A Dose Ranging Phase IIa Study of 6 Hour Intravenous Dosages of CXL-1427 in Patients Hospitalized With Heart Failure

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02157506
• Collaborator: Cardioxyl Pharmaceuticals, Inc (Industry)
• Enrollment: 70
• Locations: 35
• Arms: 7
• Actual Duration (Months): 13
• Patients Per Site: 2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

A randomized, double-blinded, placebo-controlled study of continuous 6-hour IV infusions of CXL-1427 in hospitalized patients with systolic heart failure.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure; Decompensated Heart Failure; Acute Heart Failure	Drug: CXL-1427; Drug: Placebo	Phase 2

Detailed Description

This is a dose finding, randomized, double-blinded, placebo-controlled study of continuous 6-hour IV infusions of CXL-1427 in hospitalized patients with systolic heart failure which will first evaluate up to four ascending dose levels of CXL-1427 in up to four cohorts of 8 patients each (the "Dose Escalation" cohorts). Subsequently, up to three of the initial dose levels of CXL-1427 may be assessed in the additional "Expansion" cohorts of up to approximately 16 patients to gain further confidence in the results at these dose levels. The CXL-1427 dose that will be evaluated in the first cohort will be 3µg/kg/min. The dose levels for the next three sequential Dose Escalation cohorts will be dependent on clinical safety and tolerability, as well as the results of the invasive hemodynamic measurements.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase IIa Study of the Safety, Tolerability and Hemodynamic Effects of a Continuous 6 Hour Intravenous Infusion of CXL-1427 in Hospitalized Patients With Systolic Heart Failure
• Actual Study Start Date: Jun 30, 2014
• Actual Primary Completion Date: May 31, 2015
• Actual Study Completion Date: Jul 31, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CXL-1427 Starting Dose The Starting dose of CXL-1427 in the dose escalation arms will be 3mcg/kg/min	Drug: CXL-1427; Other Names: BMS-986231
Experimental: CXL-1427 Dose Level 2 The Second Dose level of CXL-1427 will be evaluated in the Dose Escalation Arm of the study as determined by the independent dose escalation committee	Drug: CXL-1427; Other Names: BMS-986231
Experimental: CXL-1427 Dose Level 3 The Third Dose level of CXL-1427 will be evaluated in the Dose Escalation Arm of the study as determined by the independent dose escalation committee	Drug: CXL-1427; Other Names: BMS-986231
Experimental: CXL-1427 Dos Level 3 The Third Dose level of CXL-1427 will be evaluated in the Dose Escalation Arm of the study as determined by the independent dose escalation committee	Drug: CXL-1427; Other Names: BMS-986231
Experimental: CXL-1427 Dose Level 4 The forth level of CXL-1427 will be evaluated in the Dose Escalation Arm of the study as determined by the independent dose escalation committee	Drug: CXL-1427; Other Names: BMS-986231
Experimental: Expansion Cohort 1 Up to 16 Patients will be enrolled across 1 or more of the previously evaluated Dose escalation Levels as determined by the independent dose escalation committee	Drug: CXL-1427; Other Names: BMS-986231
Placebo Comparator: Placebo for Dose Escalation and Expansion Cohort Each Dose escalation Arm of the study will have a placebo group in a 2:1 ratio to active treatment for the first 3 patients enrolled and 4:1 to active treatment in the remaining 5 patients so that the overall randomization ratio in each Dose escalation arm will be 3:1 active to placebo. In the expansion Cohort of the study, the ratio of patients randomized to receive a 6-hour infusion of active CXL-1427 or placebo will be 3:1	Drug: Placebo; Other Names: 5% Dextrose & 10mM potassium acetate as same IV solution diluents used in active

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events [30 days following the initiation of treatment]

   A treatment-emergent adverse event (TEAE) was defined as an AE with onset after the start of the study drug infusion at Hour 00:00 through 30 days after the stop of the study drug infusion. All TEAEs and pertinent subsets of TEAEs (e.g., TEAEs with onset during the infusion of study drug, serious TEAEs, etc.) were summarized by system organ class (SOC), preferred term (PT) and treatment group

2. Mean Time Averaged Change From Baseline in Adjudicated Pulmonary Capillary Wedge Pressure (PCWP) During Infusion [Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion]

   The effect of CXL-1427 on PCWP is presented as the mean time-averaged change from baseline over the course of infusion of CXL-1427 or placebo in adjudicated pulmonary capillary wedge pressure (PCWP) on a modified intent-to-treat population

3. Mean Time-Averaged Change From Baseline in Adjudicated Pulmonary Artery Diastolic Pressure (PAD) During the Infusion [Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion initiation]

   Pulmonary artery diastolic pressure (PAD) was measured by an indwelling PA catheter. Pulmonary artery diastolic pressure (PAD) approximates pulmonary capillary wedge pressure in normal individuals. The effects of CXL-1427 on time-averaged PAD during the course of the infusion are presented.

4. Mean Time-Averaged Percent Change From Baseline in Cardiac Index (Fick) [Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion initiation]

   Cardiac index is a measure of cardiac function, relating the cardiac output from the left ventricle in one minute to body surface area. It is calculated using the Fick principle, using oxygen consumption measured with a metabolic cart, hemoglobin levels, and the difference between arterial and superior vena cava oxygen saturation measured by co-oximetry. Cardiac index as calculated by the Fick method was performed using an assumed oxygen consumption value of 125 ml/min per m2 of body surface area. i.e., an assumed Fick method.

Secondary Outcome Measures

1. Mean Time-Averaged Change From Baseline in Adjudicated Pulmonary Artery Systolic Pressure (PAS) During the Infusion [Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion initiation]

   Pulmonary artery systolic pressure (PAS) was measured by an indwelling PA catheter. The effects of CXL-1427 on time-averaged PAS during the course of the infusion are presented

2. Mean Time-Averaged Change From Baseline in Adjudicated Right Atrial Pressure (RAP) During the Infusion [Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion initiation]

   The effects of CXL-1427 on time-averaged RAP during the course of the infusion are presented

3. Mean Time-Averaged Change From Baseline in Mean Arterial Blood Pressure (MAP) During the Infusion [Baseline, Hour 24 after infusion, Follow-up visit 1]

   Mean arterial pressure during infusion of CXL-1427 or placebo on a modified intent-to-treat population is presented

4. Mean Time-Averaged Change From Baseline in Systolic Blood Pressure (SBP) During the Infusion [Baseline, Hour 24 after infusion, Follow-up visit 1]

   Mean Time-Averaged Change from Baseline in Systolic Blood Pressure during infusion of CXL-1427 or placebo on a modified intent-to-treat population is presented

5. Mean Time-Averaged Change From Baseline in Diastolic Blood Pressure (DBP) During the Infusion [Baseline, Hour 24 after infusion, Follow-up visit 1]

   Mean Time-Averaged Change from Baseline in Diastolic Blood Pressure during infusion of CXL-1427 or placebo on a modified intent-to-treat population is presented

6. Mean Time-Averaged Change From Baseline in Heart Rate (HR) During the Infusion [Baseline, Hour 24 after infusion, Follow-up visit 1]

   Mean Time-Averaged Change from Baseline in Heart Rate during infusion of CXL-1427 or placebo on a modified intent-to-treat population is presented

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Inclusion Criteria -In order to be eligible for study participation, a patient MUST:

• Be ≥ 18 and ≤ 85 years of age;

• Have a left ventricular ejection fraction (LVEF) ≤40%, as assessed by echocardiography, a multigated acquisition (MUGA) scan or magnetic resonance imaging (MRI) within 3 months prior to or during the current hospitalization;

• Be hospitalized with a primary heart failure or heart failure-related reason, e.g., acute decompensation of heart failure, transplant evaluation, hemodynamic optimization prior to ambulatory inotropes or left ventricular assist device placement;

• Have an indwelling pulmonary artery (PA) catheter in place for assessment of central hemodynamic parameters; [Note: The indwelling catheter may already be in place for medically-indicated reasons, OR be placed for the primary purpose of monitoring the hemodynamic effects of the study drug. If the pulmonary artery catheter is to be placed for the sole purpose of monitoring the hemodynamic effect of the study drug, the patient must have a cardiac index (CI) ≤ 2.2L/min•m2 as measured by a non-invasive cardiac output monitor (NICaS device) ≤6 hours prior to placement of the catheter. In this setting, Exclusion Criteria 3 below also applies.]

• Have a Fick and/or thermodilution determination of cardiac index ≤2.5L/min•m2 at screening, i.e., ≤4 hours before the intended start of the study drug infusion; [Note: For determinations of CI using the thermodilution method, a mean of three consecutive values measured approximately 5 minutes apart, none of which differs from the mean value by more than 15%, should be used.]

• Have a screening and baseline PCWP (or PAD, if a PCWP waveform cannot be reliably obtained) of ≥20 mmHg if systolic blood pressure is ≥100mmHg OR ≥22mmHg if systolic blood pressure is between 95-99mmHg (inclusive);

• Be considered sufficiently stable to be expected not to require administration of any IV or oral vasoactive medications, including diuretics, for at least ~10 hours, i.e., from 4 hours before performing baseline hemodynamic assessments until after the completion of the 6-hour study drug infusion;

• Have a body weight of at least 50kg (110 pounds), but not more than 125kg (275 pounds), and have a body mass index (BMI) <40kg/m2;

• Have adequate peripheral forearm vein access or an available central line port for administration of study drug;

• Be capable of understanding the nature of the trial; be willing and able to comply with the inpatient and outpatient study protocol requirements for the duration of the study (screening period, treatment period, and 30-day post-infusion follow-up period); and be willing to participate in the study, as documented by written informed consent.

Exclusion Criteria- - In order to be eligible for study participation, a patient MUST NOT:

• Have a heart rate <50 or >110 beats per minute (bpm) at baseline;

• Have a screening OR baseline systolic blood pressure (SBP) of >150mmHg or <100mmHg, if PCWP ≥ 20mmHg, but <22mmHg OR <95mmHg, if PCWP ≥ 22mmHg;

• Have tricuspid or pulmonary valve prosthesis or endocarditis, right heart mass, a history of pneumothorax or hemothorax, a bleeding diathesis that would preclude placement of a PAL, or a history of complications from previous pulmonary artery catheter placement, when a pulmonary artery catheter is to be placed solely for the purposes of monitoring the hemodynamic effects of the study drug; In this setting, patients with multiple intracardiac leads and/or left bundle branch block should have such elective pulmonary artery catheter placement performed under radiologic guidance by experienced personnel, e.g. in the cardiac catheterization laboratory. [Note: Other pertinent history, such as trauma, vascular injury or previous surgery should guide selection of the vessel for PAL placement.]

• Have a primary HF etiology attributable to either restrictive/obstructive cardiomyopathy, idiopathic hypertrophic cardiomyopathy (as defined by any wall thickness > 1.8cm) or uncorrected severe valvular disease as defined by AHA/ACC/ESC criteria;

• Have been treated with dopamine, dobutamine, enoximone, nesiritide, nitroglycerine or nitroprusside within 4 hours, or with levosimendan, amrinone or milrinone within 8 hours, prior to performing baseline hemodynamic assessments, or have an anticipated need to be treated with any of these agents before the completion of the 6-hour study drug infusion;

• Be receiving concomitant parenteral therapy with any antiarrhythmic drugs (oral therapy is allowed);

• Be in atrial fibrillation/flutter with an uncontrolled rate (≥100bpm) at the time of randomization; [Note: Patients with a history of A-fib/flutter are eligible, if heart rate is controlled with a ventricular rate not exceeding 100bpm.]

• Have non-sustained ventricular tachycardia (NSVT) of 10 beats or more during any bedside monitoring within 2 hours prior to randomization, or have excessive premature ventricular contractions (PVCs) or complex multifocal ventricular ectopy exceeding 10 beats per minute on a 2-minute rhythm strip taken within 2 hours prior to randomization;

• Require, or be expected to require, any alteration of settings to an implantable cardioverter-defibrillator (ICD), single chamber or biventricular pacemaker, if applicable, from 2 hours before the intended start of the study drug infusion, until after the completion of the study drug infusion;

• Have a history of sudden cardiac death/resuscitation or other appropriate ICD firing within the past 1 year. (Inappropriate ICD firings are not exclusionary);

