E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary hypertension (PH) is a serious and life-threatening disease of the pulmonary vasculature, characterized by profound vasoconstriction and an abnormal proliferation of smooth muscle cells in the walls of the pulmonary arteries. |
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E.1.1.1 | Medical condition in easily understood language |
Pulmonary arterial hypertension is high blood pressure in the blood vessels (the pulmonary arteries) that carry blood from the heart to the lungs.
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to compare the change in exercise capacity following treatment with cicletanine hydrochloride (HCl) or placebo in subjects with pulmonary arterial hypertension (PAH). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To compare the change in other clinical measures of PAH following treatment with
cicletanine HCl or placebo in subjects with PAH
• To compare the safety and tolerability of cicletanine HCl to placebo in subjects with
PAH
Additionally, the long-term safety, tolerability, and efficacy of cicletanine HCl treatment will be evaluated. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
There are 3 addtional sub studies as detailed in the main protocol. Information can be found on the following pages;
Cardiopulmonary Hemodynamic Substudy Section 7.12 Page 71
Steady-state Cicletanine Pharmacokinetics Substudy Section 7.13.2 Page 74
Fractional Exhaled Nitric Oxide Substudy Section 7.14 Page 74 |
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E.3 | Principal inclusion criteria |
1. Subject must be between 16 and 70 years of age, inclusive, at the Screening Visit
2. Subject must weigh ≥40 kg at the Screening Visit
3. Subject must have a current diagnosis of IPAH, FPAH, or PAH that is primarily due to:
a. Connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed CTD,
systemic lupus erythematosus, or overlap syndrome)
b. Congenital heart defects repaired greater than 1 year prior to Screening (i.e., atrial septal
defects, ventricular septal defects, and patent ductus arteriosus)
c. Drug and toxin use
d. HIV infection
4. Subject must meet all of the following hemodynamic criteria by means of a RHC completed prior to or during Screening:
a. mPAP of ≥25 mmHg
b. PVR >240 dyne-sec/cm5 c. PCWP or LVEDP of ≤15 mmHg
c. PCWP or LVEDP of ≤15 mmHg
5. Subject must walk a distance of at least 100 m but no more than 450 m during the screening 6MWT
6. Subject must have WHO functional class II, III, or IV symptoms at the Screening Visit, as assessed by the Investigator
7. Subject must meet all of the following pulmonary function tests completed no more than 12 weeks before the Screening visit, performed with or without bronchodilation:
a. Total lung capacity (TLC) ≥60% of predicted normal and
b. Forced expiratory volume in one second (FEV1) ≥65% of predicted normal
c. FEV1:FVC ratio >0.60
8. Subject must have laboratory results within 90% of the lower limit of normal (≥0.9xLLN) to 1.5 times the upper limit of normal (≤1.5xULN) for serum sodium, serum potassium, serum chloride, and serum magnesium at the Screening Visit
9. Subject currently receiving treatment with an approved ERA , PDE5i, and /or parenteral prostanoid must be receiving this therapy for ≥12 weeks prior to the Screening Visit and must be at a stable dose for ≥4 consecutive weeks prior to the Screening Visit. Eligible therapies allowed at Screening include:
a. Monotherapy with an ERA, PDE5i, or parenteral prostnoid that is approved for the treatment of PAH.
b. Combination therapy with two eligible PAH treatments (any combination of ERA, PDE5i or parenteral prostnoid
10. Subject receiving diuretic treatment must be on stable therapy for at least 4 weeks prior to the Screening Visit
11. Subject receiving digitalis, CCBs, angiotensin receptor blockers (ARBs), angiotensin converting enzyme (ACE) inhibitors, or beta-blocking agents must be on stable therapy for at least 4 weeks prior to the Screening Visit
12. Subject receiving 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) must be on stable therapy for at least 4 weeks prior to the Screening Visit
13. Subject with a diagnosis of HIV must have stable disease status. For this study, stable HIV status is defined as:
a. No addition of medications for treatment of HIV for at least 8 weeks prior to screening
b. No active opportunistic infection during the Screening Period
c. No hospitalizations due to HIV for at least 4 weeks prior to screening
14. Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Randomization Visit.
15. Female subjects of childbearing potential must agree to use 2 reliable methods of contraception from the Screening Visit until study completion and for at least 30 days following the last dose of study drug.
16. Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study, with the exception of a clinical registry
17. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form (ICF) and must sign the form prior to the initiation of any study procedures
18. Subject has not enrolled in an exercise training program for pulmonary rehabilitation within 12 weeks prior to the Screening Visit and must agree not to enroll in an exercise training program for pulmonary rehabilitation
during the Screening Period and the first 12 weeks of the study
19. Subject has been enrolled in an exercise training program for pulmonary rehabilitation for >12 weeks prior to
the Screening Visit and must agree to maintain their current level of rehabilitation for the first 12 weeks of the study
20.Subject must be on background PAH therapy at Screening unless the subject does not have access to or can not tolerate currently approved PAH medical therapies.
