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. La hipertensión pulmonar (PH) es una enfermedad grave y potencialmente mortal de la vasculatura pulmonar, caracterizada por una vasoconstricción profunda y una proliferación anómala de células musculares lisas en las paredes de las arterías pulmonares |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
|
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). |
|
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. |
|
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 |
|
E.3 | Principal inclusion criteria |
1. Subject must be between 16 and 65 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 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 150 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: 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 monotherapy with an approved ERA must be receiving this therapy continuously for ?12 weeks prior to the Screening Visit and must be at a stable dose for ?8 consecutive weeks prior to the Screening Visit 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 |
|
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 4. Subject has received chronic prostanoid or PDE5i therapy for the treatment of PAH within the 12 weeks prior to the Screening Visit. Chronic use is considered >7 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) ?59 mL/min/1.73 m2 at the Screening Visit 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, cisapride, 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 12 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) |
|
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. |
|
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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.8.3 |
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 | Information not present in EudraCT |
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 |
|
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
|
|
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 |