day -1 to week 12
measure: Changes in haemodynamic parameters: Cardiac index (CI)
timeFrame: From Baseline to week 12, and from Day -1 to week 12
measure: Changes in haemodynamic parameters: mixed venous oxygen saturation (SvO2)
timeFrame: From Baseline to week 12, and from Day -1 to week 12
measure: Changes in the New York Heart Association / World Health Organization (NYHA/WHO) functional class
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 12
measure: Changes in the 6-minute walk test (6-MWT): Distance Covered
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 12
measure: Changes in Biomarker N-terminal pro brain natriuretic peptide (NT-proBNP)
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 12
measure: Changes in echocardiogram parameters
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 12
measure: Changes in Quality of life 36-item Short Form Health Survey version 2 (SF-36v2)
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 12
measure: Minimum Plasma Concentration (Cmin) of zamicastat and its metabolites (BIA 5-961 and BIA 5-453)
timeFrame: Day -1, week 6 and week 12
measure: Changes in plasma of dopamine ß-hydroxylase (DβH) activity
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 12
measure: Catecholamine (norepinephrine and dopamine) levels urinary pharmacodynamic change from baseline: changes in 24-hour
timeFrame: From baseline to week 6 and week 12, and from day -1 to week 12
Other outcomes:
Locations:
city: Linz
country: Austria
facility: Ordensklinikum Linz Elisabethinen, Interne 2 - Kardiologie, Angiologie & Interne Intensivmedizin Fadingerstraße 1
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik I, Pneumologie Fetscherstraße 74
city: Monza
country: Italy
facility: ASST di Monza-Ospedale San Gerardo -Dipartimento di Pneumologia via Pergolesi 33
city: Roma
country: Italy
facility: AOU di Roma-Policlinico Umberto I-Unità Dipartimentale Malattie del Circolo Polmonare Viale del Policlinico 155
city: Lisboa
country: Portugal
facility: Centro Hospitalar Lisboa Norte, E.P.E. - Hospital Pulido Valente Consulta Externa de Hipertensão Pulmonar Alameda das Linhas de Torres, 117
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona Calle Villarroel, 170
city: Madrid
country: Spain
facility: Hospital Universitario "12 de Octubre" Avda. de Córdoba, s/n
city: Salamanca
country: Spain
facility: Complejo Asistencial Universitario de Salamanca Pº. San Vicente, 58
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla Avenida Valdecilla, 25
city: Clydebank
country: United Kingdom
facility: Golden Jubilee National Hospital Golden Jubilee National Hospital Agamemnon St, Scottish Pulmonary Vascular Unit Golden Jubilee National Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital Pond Street
Study officials:
References:
citation: 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.
citation: 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.