increase of blood pressure in the pulmonary artery Pulmonary Arterial Hypertension
Conditions
Interventions
PERIOD 1: Screening & 24-Week Placebo-Controlled Treatment
Subjects will be screened for study eligibility within 4 weeks prior to
randomization. Subjects who meet all entry criteria other than the h
therefore, the investigator
should ensure that the subject is at a stable dose as defined by the inclusion
exclusion criteria. No increases in current background oral PAH doses or
addition of a new
Pulmonary Arterial Hypertension
Sponsors
Gilead Sciences
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: Subjects must meet all of the following inclusion criteria to be eligible for participation in this study:;1) Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures 2) Man or woman age 18 through 75 years 3) Diagnosis of one of the following: a) IPAH b) HPAH c) Drug- and toxin-induced PAH d) PAH associated with one of the following: i) Connective tissue disease (CTD; e.g. limited scleroderma, diffuse scleroderma, mixed CTD systemic lupus erythematous or overlap syndrome), ii) HIV infection iii) Congenital heart defects, repaired greater than 1 year prior to screening (atrial septal defects, ventricular septal defects, and patent ductus arteriosus) 4) Confirm the diagnosis of PAH and meet all of the following hemodynamic criteria by means of a screening RHC completed prior to randomization: a) Mean pulmonary artery pressure (mPAP) of * 25 mmHg b) Pulmonary vascular resistance (PVR) * 400 dyne*sec/cm5 c) Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) of * 12 mmHg if PVR * 400 and < 500 dynes*sec/cm5, or PCWP/LVEDP * 15 mmHg if PVR * 500 dynes*sec/cm5 5) Be able to walk a distance of at least 100 m during the screening visit 6-minute walk test (6MWT) and have screening and randomization visit 6MWD that do not vary by more than 10% 6) Have WHO Functional Class II or III symptoms at the screening visit, as assessed by the investigator 7) Meet the following criteria determined by pulmonary function tests completed no more than 24 weeks prior to screening, performed with or without bronchodilation: a) Forced expiratory volume in one second (FEV1) * 55% of predicted normal b) FEV1:FVC ratio * 0.60 8) Currently on a stable treatment regimen with one or more drugs approved for PAH. Stable therapy is defined as dosing of the same treatments for * 12 weeks prior to the screening RHC and at a stable dose for * 8 weeks prior to the screening RHC. Any instances where doses have been missed prior to RHC must be discussed with the medical monitor prior to performing the RHC. 9) If diagnosed with HIV, must have stable disease status. For this study, stable HIV status is defined as follows: a) Stable treatment with HIV medications for at least 8 weeks prior to screening, b) No active opportunistic infection during the screening period, and c) No hospitalizations due to HIV for at least 4 weeks prior to screening 10) Have documented evidence of the exclusion of chronic thromboembolic pulmonary hypertension (CTEPH) by a negative or low probability lung ventilation/perfusion (V/Q) scan or negative pulmonary arteriogram 11) Women of childbearing potential must have a negative serum pregnancy test at Screening 12) If engaged in heterosexual activity and of child-bearing potential, must agree to use protocol-specified method(s) of contraception 13) If participating in an exercise program for pulmonary rehabilitation, the program must have been initiated *12 weeks prior to screening, and subjects must agree to maintain the current level of rehabilitation for the first 24 weeks of study treatment 14) If not participating in an exercise training program for pulmonary rehabilitation, must agree not to enroll in an exercise training program for pulmonary rehabilitation during the screening period and the first 24 wee
Exclusion criteria
Exclusion criteria: Subjects who meet any of the following exclusion criteria are not to be enrolled in this study: 15) Diagnosis of PAH associated with: a) Significant venous or capillary involvement (PCWP > 15 mm Hg) b) Pulmonary capillary hemangiomatosis c) Portal hypertension d) Unrepaired congenital heart defects 16) Pulmonary hypertension (PH) belonging to groups 2 to 5 of the 2013 NICE classification. a) Group 2: PH due to left heart disease b) Group 3: PH due to lung diseases and/or hypoxia c) Group 4: Chronic thromboembolic pulmonary hypertension d) Group 5: PH with unclear multifactorial mechanisms 17) Evidence of * 3 of the following left ventricular disease/dysfunction risk factors (a-d): a) Body mass index (BMI) * 30 b) Established diagnosis of essential hypertension and active treatment during the 2 years prior to screening c) Diabetes mellitus * any type d) Historical evidence of significant coronary artery disease (CAD) established by any one of the following: i) History of myocardial infarction ii) History of percutaneous intervention iii) Angiographic evidence of CAD (> 50% stenosis in at least one vessel), either by invasive angiography or by CT angiography iv) Positive stress test with imaging (either pharmacologic or with exercise) v) Previous coronary artery surgery vi) Chronic stable angina 18) Left ventricular ejection fraction (LVEF) * 40% or clinically significant ischemic, valvular or constrictive heart disease 19) Receiving intravenous inotropes within 4 weeks prior to the screening visit (e.g. dopamine, dobutamine) 20) Receiving treatment with a strong CYP3A4 inhibitor (e.g. protease inhibitors, systemic ketoconazole or systemic itraconazole) within 2 weeks prior to randomization. 21) Receiving treatment with a strong CYP3A4 inducer (e.g. rifampin). within 2 weeks prior to randomization. 22) Uncontrolled hypertension (*180/110 mm Hg) at screening 23) End stage renal disease (receiving peritoneal dialysis, hemodialysis, or status after renal transplantation) 24) Severe liver disease (Child-Pugh Class C, with or without cirrhosis) 25) Severe arthritis, musculoskeletal problems, or morbid obesity that, in the opinion of the investigator, is the cause of the subject*s functional limitation and would affect the subject*s ability to perform or complete the 6MWT 26) History of malignancies within the past 5 years, except for a subject with localized, nonmetastatic basal or squamous 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 27) Pregnant or breastfeeding; lactating females must agree to discontinue nursing before the study drug is administered 28) Demonstrated noncompliance with previous medical regimens 29) Current alcohol or substance abuse judged by the Investigator to potentially interfere with subject compliance or subject safety 30) Participation in a clinical study involving another investigational drug or device within 4 weeks before the screening visit. Current participation in a drug access study for an eligible PAH therapy in a country where the therapy is approved but not yet commercially available to the subject is allowed. 31) Known hypersensitivity to the study drug, the metabolites, or formulation
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary objective of this study is to: Evaluate the effect of GS-4997 on pulmonary vascular resistance (PVR), as measured by right heart catheterization (RHC) in subjects with pulmonary arterial hypertension (PAH) | — |
Secondary
| Measure | Time frame |
|---|---|
| The secondary objectives of this study are to evaluate, in subjects with PAH, the effect of GS-4997 on the following: - Cardiac index (CI), mean pulmonary artery pressure (mPAP), mean right atrial pressure (mRAP), mixed venous oxygen saturation (SvO2), and right ventricular cardiac power - Clinical measures of PAH, including the 6-minute walk distance (6MWD), Borg Dyspnea index (BDI), heart rate recovery (HRR), WHO Functional Class, and N-terminal pro-brain natriuretic peptide (NT-proBNP) - Quality of life (QoL) as measured by the SF-36® Health Survey and the emPHasis-10 questionnaire - Time to clinical worsening (TTCW) - Echocardiographic measures of right ventricular function - Safety and tolerability The additional objectives of this study are to evaluate the following in subjects with PAH: - The pharmacokinetics of GS-4997 and its metabolite, GS-607509 - The effect of GS-4997 on disease- and target-specific biomarkers | — |
Countries
Canada, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States of America
Outcome results
None listed