Pulmonary Arterial Hypertension
Conditions
Brief summary
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.
Interventions
DRUGPlacebo
Tablet administered orally once daily
DRUGSelonsertib
Tablets administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24, as Measured by Right Heart Catheterization (RHC) | Baseline to Week 24 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mPAP | Baseline to Week 24 | 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. |
| Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mRAP | Baseline to Week 24 | 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. |
| Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Mixed Venous Oxygen Saturation (SVO2) (%) | Baseline to Week 24 | 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. |
| Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Right Ventricular Cardiac Power (RVCP) | Baseline to Week 24 | 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. |
| Change From Baseline at Week 24 in 6MWD Test | Baseline to Week 24 | 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. |
| Change From Baseline at Week 24 in BDI After the 6MWD Test | Baseline to Week 24 | 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. |
| Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Baseline to Week 24 | 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. |
| Change From Baseline at Week 24 in NT-proBNP | Baseline to Week 24 | 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. |
| Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Cardiac Index | Baseline to Week 24 | 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. |
| Change From Baseline at Week 24 in emPHasis-10 Questionnaire Score | Baseline to Week 24 | 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. |
| Change From Baseline at Week 24 in Heart Rate Recovery (HRR) After the 6MWD Test | Baseline to Week 24 | 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. |
| Kaplan-Meier Estimate of Time to Clinical Worsening (TTCW) Evaluated in Period 1 | Baseline up to Week 24 | 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. |
| Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: TAPSE | Baseline to Week 24 | 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. |
| Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Myocardial Strain (%) | Baseline to Week 24 | 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. |
| Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Tricuspid Annular Peak Sys Myocard Velocity (TAS) | Baseline to Week 24 | 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. |
| Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Tei Index (RVTI) | Baseline to Week 24 | 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. |
| Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Fractional Area Change (RVFAC) | Baseline to Week 24 | 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. |
| Change From Baseline at Week 24 in Short Form (SF-36) Physical Functioning Scale | Baseline to Week 24 | 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. |
Countries
Canada, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in North America and Europe. The first participant was screened on 12 November 2014. The last study visit occurred on 13 December 2016.
Pre-assignment details
185 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Selonsertib 2 mg Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1). | 39 |
| Selonsertib 6 mg Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1). | 37 |
| Selonsertib 18 mg Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1). | 37 |
| Placebo Participants received placebo tablet once daily for 24 weeks (Period 1). | 37 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Long-Term Treatment Period | Adverse Event | 4 | 0 | 5 | 0 | 1 | 1 | 1 |
| Long-Term Treatment Period | Death | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Long-Term Treatment Period | Investigator's discretion | 1 | 3 | 2 | 0 | 0 | 0 | 1 |
| Long-Term Treatment Period | Study Discontinued by Sponsor | 28 | 27 | 25 | 0 | 9 | 10 | 8 |
| Long-Term Treatment Period | Withdrew Consent | 0 | 1 | 1 | 0 | 0 | 0 | 0 |
| Treatment Period (24 Weeks) | Adverse Event | 3 | 1 | 2 | 3 | 0 | 0 | 0 |
| Treatment Period (24 Weeks) | Death | 1 | 2 | 0 | 1 | 0 | 0 | 0 |
| Treatment Period (24 Weeks) | Investigator's discretion | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period (24 Weeks) | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Treatment Period (24 Weeks) | Randomized but not treated | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | Selonsertib 18 mg | Selonsertib 6 mg | Selonsertib 2 mg |
|---|---|---|---|---|---|
| 6-Minute Walk Distance (6MWD) Test | 437 meters STANDARD_DEVIATION 103.1 | 412 meters STANDARD_DEVIATION 109.3 | 437 meters STANDARD_DEVIATION 102.7 | 449 meters STANDARD_DEVIATION 85.3 | 452 meters STANDARD_DEVIATION 111.9 |
| Age, Continuous | 50 years STANDARD_DEVIATION 14.5 | 55 years STANDARD_DEVIATION 15.5 | 48 years STANDARD_DEVIATION 14.1 | 49 years STANDARD_DEVIATION 13.7 | 50 years STANDARD_DEVIATION 13.9 |
| Borg Dyspnea Index (BDI) | 3.6 units on a scale STANDARD_DEVIATION 2.01 | 3.6 units on a scale STANDARD_DEVIATION 1.94 | 3.5 units on a scale STANDARD_DEVIATION 1.53 | 3.7 units on a scale STANDARD_DEVIATION 2.41 | 3.5 units on a scale STANDARD_DEVIATION 2.13 |
| Cardiac Index | 2.77 liters/minute/square meter (L/min/m^2) STANDARD_DEVIATION 0.674 | 2.64 liters/minute/square meter (L/min/m^2) STANDARD_DEVIATION 0.501 | 2.69 liters/minute/square meter (L/min/m^2) STANDARD_DEVIATION 0.649 | 2.86 liters/minute/square meter (L/min/m^2) STANDARD_DEVIATION 0.679 | 2.87 liters/minute/square meter (L/min/m^2) STANDARD_DEVIATION 0.818 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 2 Participants | 3 Participants | 5 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 129 Participants | 35 Participants | 32 Participants | 31 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 0 Participants | 2 Participants | 1 Participants | 2 Participants |
| Mean Pulmonary Artery Pressure (mPAP) | 54.1 mm Hg STANDARD_DEVIATION 12.38 | 51.3 mm Hg STANDARD_DEVIATION 9.94 | 55.0 mm Hg STANDARD_DEVIATION 12.51 | 56.7 mm Hg STANDARD_DEVIATION 10.79 | 53.4 mm Hg STANDARD_DEVIATION 15.28 |
| Mean Right Atrial Pressure (mRAP) | 8 millimeters of mercury (mm Hg) STANDARD_DEVIATION 4.2 | 8 millimeters of mercury (mm Hg) STANDARD_DEVIATION 3.5 | 9 millimeters of mercury (mm Hg) STANDARD_DEVIATION 4.3 | 9 millimeters of mercury (mm Hg) STANDARD_DEVIATION 4.4 | 8 millimeters of mercury (mm Hg) STANDARD_DEVIATION 4.3 |
| N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | 412 picograms per milliliter (pg/mL) | 492 picograms per milliliter (pg/mL) | 352 picograms per milliliter (pg/mL) | 431 picograms per milliliter (pg/mL) | 385 picograms per milliliter (pg/mL) |
| Pulmonary Vascular Resistance (PVR) | 772 dynes*second/centimeter^5 (dyn*sec/cm^5) STANDARD_DEVIATION 333.5 | 743 dynes*second/centimeter^5 (dyn*sec/cm^5) STANDARD_DEVIATION 268.2 | 809 dynes*second/centimeter^5 (dyn*sec/cm^5) STANDARD_DEVIATION 366.1 | 806 dynes*second/centimeter^5 (dyn*sec/cm^5) STANDARD_DEVIATION 381.2 | 734 dynes*second/centimeter^5 (dyn*sec/cm^5) STANDARD_DEVIATION 313.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 2 Participants | 0 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 139 Participants | 35 Participants | 36 Participants | 33 Participants | 35 Participants |
| Right Ventricular Fractional Area Change (RVFAC) | 34.5 percentage of RV area STANDARD_DEVIATION 9.04 | 32.3 percentage of RV area STANDARD_DEVIATION 9.59 | 37.3 percentage of RV area STANDARD_DEVIATION 8.47 | 33.6 percentage of RV area STANDARD_DEVIATION 9.68 | 34.7 percentage of RV area STANDARD_DEVIATION 8 |
| Sex: Female, Male Female | 119 Participants | 30 Participants | 32 Participants | 27 Participants | 30 Participants |
| Sex: Female, Male Male | 31 Participants | 7 Participants | 5 Participants | 10 Participants | 9 Participants |
| Tricuspid Annular Plane Systolic Excursion (TAPSE) | 1.5 cm STANDARD_DEVIATION 0.32 | 1.5 cm STANDARD_DEVIATION 0.31 | 1.5 cm STANDARD_DEVIATION 0.29 | 1.5 cm STANDARD_DEVIATION 0.37 | 1.5 cm STANDARD_DEVIATION 0.31 |
| World Health Organization (WHO) Functional Class Class II | 90 Participants | 24 Participants | 19 Participants | 23 Participants | 24 Participants |
| World Health Organization (WHO) Functional Class Class III | 60 Participants | 13 Participants | 18 Participants | 14 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 43 / 49 | 44 / 49 | 44 / 47 | 34 / 37 |
| serious Total, serious adverse events | 14 / 49 | 17 / 49 | 16 / 47 | 7 / 37 |
Outcome results
Primary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set (all randomized participants who received ≥ 1 dose of study drug) with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24, as Measured by Right Heart Catheterization (RHC) | 35 dyne*sec/cm^5 | Standard Error 35.4 |
| Selonsertib 6 mg | Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24, as Measured by Right Heart Catheterization (RHC) | -28 dyne*sec/cm^5 | Standard Error 30.2 |
| Selonsertib 18 mg | Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24, as Measured by Right Heart Catheterization (RHC) | -21 dyne*sec/cm^5 | Standard Error 37.9 |
| Placebo | Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24, as Measured by Right Heart Catheterization (RHC) | 6 dyne*sec/cm^5 | Standard Error 28 |
Comparison: The protocol-specified primary analysis was to compare each selonsertib dose group with the placebo group, using Wilcoxon (van Elteren) test, with respect to change from baseline in PVR at Week 24, stratifying by randomization stratum (the underlying etiology of PAH idiopathic/heritable \[yes/no\] and the number of background PAH therapies they were receiving {1, 2, or greater than or equal to \[≥\] 3}).p-value: =0.214gvE/vE
Comparison: The protocol-specified primary analysis was to compare each selonsertib dose group with the placebo group, using Wilcoxon (van Elteren) test, with respect to change from baseline in PVR at Week 24, stratifying by randomization stratum (the underlying etiology of PAH idiopathic/heritable \[yes/no\] and the number of background PAH therapies they were receiving \[1, 2, or ≥ 3\]).p-value: =0.27gvE/vE
Comparison: The protocol-specified primary analysis was to compare each selonsertib dose group with the placebo group, using Wilcoxon (van Elteren) test, with respect to change from baseline in PVR at Week 24, stratifying by randomization stratum (the underlying etiology of PAH idiopathic/heritable \[yes/no\] and the number of background PAH therapies they were receiving \[1, 2, or ≥ 3\]).p-value: =0.604gvE/vE
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline at Week 24 in 6MWD Test | 4.7 meters | Standard Error 6.63 |
| Selonsertib 6 mg | Change From Baseline at Week 24 in 6MWD Test | 3.5 meters | Standard Error 8.27 |
| Selonsertib 18 mg | Change From Baseline at Week 24 in 6MWD Test | -15.9 meters | Standard Error 8.01 |
| Placebo | Change From Baseline at Week 24 in 6MWD Test | -15.0 meters | Standard Error 8.6 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline at Week 24 in BDI After the 6MWD Test | -0.1 units on a scale | Standard Error 0.24 |
| Selonsertib 6 mg | Change From Baseline at Week 24 in BDI After the 6MWD Test | 0.1 units on a scale | Standard Error 0.26 |
| Selonsertib 18 mg | Change From Baseline at Week 24 in BDI After the 6MWD Test | 0.1 units on a scale | Standard Error 0.23 |
| Placebo | Change From Baseline at Week 24 in BDI After the 6MWD Test | 0.3 units on a scale | Standard Error 0.27 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline at Week 24 in emPHasis-10 Questionnaire Score | 0 units on a scale | Standard Error 1.1 |
| Selonsertib 6 mg | Change From Baseline at Week 24 in emPHasis-10 Questionnaire Score | -1 units on a scale | Standard Error 1.2 |
| Selonsertib 18 mg | Change From Baseline at Week 24 in emPHasis-10 Questionnaire Score | 1 units on a scale | Standard Error 1.1 |
| Placebo | Change From Baseline at Week 24 in emPHasis-10 Questionnaire Score | -1 units on a scale | Standard Error 1 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline at Week 24 in Heart Rate Recovery (HRR) After the 6MWD Test | 4.0 beats per minute (bpm) | Standard Error 2.42 |
| Selonsertib 6 mg | Change From Baseline at Week 24 in Heart Rate Recovery (HRR) After the 6MWD Test | 0.1 beats per minute (bpm) | Standard Error 2.52 |
| Selonsertib 18 mg | Change From Baseline at Week 24 in Heart Rate Recovery (HRR) After the 6MWD Test | -3.0 beats per minute (bpm) | Standard Error 3.07 |
| Placebo | Change From Baseline at Week 24 in Heart Rate Recovery (HRR) After the 6MWD Test | 2.4 beats per minute (bpm) | Standard Error 2.08 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline at Week 24 in NT-proBNP | 1.17 pg/mL | Standard Error 0.093 |
| Selonsertib 6 mg | Change From Baseline at Week 24 in NT-proBNP | 1.01 pg/mL | Standard Error 0.093 |
| Selonsertib 18 mg | Change From Baseline at Week 24 in NT-proBNP | 1.01 pg/mL | Standard Error 0.082 |
| Placebo | Change From Baseline at Week 24 in NT-proBNP | 1.25 pg/mL | Standard Error 0.103 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Cardiac Index | -0.1 L/min/m^2 | Standard Error 0.1 |
| Selonsertib 6 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Cardiac Index | 0.1 L/min/m^2 | Standard Error 0.09 |
| Selonsertib 18 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Cardiac Index | 0.0 L/min/m^2 | Standard Error 0.09 |
| Placebo | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Cardiac Index | 0.0 L/min/m^2 | Standard Error 0.09 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Mixed Venous Oxygen Saturation (SVO2) (%) | 0.0 percentage of oxygen saturation | Standard Error 0.85 |
| Selonsertib 6 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Mixed Venous Oxygen Saturation (SVO2) (%) | 0.1 percentage of oxygen saturation | Standard Error 2.13 |
| Selonsertib 18 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Mixed Venous Oxygen Saturation (SVO2) (%) | 1.1 percentage of oxygen saturation | Standard Error 2.07 |
| Placebo | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Mixed Venous Oxygen Saturation (SVO2) (%) | -2.0 percentage of oxygen saturation | Standard Error 1 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mPAP | 1 mm Hg | Standard Error 1.3 |
| Selonsertib 6 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mPAP | -1 mm Hg | Standard Error 1.1 |
| Selonsertib 18 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mPAP | -3 mm Hg | Standard Error 1.4 |
| Placebo | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mPAP | 0 mm Hg | Standard Error 1.2 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mRAP | 1 mm Hg | Standard Error 0.5 |
| Selonsertib 6 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mRAP | 0 mm Hg | Standard Error 0.7 |
| Selonsertib 18 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mRAP | -1 mm Hg | Standard Error 0.5 |
| Placebo | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mRAP | 1 mm Hg | Standard Error 0.5 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Right Ventricular Cardiac Power (RVCP) | -0.01 watts | Standard Error 0.026 |
| Selonsertib 6 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Right Ventricular Cardiac Power (RVCP) | 0.00 watts | Standard Error 0.024 |
| Selonsertib 18 mg | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Right Ventricular Cardiac Power (RVCP) | -0.03 watts | Standard Error 0.028 |
| Placebo | Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Right Ventricular Cardiac Power (RVCP) | -0.01 watts | Standard Error 0.027 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline at Week 24 in Short Form (SF-36) Physical Functioning Scale | 0 units on a scale | Standard Error 0.8 |
| Selonsertib 6 mg | Change From Baseline at Week 24 in Short Form (SF-36) Physical Functioning Scale | 2 units on a scale | Standard Error 0.9 |
| Selonsertib 18 mg | Change From Baseline at Week 24 in Short Form (SF-36) Physical Functioning Scale | 0 units on a scale | Standard Error 0.8 |
| Placebo | Change From Baseline at Week 24 in Short Form (SF-36) Physical Functioning Scale | 0 units on a scale | Standard Error 0.9 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Fractional Area Change (RVFAC) | -0.3 percentage of RV area | Standard Error 1.16 |
| Selonsertib 6 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Fractional Area Change (RVFAC) | 0.0 percentage of RV area | Standard Error 1.23 |
| Selonsertib 18 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Fractional Area Change (RVFAC) | -1.1 percentage of RV area | Standard Error 1.25 |
| Placebo | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Fractional Area Change (RVFAC) | -0.6 percentage of RV area | Standard Error 1.12 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Myocardial Strain (%) | 1 percentage of strain | Standard Error 0.7 |
| Selonsertib 6 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Myocardial Strain (%) | 2 percentage of strain | Standard Error 0.6 |
| Selonsertib 18 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Myocardial Strain (%) | -1 percentage of strain | Standard Error 0.7 |
| Placebo | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Myocardial Strain (%) | 1 percentage of strain | Standard Error 0.9 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Tei Index (RVTI) | 0.08 units on a scale | Standard Error 0.037 |
| Selonsertib 6 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Tei Index (RVTI) | 0.05 units on a scale | Standard Error 0.052 |
| Selonsertib 18 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Tei Index (RVTI) | 0.01 units on a scale | Standard Error 0.021 |
| Placebo | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Tei Index (RVTI) | -0.02 units on a scale | Standard Error 0.038 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: TAPSE | 0.0 cm | Standard Error 0.04 |
| Selonsertib 6 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: TAPSE | -0.1 cm | Standard Error 0.06 |
| Selonsertib 18 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: TAPSE | 0.0 cm | Standard Error 0.04 |
| Placebo | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: TAPSE | 0.0 cm | Standard Error 0.04 |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Tricuspid Annular Peak Sys Myocard Velocity (TAS) | 1 centimeters per second (cm/sec) | Standard Error 0.4 |
| Selonsertib 6 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Tricuspid Annular Peak Sys Myocard Velocity (TAS) | 0 centimeters per second (cm/sec) | Standard Error 0.3 |
| Selonsertib 18 mg | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Tricuspid Annular Peak Sys Myocard Velocity (TAS) | 0 centimeters per second (cm/sec) | Standard Error 0.2 |
| Placebo | Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Tricuspid Annular Peak Sys Myocard Velocity (TAS) | 0 centimeters per second (cm/sec) | Standard Error 0.4 |
Secondary
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.
Time frame: Baseline up to Week 24
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selonsertib 2 mg | Kaplan-Meier Estimate of Time to Clinical Worsening (TTCW) Evaluated in Period 1 | NA days |
| Selonsertib 6 mg | Kaplan-Meier Estimate of Time to Clinical Worsening (TTCW) Evaluated in Period 1 | NA days |
| Selonsertib 18 mg | Kaplan-Meier Estimate of Time to Clinical Worsening (TTCW) Evaluated in Period 1 | 225.0 days |
| Placebo | Kaplan-Meier Estimate of Time to Clinical Worsening (TTCW) Evaluated in Period 1 | 178.0 days |
Secondary
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.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Selonsertib 2 mg | Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Improved | 7 Participants |
| Selonsertib 2 mg | Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Worsened | 2 Participants |
| Selonsertib 2 mg | Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Unchanged | 27 Participants |
| Selonsertib 6 mg | Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Improved | 6 Participants |
| Selonsertib 6 mg | Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Worsened | 3 Participants |
| Selonsertib 6 mg | Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Unchanged | 24 Participants |
| Selonsertib 18 mg | Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Unchanged | 28 Participants |
| Selonsertib 18 mg | Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Improved | 5 Participants |
| Selonsertib 18 mg | Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Worsened | 4 Participants |
| Placebo | Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Improved | 1 Participants |
| Placebo | Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Worsened | 2 Participants |
| Placebo | Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class | Unchanged | 29 Participants |