| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Men and women, ages 18 through 75 years, with a diagnosis of idiopathic PAH, heritable PAH or PAH associated with connective tissue disease (PAH-CTD), congenital heart defects (repaired), drug and toxin use, or human immunodeficiency virus (HIV) infection. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subject with pulmonary arterial hypertension |
|
| 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 | 18.1 |
| 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 |
|
| 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 |
| 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) |
|
| E.2.2 | Secondary objectives of the trial |
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 test (6MWT), 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 |
|
| 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 |
A PK sub-study with intensive PK sampling will be performed in approximately 6 subjects per treatment arm at selected sites. Samples will be collected at 0 (pre-dose) and 1, 2, 4, 6, 10, and 24 hours post-dose at any time between Week 4 and Week 20 (inclusive).
The PK of GS-4997 and its metabolite, GS-607509, will be evaluated. The PK of background PAH medications and other GS-4997 metabolites may be explored |
|
| E.3 | Principal inclusion criteria |
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% (see Section 6.8.5 for further details).
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 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 pulmonary arteriogram negative
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 weeks of study treatment |
|
| E.4 | Principal exclusion criteria |
1)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
2)Pulmonary hypertension (PH) belonging to groups 2 to 5 of the 2013 NICE classification {29019}.
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
3)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
4)Left ventricular ejection fraction (LVEF) ≤ 40% or clinically significant ischemic, valvular or constrictive heart disease
5)Receiving intravenous inotropes within 4 weeks prior to the screening visit (e.g. dopamine, dobutamine)
6)Receiving treatment with a strong CYP3A4 inhibitor (e.g. protease inhibitors, systemic ketoconazole or systemic itraconazole) within 2 weeks prior to randomization. See Section 5.4 for further details
7)Receiving treatment with a strong CYP3A4 inducer (e.g. rifampin) within 2 weeks prior to randomization. See Section 5.4 for further details
8)Uncontrolled hypertension (≥180/110 mm Hg) at screening
9)End stage renal disease (receiving peritoneal dialysis, hemodialysis, or status after renal transplantation)
10)Severe liver disease (Child-Pugh Class C, with or without cirrhosis)
11)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
12)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
13)Pregnant or breastfeeding; lactating females must agree to discontinue nursing before the study drug is administered
14)Demonstrated noncompliance with previous medical regimens
15)Current alcohol or substance abuse judged by the Investigator to potentially interfere with subject compliance or subject safety
16)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.
17)Known hypersensitivity to the study drug, the metabolites, or formulation excipients.
Subjects may be rescreened one additional time with prior notification to and approval by the sponsor. Each screening must be adequately documented in the source documents. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is change from baseline in pulmonary vascular resistance (PVR) evaluated at Week 24, as measured by right heart catheterization. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PVR is evaluated at Week 24 |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
•Change from baseline evaluated at Week 24 in other cardiopulmonary hemodynamic measures
•Change from baseline at Week 24 in:
—6MWD
—BDI immediately following exercise
—WHO Functional Class
—NT-proBNP
—SF-36 Health Survey physical functioning scale
—emPHasis-10 questionnaire
—HRR after the 6MWT
•Time to clinical worsening (TTCW) evaluated in Period 1
•Change from baseline in echocardiographic assessments of right ventricular function at Week 24. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the period 1, clinic visits uccur on Week 4, Week 8, Week 16, and Week 24. During the period 2, clinic visits ocur on Week 28, Week 32, Week 48 and every 24 weeks until the end of trial. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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