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E.4 | Principal exclusion criteria |
1. Subject with a current PH diagnosis other than IPAH, FPAH, or PAH that is primarily due to:
a. Connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed CTD, systemic lupus erythematosus, or overlap syndrome)
b. Congenital heart defects repaired greater than 1 year prior to Screening (i.e., atrial septal defects, ventricular septal defects, and patent ductus arteriosus)
c. Drug and toxin use
d. HIV infection
2. Subject with left ventricular ejection fraction (LVEF) ≤40% or clinically significant
ischemic, valvular, or constrictive heart disease 3. Subject with WHO functional class I symptoms at the Screening Visit, as assessed by the Investigator
3. Subject with WHO functional class I symptoms at the Screening Visit, as assessed by the Investigator
4b. Subject has chronically received an ineligible PAH treatment regimen within the 4 weeks prior to the Screening Visit, specifically:
- inhaled iloprost or inhaled trepostinil
- combination treatment with three PAH therapies (e.g., ERA, PDE5i, and prostnoid)
- any investigational therapy for the tretment of PAH
Chronic Use is considered> 7 consecutive days of treatment
5. Subject receiving iv inotropes within 2 weeks prior to the Screening Visit
6. Subject with SBP ≥150 mmHg or <90mmHg at the Screening Visit
7. Subject with moderate to severe liver disease (Child-Pugh Score of ≥7, Class B or C) at the Screening Visit
8. Subject with moderate or severe renal impairment, defined by an estimated glomerular filtration rate (eGFR) ≤50 mL/min/1.73 m2 at the Screening Visit. The eGFR value will be calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) equation.
9. Subject receiving lithium within the 2 weeks prior to the Screening Visit
10. Subject requiring intermittent or chronic treatment with nitrates
11. Subject receiving non-anti-arrhythmic drugs that induce torsades de pointes within the 2 weeks prior to the Screening Visit. This includes, but is not limited to: astemizole, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, domperidone, droperidol, erythromycin, halofantrine, haloperidol, levomethadyl, methadone, pentamidine, pimozide, probucol, procainamide, sparfloxacin, sultopride, terfenadine, thioridazine, or vincamine.
12. Subject has a diagnosis of long QT syndrome
13. Subject with evidence of chronic thromboembolic disease, as determined by a computed axial tomography (CT) or ventilation-perfusion scan conducted prior to the Screening Visit
14. Subject with obstructive lung disease as evidenced by a FEV1:FVC ratio ≤0.60 on pulmonary function tests completed no more than 12 weeks before the Screening visit
15. Subject with severe arthritis, musculoskeletal problems, or morbid obesity that, in the opinion of the Investigator, would affect the subject’s ability to perform or complete the 6MWT
16. Subject has a history of malignancies within the past 5 years, except for a subject with localized, non-metastatic basal cell carcinoma of the skin, in situ carcinoma of the cervix, or prostate cancer who is not currently or expected (during the study) to undergo radiation therapy, chemotherapy, hormonal treatment, and/or surgical intervention
17. Subject with cardiovascular, liver, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or efficacy of the study drug or severely limit the lifespan of the subject
18. Female subject who is pregnant or breastfeeding
19. Subject has demonstrated noncompliance with previous medical regimens
20. Subject has a recent history of abusing alcohol or illicit drugs
21. Subject has participated in a clinical study involving another investigational drug or device within 4 weeks before the Screening Visit
22. Subject has a known hypersensitivity to the study drug, the metabolites, or formulation excipients (i.e., lactose monohydrate, talc)
23. Subject receiving an oral arginine supplement within 2 weeks prior to the Screening Visit.
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E.5 End points |
E.5.1 | Primary end point(s) |
The Primary Endpoint is the change from baseline in 6MWD evaluated after 12 weeks of treatment.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation after 12 weeks of treatment
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E.5.2 | Secondary end point(s) |
• Change from baseline in BDI immediately following exercise evaluated after 12 weeks
• Change from baseline in WHO functional class evaluated after 12 weeks
• Time to clinical worsening of PAH, defined by the time from randomization to the first occurrence of death, surgical intervention (atrial septostomy or lung/heart-lung transplant), hospitalization for PAH, disease progression (defined as a 20% decrease from baseline in 6MWD combined with an increase from baseline in WHO functional class, or discontinuation of randomized treatment due to early escape), or the initiation of chronic parenteral prostanoid therapy, evaluated for the 12-week placebo-controlled treatment
period.
• Change from baseline in NT-proBNP evaluated after 12 weeks
• Change from baseline in SF-36® Health Survey physical functioning scale evaluated after
12 weeks
• Change from baseline in cardiopulmonary hemodynamics (including PVR, mPAP, mean RAP, and cardiac index) evaluated after 12 weeks
Cardiopulmonary hemodynamics will be evaluated in a subset of subjects based on voluntary enrollment into the hemodynamic substudy. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluation after 12 weeks
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Belgium |
Canada |
Germany |
Israel |
Mexico |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |