A Phase 2, Randomized, Double-blind, Placebo-controlled, Multicenter, Dose-ranging Study of Cicletanine in Subjects with Pulmonary Arterial Hypertensio

• Conditions: 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.; MedDRA version: 13.1Level: PTClassification code 10064911Term: Pulmonary arterial hypertensionSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

• Registration Number: EUCTR2008-007455-26-AT
• Lead Sponsor: Gilead Sciences, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2009-03-10
• Last Update Posted: 26 June 2012

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 160

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

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
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 consecutitive 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
8a. 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, cisapride, chloroquine, chlorpromazine, 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 dem

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified