Selonsertib in Adults With Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the effect of selonsertib (GS-4997) on pulmonary vascular resistance (PVR), as measured by right heart catheterization (RHC) in adults with pulmonary arterial hypertension (PAH). The study will consist of a 24-week placebo-controlled treatment period and a long-term selonsertib treatment period. Participants completing the 24-week placebo-controlled period will be eligible to receive active treatment with selonsertib in the long-term treatment period.

Official Title
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A Phase 2, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled Study of GS-4997 in Subjects With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Placebo
* Drug: Selonsertib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of idiopathic pulmonary arterial hypertension (IPAH), heritable pulmonary arterial hypertension (HPAH), drug- and toxin-induced PAH, or PAH associated with connective tissue disease, human immunodeficiency virus (HIV) infection, or congenital heart defects (repaired greater than 1 year prior to Screening) Meet all of the following hemodynamic criteria by means of a screening right heart catheterization (RHC) completed prior to randomization: Mean pulmonary artery pressure (mPAP) of greater than or equal to (≥) 25 millimeters of mercury (mm Hg) Pulmonary vascular resistance (PVR) ≥ 400 dyne* second/centimeter^5 (dynes*sec/cm^5) Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) of less than or equal to (≤) 12 mm Hg if PVR ≥ 400 and less than (<) 500 dynes*sec/cm^5, or PCWP/LVEDP ≤ 15 mm Hg if PVR ≥ 500 dynes•sec/cm^5 Be able to walk a distance of at least 100 meters Have World Health Organization (WHO) Functional Class II or III symptoms Meet the following criteria determined by pulmonary function tests completed no more than 24 weeks prior to screening, performed with or without bronchodilation: Forced expiratory volume in one second (FEV1) ≥ 55 percent (%) of predicted normal FEV1: forced vital capacity (FVC) ratio ≥ 0.60 Receiving treatment with one or more drugs approved for PAH for ≥ 12 consecutive weeks and at stable dose for ≥ 8 consecutive weeks Key Exclusion Criteria: Diagnosis of PAH associated with significant venous or capillary involvement (PCWP greater than [>] 15 mm Hg), pulmonary capillary hemangiomatosis, portal hypertension, or unrepaired congenital heart defects Pulmonary hypertension (PH) belonging to groups 2 to 5 of the 2013 NICE classification Left ventricular ejection fraction (LVEF) ≤ 40% or clinically significant ischemic, valvular or constrictive heart disease Uncontrolled hypertension (≥ 180/110 mm Hg) at Screening End stage renal disease (receiving peritoneal dialysis, hemodialysis, or status after renal transplantation) Severe liver disease (Child-Pugh Class C, with or without cirrhosis) Individuals may be rescreened one additional time with prior notification to and approval by the sponsor. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selonsertib 2 mg<br>Participants will receive selonsertib 2 milligrams (mg) for 24 weeks and may continue on this dose during the long-term treatment phase. | Drug: Selonsertib<br>* Tablets administered orally once daily<br>* Other names: GS-4997;|
| Experimental: Selonsertib 6 mg<br>Participants will receive selonsertib 6 mg for 24 weeks and may continue on this dose during the long-term treatment phase. | Drug: Selonsertib<br>* Tablets administered orally once daily<br>* Other names: GS-4997;|
| Experimental: Selonsertib 18 mg<br>Participants will receive selonsertib 18 mg for 24 weeks and may continue on this dose during the long-term treatment phase. | Drug: Selonsertib<br>* Tablets administered orally once daily<br>* Other names: GS-4997;|
| Experimental: Placebo<br>Participants will receive selonsertib placebo for 24 weeks, and may then be rerandomized 1:1:1 to selonsertib 2, 6, or 18 mg during the long-term treatment phase. | Drug: Placebo<br>* Tablet administered orally once daily<br>* Other names: GS-4997;Drug: Selonsertib<br>* Tablets administered orally once daily<br>* Other names: GS-4997;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24, as Measured by Right Heart Catheterization (RHC) | PVR is a measure of the extent to which pulmonary circulation resists cardiac output. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Cardiac Index | Cardiac index is the amount of blood pumped by the heart, per minute, per meter square of body surface area. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mPAP | mPAP is the mean blood pressure in the pulmonary artery. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mRAP | mRAP is the mean blood pressure in the right atrium of the heart. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Mixed Venous Oxygen Saturation (SVO2) (%) | SVO2 is the percentage of oxygen bound to hemoglobin in blood returning to the right side of the heart. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Right Ventricular Cardiac Power (RVCP) | RVCP is a cardiopulmonary hemodynamic assessment. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline at Week 24 in 6MWD Test | The 6MWD test was conducted according to the American Thoracic Society guidelines in accordance with local standard operating procedures. It measures the distance a participant is able to walk in a period of six minutes. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline at Week 24 in BDI After the 6MWD Test | Immediately following completion of the 6-minute walk test, participants were asked to assess breathlessness using the BDI score as follows: 0 = no breathlessness, 10 = extremely strong (maximal breathlessness), any number > 10 = Highest possible. Therefore, the minimum for BDI score was 0 and there was no upper bound. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Class I: no symptoms with exercise or at rest. Class II: No symptoms at rest but uncomfortable and short of breath with normal activity such as climbing a flight of stairs, grocery shopping, or making the bed. Class III: May not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting (e.g., doing normal chores around the house, have to take breaks while doing activities of daily living). Class IV: Symptoms at rest and severe symptoms with any activity. Most participants also have edema in the feet and ankles as result of right heart failure. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline at Week 24 in NT-proBNP | NT-proBNP is used to detect, diagnose, and evaluate the severity of heart failure. In general, NT-proBNP levels are higher in participants with heart failure than those who have normal heart function. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline at Week 24 in Short Form (SF-36) Physical Functioning Scale | Quality of life was assessed using the SF-36 questionnaire, a self-administered multi-item survey that asks 36 questions to measure functional health and well-being from the participant's point of view and consists of eight health domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health) as well as 2 summary measures (Physical Health and Mental Health). Data presented are for 1 of the domains only: Physical Functioning. Scores can range from 0 to 100, with a higher score representing a higher level of functioning. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline at Week 24 in emPHasis-10 Questionnaire Score | Quality of life was assessed using the emPHasis-10 questionnaire, a disease-specific self-administered 10-question questionnaire designed for routine assessment of health-related quality of life in pulmonary hypertension. Total score can range from 0 to 50, with higher scores indicating a worse quality of life. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline at Week 24 in Heart Rate Recovery (HRR) After the 6MWD Test | HRR was assessed after the 6MWD test. The HRR was calculated as the difference between the heart rate measured immediately after completing the 6MWD test and the second heart rate measured 1 minute after the 6MWD test. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Kaplan-Meier Estimate of Time to Clinical Worsening (TTCW) Evaluated in Period 1 | TTCW was defined as time to the first occurrence of: death (all-cause), hospitalization for worsening pulmonary arterial hypertension (PAH) (any hospitalization for worsening PAH, lung or heart/lung transplant, atrial septostomy, or initiation of continuously infused prostanoid therapy), or disease progression (defined as both > 15% decrease from baseline in 6MWD test and WHO class III or IV symptoms at two consecutive postbaseline clinic visits separated by ≥ 14 days). TTCW was evaluated using Kaplan-Meier estimates. | Baseline up to Week 24 | 
| Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: TAPSE | TAPSE is an echocardiographic assessment of right ventricular function. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Myocardial Strain (%) | Right ventricular myocardial strain is an echocardiographic assessment of right ventricular function. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Tricuspid Annular Peak Sys Myocard Velocity (TAS) | TAS is an echocardiographic assessment of right ventricular function. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Tei Index (RVTI) | The Tei-index is defined as the sum of the isovolumic contraction and the isovolumic relaxation time divided by ejection time, and thus incorporates elements of both systolic and diastolic phases in the assessment of global ventricular function. An increased Tei-index results from ventricular dysfunction and provides prognostic information for a variety of myocardial conditions. The RVTI is a candidate to increase the non-invasive diagnosis of PAH because it reflects the right ventricular function, is easy to assess, and can be estimated in the same session as the echocardiographic PAP. The normal value of the RVTI is 0.28 +/- 0.04. An increased RVTI is associated with either left ventricular diastolic abnormalities or pulmonary hypertension. This score has no bounds. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 | 
| Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Fractional Area Change (RVFAC) | RVFAC is an echocardiographic assessment of right ventricular function. Change from Baseline was calculated as the value at Week 24 minus the value at Baseline. The Week 24 value was defined as the last assessment at or prior to Week 24. | Baseline to Week 24 |