Trial Outcomes & Findings for A Study to Investigate the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of an Intravenous Solution of JNJ-39588146 or Placebo in Patients With Heart Failure (NCT NCT01120210)

Results Overview

The effect of JNJ-39588146 on cardiac index (CI), a hemodynamic parameter that relates heart performance to the size of the individual measured in liters per minute per square metre (l/min/m2) was evaluated in patients with heart failure (HF). The primary analysis of this study focused on the differences between the treatment groups in terms of Least Squares (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from Baseline in CI at each time point as well as treatment group LS means and Standard Errors.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

62 participants

Primary outcome timeframe

Baseline up through 3 hours post infusion initiation

Results posted on

2013-07-19

Participant Flow

This study was conducted in 5 countries: Belgium (3 sites), Germany (3 sites), Italy (5 sites), Poland (3 sites), and Romania (3 sites). A total of 62 subjects (16 subjects in the placebo group and 46 subjects in the JNJ-39588146 group) were randomized and treated with the study drug.

Patients had an option to participate in an 18 hour extended infusion sub-study following the initial 3-hour infusion main study with the highest dose. A total of 10 patients (7 patients in the JNJ-39588146 group and 3 patients in the placebo group) participated in the sub-study.

Participant milestones

Participant milestones
Measure	Placebo Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Patients had an option to participate in an 18-hour extended infusion sub-study following the initial 3-hour infusion main study with the highest dose.	JNJ-39588146 Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Patients had an option to participate in an 18-hour extended infusion sub-study following the initial 3-hour infusion main study with the highest dose.
MAIN INFUSION STARTED	16	46
MAIN INFUSION COMPLETED	15	45
MAIN INFUSION NOT COMPLETED	1	1
18-HOUR EXTENDED INFUSION SUBSTUDY STARTED	3	7
18-HOUR EXTENDED INFUSION SUBSTUDY COMPLETED	3	7
18-HOUR EXTENDED INFUSION SUBSTUDY NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Patients had an option to participate in an 18-hour extended infusion sub-study following the initial 3-hour infusion main study with the highest dose.	JNJ-39588146 Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Patients had an option to participate in an 18-hour extended infusion sub-study following the initial 3-hour infusion main study with the highest dose.
MAIN INFUSION Adverse Event	1	0
MAIN INFUSION Withdrawal by Subject	0	1

Baseline Characteristics

A Study to Investigate the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of an Intravenous Solution of JNJ-39588146 or Placebo in Patients With Heart Failure

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=16 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Patients had an option to participate in an 18-hour extended infusion sub-study following the initial 3-hour infusion main study with the highest dose.	JNJ-39588146 n=46 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Patients had an option to participate in an 18-hour extended infusion sub-study following the initial 3-hour infusion main study with the highest dose.	Total n=62 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	11 Participants n=5 Participants	35 Participants n=7 Participants	46 Participants n=5 Participants
Age, Categorical >=65 years	5 Participants n=5 Participants	11 Participants n=7 Participants	16 Participants n=5 Participants
Age Continuous	57.6 years STANDARD_DEVIATION 10.46 • n=5 Participants	56.6 years STANDARD_DEVIATION 12.91 • n=7 Participants	56.8 years STANDARD_DEVIATION 12.25 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	15 Participants n=5 Participants	41 Participants n=7 Participants	56 Participants n=5 Participants
Region of Enrollment Belgium	0 participants n=5 Participants	4 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Germany	5 participants n=5 Participants	2 participants n=7 Participants	7 participants n=5 Participants
Region of Enrollment Italy	2 participants n=5 Participants	7 participants n=7 Participants	9 participants n=5 Participants
Region of Enrollment Poland	4 participants n=5 Participants	21 participants n=7 Participants	25 participants n=5 Participants
Region of Enrollment Romania	5 participants n=5 Participants	12 participants n=7 Participants	17 participants n=5 Participants
AgeCategorical <=10 years	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
AgeCategorical 11 - 20 years	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
AgeCategorical 21 - 50 years	4 participants n=5 Participants	12 participants n=7 Participants	16 participants n=5 Participants
AgeCategorical 50 - 64 years	7 participants n=5 Participants	23 participants n=7 Participants	30 participants n=5 Participants
AgeCategorical >=65 years	5 participants n=5 Participants	11 participants n=7 Participants	16 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline up through 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The effect of JNJ-39588146 on cardiac index (CI), a hemodynamic parameter that relates heart performance to the size of the individual measured in liters per minute per square metre (l/min/m2) was evaluated in patients with heart failure (HF). The primary analysis of this study focused on the differences between the treatment groups in terms of Least Squares (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from Baseline in CI at each time point as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=46 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Cardiac Index (CI) 2 hour infusion (15 ng/kg/min)	-0.15 L/min/m2 Standard Error 0.17	0.18 L/min/m2 Standard Error 0.13
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Cardiac Index (CI) 1 hour infusion (5 ng/kg/min)	-0.03 L/min/m2 Standard Error 0.19	0.24 L/min/m2 Standard Error 0.14
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Cardiac Index (CI) 3 hour infusion (30 ng/kg/min)	-0.05 L/min/m2 Standard Error 0.23	0.52 L/min/m2 Standard Error 0.17

PRIMARY outcome

Timeframe: Baseline up through 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The effect of JNJ-39588146 on pulmonary capillary wedge pressure (PCWP) was evaluated by administering multiple ascending doses of JNJ-39588146 or placebo over a 3-hour intravenous (IV) infusion period to patients with heart failure. The primary analysis of this study focused on the differences between the treatment groups in terms of Least Squares (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from baseline in PCWP at each time point as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=46 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Pulmonary Capillary Wedge Pressure (PCWP) 1 hour infusion (5 ng/kg/min)	-0.75 mmHg Standard Error 1.43 • Interval -2.312 to 2.131	-0.84 mmHg Standard Error 1.03
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Pulmonary Capillary Wedge Pressure (PCWP) 2 hour infusion (15 ng/kg/min)	0.15 mmHg Standard Error 1.81 • Interval -4.164 to 1.464	-1.20 mmHg Standard Error 1.31
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Pulmonary Capillary Wedge Pressure (PCWP) 3 hour infusion (30 ng/kg/min)	0.05 mmHg Standard Error 1.97 • Interval -5.639 to 0.483	-2.53 mmHg Standard Error 1.42

SECONDARY outcome

Timeframe: At 1-hour, 2 hours and 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The primary analysis of this study focused on the differences between the treatment groups in terms of Least Squares (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from Baseline in heart rate (HR) at each time point as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=44 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Heart Rate (HR) 2 hour infusion (15 ng/kg/min)	3.72 beats per minute (bpm) Standard Error 1.69 • Interval -1.764 to 4.235	4.96 beats per minute (bpm) Standard Error 1.24
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Heart Rate (HR) 3 hour infusion (30 ng/kg/min)	3.07 beats per minute (bpm) Standard Error 1.81 • Interval -1.046 to 5.372	5.23 beats per minute (bpm) Standard Error 1.32
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Heart Rate (HR) 1 hour infusion (5 ng/kg/min)	3.02 beats per minute (bpm) Standard Error 1.24 • Interval -2.527 to 1.879	2.69 beats per minute (bpm) Standard Error 0.91

SECONDARY outcome

Timeframe: Baseline up through 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The primary analysis of this study focused on the differences between the treatment groups in terms of Least Squares (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from Baseline in systolic blood pressure (SBP) at each time point as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=46 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Systolic Blood Pressure (SBP) 1 hour infusion (5 ng/kg/min)	0.15 mmHg Standard Error 2.95 • Interval -6.06 to 4.718	-0.53 mmHg Standard Error 2.12
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Systolic Blood Pressure (SBP) 2 hour infusion (15 ng/kg/min)	6.94 mmHg Standard Error 3.17 • Interval -7.781 to 3.801	4.94 mmHg Standard Error 2.28
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Systolic Blood Pressure (SBP) 3 hour infusion (30 ng/kg/min)	6.32 mmHg Standard Error 4.09 • Interval -11.251 to 3.708	2.55 mmHg Standard Error 2.94

SECONDARY outcome

Timeframe: Baseline up through 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The primary analysis of this study focused on the differences between the treatment groups in terms of LS mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in Least Square (LS) means (and associated confidence intervals) for change from Baseline in diastolic blood pressure(DBP) at each time point as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=46 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Diastolic Blood Pressure (DBP) 1 hour infusion (5 ng/kg/min)	-0.43 mmHg Standard Error 2.57 • Interval -8.047 to 1.331	-3.78 mmHg Standard Error 1.83
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Diastolic Blood Pressure (DBP) 2 hour infusion (15 ng/kg/min)	1.83 mmHg Standard Error 2.70 • Interval -10.482 to -0.622	-3.72 mmHg Standard Error 1.93
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Diastolic Blood Pressure (DBP) 3 hour infusion (30 ng/kg/min)	3.05 mmHg Standard Error 2.60 • Interval -11.818 to -2.332	-4.03 mmHg Standard Error 1.86

SECONDARY outcome

Timeframe: Baseline up through 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The primary analysis of this study focused on the differences between the treatment groups in terms of Least Squares (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from Baseline in left ventricular end systolic volume (LVESV) at the end of the 30 ng/kg/min infusion as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=36 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 3-hours Post Infusion Initiation [ie, at the End of the 30 ng/kg/Min Infusion]) in Left Ventricular End Systolic Volume (LVESV)	-15.51 mL Standard Error 8.93 • Interval -16.347 to 16.823	-15.28 mL Standard Error 6.36

SECONDARY outcome

Timeframe: Baseline up through 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The primary analysis of this study focused on the differences between the treatment groups in terms of Least Squares (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from Baseline in Left Ventricular End Diastolic Volume (LVEDV) at the end of the 30 ng/kg/min infusion as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=36 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 3-hours Post Infusion Initiation [ie, at the End of 30 ng/kg/Min Infusion]) in Left Ventricular End Diastolic Volume (LVEDV)	-13.91 mL Standard Error 10.05 • Interval -16.592 to 20.551	-11.93 mL Standard Error 7.11

SECONDARY outcome

Timeframe: Baseline up through 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The primary analysis of this study focused on the differences between the treatment groups in terms of Least Squares (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from Baseline in Left Ventricular Ejection Fraction (LVEF) at the end of the 30 ng/kg/min infusion as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=12 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=36 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 3-hours Post Infusion Initiation [ie, at the End of the 30 ng/kg/Min Infusion]) in Left Ventricular Ejection Fraction (LVEF)	3.61 percentage Standard Error 1.93 • Interval -3.352 to 3.968	3.92 percentage Standard Error 1.38

SECONDARY outcome

Timeframe: Baseline up through 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The primary analysis of this study focused on the differences between the treatment groups in terms of Least Squares (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from Baseline in Fractional Shortening (FS) at the end of the 30 ng/kg/min infusion as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=13 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=33 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 3-hours Post Infusion Initiation [ie, at the End of the 30 ng/kg/Min Infusion]) in Fractional Shortening (FS)	0.22 percentage Standard Error 1.54 • Interval -1.204 to 3.102	1.17 percentage Standard Error 1.14

SECONDARY outcome

Timeframe: Baseline up through 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The primary analysis of this study focused on the differences between the treatment groups in terms of Least Squares (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from Baseline in Stroke Volume (SV) at the end of the 30 ng/kg/min infusion as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=44 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Stroke Volume (SV) 3 hour infusion (30 ng/kg/min)	-0.62 mL/beat Standard Error 6.7 • Interval 2.557 to 25.771	13.54 mL/beat Standard Error 4.98
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Stroke Volume (SV) 1 hour infusion (5 ng/kg/min)	-1.34 mL/beat Standard Error 6.51 • Interval -4.198 to 18.359	5.75 mL/beat Standard Error 4.84
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Stroke Volume (SV) 2 hour infusion (15 ng/kg/min)	-4.33 mL/beat Standard Error 6.23 • Interval -2.016 to 19.575	4.45 mL/beat Standard Error 4.63

SECONDARY outcome

Timeframe: Baseline up through 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The primary analysis of this study focused on the differences between the treatment groups in terms of Least Squares (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from Baseline in Pulmonary Arterial Systolic Pressure (PASP) at the end of 5, 15 and 30 ng/kg/min Infusions as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=46 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Pulmonary Arterial Systolic Pressure (PASP) 1 hour infusion (5 ng/kg/min)	2.69 mmHg Standard Error 2.10 • Interval -5.308 to 2.554	1.32 mmHg Standard Error 1.55
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Pulmonary Arterial Systolic Pressure (PASP) 2 hour infusion (15 ng/kg/min)	0.51 mmHg Standard Error 2.45 • Interval -5.567 to 3.594	-0.48 mmHg Standard Error 1.80
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Pulmonary Arterial Systolic Pressure (PASP) 3 hour infusion (30 ng/kg/min)	-0.79 mmHg Standard Error 2.74 • Interval -4.107 to 6.148	0.24 mmHg Standard Error 2.02

SECONDARY outcome

Timeframe: Baseline up through 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The primary analysis of this study focused on the differences between the treatment groups in terms of Least Square (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from Baseline in Pulmonary Arterial Diastolic Pressure (PADP) at the end of 5, 15 and 30 ng/kg/min Infusions as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=46 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Pulmonary Arterial Diastolic Pressure (PADP) 1 hour infusion (5 ng/kg/min)	-0.99 mmHg Standard Error 1.57 • Interval -2.197 to 3.558	-0.29 mmHg Standard Error 1.12
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Pulmonary Arterial Diastolic Pressure (PADP) 2 hour infusion (15 ng/kg/min)	-0.83 mmHg Standard Error 1.91 • Interval -3.851 to 3.153	-1.17 mmHg Standard Error 1.36
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Pulmonary Arterial Diastolic Pressure (PADP) 3 hour infusion (30 ng/kg/min)	-0.72 mmHg Standard Error 1.85 • Interval -4.138 to 2.669	-1.46 mmHg Standard Error 1.32

SECONDARY outcome

Timeframe: Baseline up through 3 hours post infusion initiation

Population: The modified intent-to-treat (MITT) population included all randomized patients who received at least 1 dose of study drug, had baseline measurement and at least 1 post-baseline measurement value of at least 1 of the primary endpoints. The efficacy analysis was to be performed using the MITT analysis set.

The primary analysis of this study focused on the differences between the treatment groups in terms of Least Squares (LS) mean change from Baseline at each time point; thus, the results provided below consist of the JNJ-39588146 minus placebo differences in LS means (and associated confidence intervals) for change from Baseline in Calculated Systemic Vascular Resistance (SVR) at the end of 5, 15 and 30 ng/kg/min Infusions as well as treatment group LS means and Standard Errors.

Outcome measures

Outcome measures
Measure	Placebo n=14 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours.	JNJ-39588146 n=45 Participants Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Planned doses were 5, 15 and 30 ng/kg/min.
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Calculated Systemic Vascular Resistance (SVR) 1 hour infusion (5 ng/kg/min)	67.41 dyn.s.cm-5 Standard Error 147.97 • Interval -529.875 to 1.147	-196.95 dyn.s.cm-5 Standard Error 105.33
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Calculated Systemic Vascular Resistance (SVR) 2 hour infusion (15 ng/kg/min)	321.97 dyn.s.cm-5 Standard Error 116.73 • Interval -592.781 to -173.867	-61.36 dyn.s.cm-5 Standard Error 83.09
Post-baseline Changes Compared to Placebo (at 1-, 2-, and 3-hours Post Infusion Initiation [ie, at the End of 5, 15 and 30 ng/kg/Min Infusions]) in Calculated Systemic Vascular Resistance (SVR) 3 hour infusion (30 ng/kg/min)	281.79 dyn.s.cm-5 Standard Error 131.69 • Interval -764.07 to -291.478	-245.98 dyn.s.cm-5 Standard Error 93.74

Adverse Events

Placebo

Serious events: 3 serious events

Other events: 8 other events

Deaths: 0 deaths

JNJ-39588146

Serious events: 5 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=16 participants at risk Patients received 3 consecutive escalating intravenous (IV) infusions of placebo identical in appearance to JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Patients had an option to participate in an 18-hour extended infusion sub-study following the initial 3-hour infusion main study with the highest dose.	JNJ-39588146 n=46 participants at risk Patients received 3 consecutive escalating intravenous (IV) infusions of JNJ-39588146. Each dose was planned to be infused over 1 hour for a total planned infusion time in the main study of 3 hours. Patients had an option to participate in an 18-hour extended infusion sub-study following the initial 3-hour infusion main study with the highest dose.
Cardiac disorders Cardiac Failure	6.2% 1/16 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).	4.3% 2/46 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).
Cardiac disorders Cardiac Arrest	0.00% 0/16 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).	2.2% 1/46 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).
Cardiac disorders Ventricular Tachycardia	6.2% 1/16 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).	0.00% 0/46 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).
Gastrointestinal disorders Diarrhoea	0.00% 0/16 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).	2.2% 1/46 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).
General disorders Chest Pain	0.00% 0/16 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).	2.2% 1/46 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).
General disorders Device Malfunction	6.2% 1/16 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).	0.00% 0/46 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).
Metabolism and nutrition disorders Hypovolaemia	0.00% 0/16 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).	2.2% 1/46 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).
Renal and urinary disorders Renal Impairment	0.00% 0/16 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).	2.2% 1/46 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/16 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).	2.2% 1/46 • The number of patients with serious adverse events (SAEs) and other adverse events reported from the time of the first dose of study drug through the last examination/follow-up visit or 4 weeks after dosing are provided in the table below. One SAE of Cardiac Failure in the JNJ-39588146 group classified as non-treatment emergent was verified as "treatment-emergent" after database lock. Thus, 3(7%) patients in the JNJ-39588146 group experienced a treatment-emergent SAE of Cardiac Failure and the total number of patients with treatment-emergent SAEs in the JNJ-39588146 group was 6(13%).

Other adverse events

Additional Information

Senior Director Translational Medicine

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Phone: 858.320.3408

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If an Investigator wishes to publish information from the study, a copy of the manuscript must be provided to the Sponsor for review at least 60 days before submission for publication or presentation. Expedited reviews will be arranged for abstracts, poster presentations, or other materials. If requested by the Sponsor in writing, the Investigator will withhold such publication for up to an additional 60 days to allow for filing of a patent application.
Publication restrictions are in place

Restriction type: OTHER