Trial Outcomes & Findings for Selonsertib in Adults With Pulmonary Arterial Hypertension (NCT NCT02234141)

Last Updated: 2019-04-10

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

151 participants

Primary outcome timeframe

Baseline to Week 24

Results posted on

2019-04-10

Participant Flow

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.

185 participants were screened.

Participant milestones

Participant milestones
Measure	Selonsertib 2 mg Participants were randomized to receive selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1) and may have continued on this dosing during the long-term treatment phase (Period 2).	Selonsertib 6 mg Participants were randomized to receive selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1) and may have continued on this dosing during the long-term treatment phase (Period 2).	Selonsertib 18 mg Participants were randomized to receive selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1) and may have continued on this dosing during the long-term treatment phase (Period 2).	Placebo Participants were randomized received placebo tablet once daily for 24 weeks (Period 1) and may have been rerandomized 1:1:1 to selonsertib 2, 6, or 18 mg during the long-term treatment phase (Period 2).	Placebo to Selonsertib 2 mg Participants received placebo in Period 1 and were rerandomized to receive selonsertib 2 mg tablet once daily during the long-term treatment phase (Period 2).	Placebo to Selonsertib 6 mg Participants received placebo in Period 1 and were rerandomized to receive selonsertib 6 mg tablet once daily during the long-term treatment phase (Period 2).	Placebo to Selonsertib 18 mg Participants received placebo in Period 1 and were rerandomized to receive selonsertib 18 mg tablet once daily during the long-term treatment phase (Period 2).
Treatment Period (24 Weeks) STARTED	39	38	37	37	0	0	0
Treatment Period (24 Weeks) COMPLETED	35	32	35	32	0	0	0
Treatment Period (24 Weeks) NOT COMPLETED	4	6	2	5	0	0	0
Long-Term Treatment Period STARTED	33	31	33	0	10	12	10
Long-Term Treatment Period COMPLETED	0	0	0	0	0	0	0
Long-Term Treatment Period NOT COMPLETED	33	31	33	0	10	12	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Selonsertib 2 mg Participants were randomized to receive selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1) and may have continued on this dosing during the long-term treatment phase (Period 2).	Selonsertib 6 mg Participants were randomized to receive selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1) and may have continued on this dosing during the long-term treatment phase (Period 2).	Selonsertib 18 mg Participants were randomized to receive selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1) and may have continued on this dosing during the long-term treatment phase (Period 2).	Placebo Participants were randomized received placebo tablet once daily for 24 weeks (Period 1) and may have been rerandomized 1:1:1 to selonsertib 2, 6, or 18 mg during the long-term treatment phase (Period 2).	Placebo to Selonsertib 2 mg Participants received placebo in Period 1 and were rerandomized to receive selonsertib 2 mg tablet once daily during the long-term treatment phase (Period 2).	Placebo to Selonsertib 6 mg Participants received placebo in Period 1 and were rerandomized to receive selonsertib 6 mg tablet once daily during the long-term treatment phase (Period 2).	Placebo to Selonsertib 18 mg Participants received placebo in Period 1 and were rerandomized to receive selonsertib 18 mg tablet once daily during the long-term treatment phase (Period 2).
Treatment Period (24 Weeks) Protocol Violation	0	0	0	1	0	0	0
Treatment Period (24 Weeks) Investigator's discretion	0	2	0	0	0	0	0
Treatment Period (24 Weeks) Death	1	2	0	1	0	0	0
Treatment Period (24 Weeks) Adverse Event	3	1	2	3	0	0	0
Treatment Period (24 Weeks) Randomized but not treated	0	1	0	0	0	0	0
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 Adverse Event	4	0	5	0	1	1	1
Long-Term Treatment Period Withdrew Consent	0	1	1	0	0	0	0
Long-Term Treatment Period Study Discontinued by Sponsor	28	27	25	0	9	10	8

Baseline Characteristics

Participants in the Safety Analysis Set with available data were analyzed.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Selonsertib 2 mg n=39 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=37 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=37 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=37 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).	Total n=150 Participants Total of all reporting groups
Age, Continuous	50 years STANDARD_DEVIATION 13.9 • n=39 Participants	49 years STANDARD_DEVIATION 13.7 • n=37 Participants	48 years STANDARD_DEVIATION 14.1 • n=37 Participants	55 years STANDARD_DEVIATION 15.5 • n=37 Participants	50 years STANDARD_DEVIATION 14.5 • n=150 Participants
Sex: Female, Male Female	30 Participants n=39 Participants	27 Participants n=37 Participants	32 Participants n=37 Participants	30 Participants n=37 Participants	119 Participants n=150 Participants
Sex: Female, Male Male	9 Participants n=39 Participants	10 Participants n=37 Participants	5 Participants n=37 Participants	7 Participants n=37 Participants	31 Participants n=150 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=39 Participants	5 Participants n=37 Participants	3 Participants n=37 Participants	2 Participants n=37 Participants	16 Participants n=150 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	31 Participants n=39 Participants	31 Participants n=37 Participants	32 Participants n=37 Participants	35 Participants n=37 Participants	129 Participants n=150 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=39 Participants	1 Participants n=37 Participants	2 Participants n=37 Participants	0 Participants n=37 Participants	5 Participants n=150 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants n=39 Participants	1 Participants n=37 Participants	0 Participants n=37 Participants	0 Participants n=37 Participants	3 Participants n=150 Participants
Race (NIH/OMB) Asian	0 Participants n=39 Participants	3 Participants n=37 Participants	0 Participants n=37 Participants	2 Participants n=37 Participants	5 Participants n=150 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=39 Participants	0 Participants n=37 Participants	0 Participants n=37 Participants	0 Participants n=37 Participants	0 Participants n=150 Participants
Race (NIH/OMB) Black or African American	1 Participants n=39 Participants	0 Participants n=37 Participants	0 Participants n=37 Participants	0 Participants n=37 Participants	1 Participants n=150 Participants
Race (NIH/OMB) White	35 Participants n=39 Participants	33 Participants n=37 Participants	36 Participants n=37 Participants	35 Participants n=37 Participants	139 Participants n=150 Participants
Race (NIH/OMB) More than one race	0 Participants n=39 Participants	0 Participants n=37 Participants	0 Participants n=37 Participants	0 Participants n=37 Participants	0 Participants n=150 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=39 Participants	0 Participants n=37 Participants	1 Participants n=37 Participants	0 Participants n=37 Participants	2 Participants n=150 Participants
World Health Organization (WHO) Functional Class Class II	24 Participants n=39 Participants	23 Participants n=37 Participants	19 Participants n=37 Participants	24 Participants n=37 Participants	90 Participants n=150 Participants
World Health Organization (WHO) Functional Class Class III	15 Participants n=39 Participants	14 Participants n=37 Participants	18 Participants n=37 Participants	13 Participants n=37 Participants	60 Participants n=150 Participants
6-Minute Walk Distance (6MWD) Test	452 meters STANDARD_DEVIATION 111.9 • n=39 Participants	449 meters STANDARD_DEVIATION 85.3 • n=37 Participants	437 meters STANDARD_DEVIATION 102.7 • n=37 Participants	412 meters STANDARD_DEVIATION 109.3 • n=37 Participants	437 meters STANDARD_DEVIATION 103.1 • n=150 Participants
N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)	385 picograms per milliliter (pg/mL) n=39 Participants	431 picograms per milliliter (pg/mL) n=37 Participants	352 picograms per milliliter (pg/mL) n=37 Participants	492 picograms per milliliter (pg/mL) n=37 Participants	412 picograms per milliliter (pg/mL) n=150 Participants
Borg Dyspnea Index (BDI)	3.5 units on a scale STANDARD_DEVIATION 2.13 • n=39 Participants	3.7 units on a scale STANDARD_DEVIATION 2.41 • n=37 Participants	3.5 units on a scale STANDARD_DEVIATION 1.53 • n=37 Participants	3.6 units on a scale STANDARD_DEVIATION 1.94 • n=37 Participants	3.6 units on a scale STANDARD_DEVIATION 2.01 • n=150 Participants
Right Ventricular Fractional Area Change (RVFAC)	34.7 percentage of RV area STANDARD_DEVIATION 8.00 • n=37 Participants • Participants in the Safety Analysis Set with available data were analyzed.	33.6 percentage of RV area STANDARD_DEVIATION 9.68 • n=36 Participants • Participants in the Safety Analysis Set with available data were analyzed.	37.3 percentage of RV area STANDARD_DEVIATION 8.47 • n=34 Participants • Participants in the Safety Analysis Set with available data were analyzed.	32.3 percentage of RV area STANDARD_DEVIATION 9.59 • n=33 Participants • Participants in the Safety Analysis Set with available data were analyzed.	34.5 percentage of RV area STANDARD_DEVIATION 9.04 • n=140 Participants • Participants in the Safety Analysis Set with available data were analyzed.
Tricuspid Annular Plane Systolic Excursion (TAPSE)	1.5 cm STANDARD_DEVIATION 0.31 • n=37 Participants • Participants in the Safety Analysis Set with available data were analyzed.	1.5 cm STANDARD_DEVIATION 0.37 • n=35 Participants • Participants in the Safety Analysis Set with available data were analyzed.	1.5 cm STANDARD_DEVIATION 0.29 • n=36 Participants • Participants in the Safety Analysis Set with available data were analyzed.	1.5 cm STANDARD_DEVIATION 0.31 • n=32 Participants • Participants in the Safety Analysis Set with available data were analyzed.	1.5 cm STANDARD_DEVIATION 0.32 • n=140 Participants • Participants in the Safety Analysis Set with available data were analyzed.
Mean Right Atrial Pressure (mRAP)	8 millimeters of mercury (mm Hg) STANDARD_DEVIATION 4.3 • n=39 Participants	9 millimeters of mercury (mm Hg) STANDARD_DEVIATION 4.4 • n=37 Participants	9 millimeters of mercury (mm Hg) STANDARD_DEVIATION 4.3 • n=37 Participants	8 millimeters of mercury (mm Hg) STANDARD_DEVIATION 3.5 • n=37 Participants	8 millimeters of mercury (mm Hg) STANDARD_DEVIATION 4.2 • n=150 Participants
Mean Pulmonary Artery Pressure (mPAP)	53.4 mm Hg STANDARD_DEVIATION 15.28 • n=39 Participants	56.7 mm Hg STANDARD_DEVIATION 10.79 • n=37 Participants	55.0 mm Hg STANDARD_DEVIATION 12.51 • n=37 Participants	51.3 mm Hg STANDARD_DEVIATION 9.94 • n=37 Participants	54.1 mm Hg STANDARD_DEVIATION 12.38 • n=150 Participants
Pulmonary Vascular Resistance (PVR)	734 dynessecond/centimeter^5 (dynsec/cm^5) STANDARD_DEVIATION 313.4 • n=38 Participants • Participants in the Safety Analysis Set with available data were analyzed.	806 dynessecond/centimeter^5 (dynsec/cm^5) STANDARD_DEVIATION 381.2 • n=37 Participants • Participants in the Safety Analysis Set with available data were analyzed.	809 dynessecond/centimeter^5 (dynsec/cm^5) STANDARD_DEVIATION 366.1 • n=37 Participants • Participants in the Safety Analysis Set with available data were analyzed.	743 dynessecond/centimeter^5 (dynsec/cm^5) STANDARD_DEVIATION 268.2 • n=37 Participants • Participants in the Safety Analysis Set with available data were analyzed.	772 dynessecond/centimeter^5 (dynsec/cm^5) STANDARD_DEVIATION 333.5 • n=149 Participants • Participants in the Safety Analysis Set with available data were analyzed.
Cardiac Index	2.87 liters/minute/square meter (L/min/m^2) STANDARD_DEVIATION 0.818 • n=39 Participants	2.86 liters/minute/square meter (L/min/m^2) STANDARD_DEVIATION 0.679 • n=37 Participants	2.69 liters/minute/square meter (L/min/m^2) STANDARD_DEVIATION 0.649 • n=37 Participants	2.64 liters/minute/square meter (L/min/m^2) STANDARD_DEVIATION 0.501 • n=37 Participants	2.77 liters/minute/square meter (L/min/m^2) STANDARD_DEVIATION 0.674 • n=150 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=35 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=34 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=36 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=31 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
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	-28 dyne*sec/cm^5 Standard Error 30.2	-21 dyne*sec/cm^5 Standard Error 37.9	6 dyne*sec/cm^5 Standard Error 28.0

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=35 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=34 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=36 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=31 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Cardiac Index	-0.1 L/min/m^2 Standard Error 0.10	0.1 L/min/m^2 Standard Error 0.09	0.0 L/min/m^2 Standard Error 0.09	0.0 L/min/m^2 Standard Error 0.09

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=36 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=34 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=36 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=31 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mPAP	1 mm Hg Standard Error 1.3	-1 mm Hg Standard Error 1.1	-3 mm Hg Standard Error 1.4	0 mm Hg Standard Error 1.2

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=36 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=34 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=36 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=31 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: mRAP	1 mm Hg Standard Error 0.5	0 mm Hg Standard Error 0.7	-1 mm Hg Standard Error 0.5	1 mm Hg Standard Error 0.5

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=36 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=34 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=35 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=31 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
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	0.1 percentage of oxygen saturation Standard Error 2.13	1.1 percentage of oxygen saturation Standard Error 2.07	-2.0 percentage of oxygen saturation Standard Error 1.00

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=35 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=34 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=36 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=31 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
Change From Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Right Ventricular Cardiac Power (RVCP)	-0.01 watts Standard Error 0.026	0.00 watts Standard Error 0.024	-0.03 watts Standard Error 0.028	-0.01 watts Standard Error 0.027

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=39 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=37 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=37 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=37 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
Change From Baseline at Week 24 in 6MWD Test	4.7 meters Standard Error 6.63	3.5 meters Standard Error 8.27	-15.9 meters Standard Error 8.01	-15.0 meters Standard Error 8.60

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=39 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=37 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=37 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=37 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
Change From Baseline at Week 24 in BDI After the 6MWD Test	-0.1 units on a scale Standard Error 0.24	0.1 units on a scale Standard Error 0.26	0.1 units on a scale Standard Error 0.23	0.3 units on a scale Standard Error 0.27

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=36 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=33 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=37 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=32 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class Improved	7 Participants	6 Participants	5 Participants	1 Participants
Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class Unchanged	27 Participants	24 Participants	28 Participants	29 Participants
Number of Participants Experiencing Change From Baseline at Week 24 in WHO Functional Class Worsened	2 Participants	3 Participants	4 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=39 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=37 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=37 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=37 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
Change From Baseline at Week 24 in NT-proBNP	1.17 pg/mL Standard Error 0.093	1.01 pg/mL Standard Error 0.093	1.01 pg/mL Standard Error 0.082	1.25 pg/mL Standard Error 0.103

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=37 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=35 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=36 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=36 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
Change From Baseline at Week 24 in Short Form (SF-36) Physical Functioning Scale	0 units on a scale Standard Error 0.8	2 units on a scale Standard Error 0.9	0 units on a scale Standard Error 0.8	0 units on a scale Standard Error 0.9

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=37 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=35 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=37 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=36 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
Change From Baseline at Week 24 in emPHasis-10 Questionnaire Score	0 units on a scale Standard Error 1.1	-1 units on a scale Standard Error 1.2	1 units on a scale Standard Error 1.1	-1 units on a scale Standard Error 1

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=39 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=37 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=37 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=37 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
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	0.1 beats per minute (bpm) Standard Error 2.52	-3.0 beats per minute (bpm) Standard Error 3.07	2.4 beats per minute (bpm) Standard Error 2.08

SECONDARY outcome

Timeframe: Baseline up to Week 24

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=39 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=37 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=37 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=37 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
Kaplan-Meier Estimate of Time to Clinical Worsening (TTCW) Evaluated in Period 1	NA days NA = Not reached due to insufficient number of events	NA days NA = Not reached due to insufficient number of events	225.0 days Interval 225.0 to 225.0	178.0 days Interval 178.0 to NA = Not reached due to insufficient number of events

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=37 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=35 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=35 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=32 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
Change From Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: TAPSE	0.0 cm Standard Error 0.04	-0.1 cm Standard Error 0.06	0.0 cm Standard Error 0.04	0.0 cm Standard Error 0.04

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=29 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=28 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=26 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=24 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
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	2 percentage of strain Standard Error 0.6	-1 percentage of strain Standard Error 0.7	1 percentage of strain Standard Error 0.9

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=37 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=37 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=35 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=32 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
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	0 centimeters per second (cm/sec) Standard Error 0.3	0 centimeters per second (cm/sec) Standard Error 0.2	0 centimeters per second (cm/sec) Standard Error 0.4

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=37 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=34 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=32 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=29 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
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	0.05 units on a scale Standard Error 0.052	0.01 units on a scale Standard Error 0.021	-0.02 units on a scale Standard Error 0.038

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Participants in the Full Analysis Set with available data were analyzed.

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.

Outcome measures

Outcome measures
Measure	Selonsertib 2 mg n=37 Participants Participants received selonsertib 2 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 6 mg n=36 Participants Participants received selonsertib 6 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Selonsertib 18 mg n=33 Participants Participants received selonsertib 18 mg tablet once daily for 24 weeks during the treatment phase (Period 1).	Placebo n=33 Participants Participants received placebo tablet once daily for 24 weeks (Period 1).
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	0.0 percentage of RV area Standard Error 1.23	-1.1 percentage of RV area Standard Error 1.25	-0.6 percentage of RV area Standard Error 1.12

Adverse Events

Selonsertib 2 mg

Serious events: 14 serious events

Other events: 43 other events

Deaths: 0 deaths

Selonsertib 6 mg

Serious events: 17 serious events

Other events: 44 other events

Deaths: 0 deaths

Selonsertib 18 mg

Serious events: 16 serious events

Other events: 44 other events

Deaths: 0 deaths

Placebo

Serious events: 7 serious events

Other events: 34 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Gilead Clinical Study Information Center

Gilead Sciences

Phone: 1-833-445-3230 (GILEAD-0)

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: * The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or * The study has been completed at all study sites for at least 2 years
Publication restrictions are in place

Restriction type: OTHER