Safety and Efficacy of BIA 5-1058 in PAH

BIAL

Status and phase: Completed; Phase 2

Conditions: Pulmonary Arterial Hypertension

Treatments: Drug: Oral zamicastat

Study type: Interventional

Funder types: Industry

Identifiers

NCT06009185

BIA-51058-202

2018-002796-18 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 20 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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20 participants in 2 patient groups

HTD < 200 mg zamicastat

Experimental group

Description:

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.

Treatment:

Drug: Oral zamicastat

HTD 200 mg zamicastat

Experimental group

Description:

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.

Treatment:

Drug: Oral zamicastat