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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
Full description
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
Enrollment
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Volunteers
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.
Primary purpose
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33 participants in 4 patient groups
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Data sourced from clinicaltrials.gov
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