• Be hospitalized with acute coronary syndrome or acute myocardial infarction during the previous 90 days prior to randomization;

• Have a history of a cerebral vascular accident (CVA or stroke) or of a transient ischemic attack (TIA) within 6 months prior to randomization;

• Have a digoxin level above 1ng/ml (1.281nmol/L) within 8 hours before initiation of the study drug infusion;

• Have persistent abnormal serum electrolytes at baseline, as defined by: a Na+ concentration <130 or >145 mEq/L, or a K+ or Mg2+ concentration outside the normal range (according to the local laboratory); [Note: Any observed electrolyte abnormalities during screening or earlier should be corrected by electrolyte supplementation and within normal acceptable concentrations should be confirmed prior to dosing. Any serum electrolyte abnormalities with associated clinical instability within 8 hours before initiation of the study drug infusion is exclusionary.]

• Have an ALT or AST >3 times the upper normal limit or a hemoglobin <10g/dl (100g/L) within 8 hours before initiation of the study drug infusion;

• Have a serum creatinine >2.5mg/dl (221µmol/L) or severe renal insufficiency [based on any standard limit and equation employed by the local lab, such as a GFR < 30mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) equation] within 8 hours before initiation of the study drug infusion;

• Have taken an oral phosphodiesterase type 5 inhibitor (PDE5) inhibitor within 96 hours before initiation of the study drug infusion;

• If female, be pregnant or of child-bearing potential (i.e., female patients must be post-menopausal or surgically sterilized);

• Be receiving a drug which is expected to possess a potential for a clinically significant pharmacokinetic interaction with CXL-1427, as defined in the CXL-1427 Investigator's Brochure;

• Be the recipient of a myocardial restraint device or flap;

• Have an anticipated survival of less than 90 days, for any reason;

• Have received an investigational drug, device or biologic product within 30 days (or if longer, 5 half-lives for a drug or biologic agent) prior to randomization, or be planning to receive an investigational agent at any time throughout the full duration of the study until at least 30 days after discontinuation of study drug;

• Have any other clinically significant laboratory abnormality, medical condition or social circumstance that, in the investigator's opinion, makes it inappropriate for the patient to participate in this clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cardioxyl Study Site	Gainesville	Florida	United States	32610
2	Cardioxyl Study Site	Jacksonville	Florida	United States	32209
3	Cardioxyl Study Site	Jacksonville	Florida	United States	32224
4	Cardioxyl Study Site	Macon	Georgia	United States	31201
5	Cardioxyl Study Site	Baltimore	Maryland	United States	21201
6	Cardioxyl Study Site	Detroit	Michigan	United States	48202
7	Cardioxyl Study Site	Newark	New Jersey	United States	07103
8	Cardioxyl Study Site	Chapel Hill	North Carolina	United States	27517
9	Cardioxyl Study Site	Cincinnati	Ohio	United States	45267
10	Cardioxyl Study Site	Columbus	Ohio	United States	43201
11	Cardioxyl Study Site	Charleston	South Carolina	United States	29425
12	Cardioxyl Study Site	Nashville	Tennessee	United States	37232
13	Cardioxyl Study Site	Salt Lake City	Utah	United States	84132
14	Cardioxyl Study Site	Richmond	Virginia	United States	23298
15	Cardioxyl Study Site	Bad Neuheim		Germany	61231
16	Cardioxyl Study Site	Cologne		Germany	50937
17	Cardioxyl Study Site	Frankfurt		Germany	60590
18	Cardioxyl Study Site	Gottingen		Germany	37075
19	Cardioxyl Study Site	Greifswald		Germany	17475
20	Cardioxyl Study Site	Kiel		Germany	2105
21	Cardioxyl Study Site	Regensberg		Germany	93053
22	Cardioxyl Study Site	Amman		Jordan	11193
23	Cardioxyl Study Site	Irbid		Jordan	22110
24	Cardioxyl Study Site	Lodz		Poland	93487
25	Cardioxyl Study SIte	Warsaw		Poland	01211
26	Cardioxyl Study Site	Warsaw		Poland	04-628
27	Cardioxyl Study Site	Wroclaw		Poland	50981
28	Cardioxyl Study Site	Kemerovo		Russian Federation	650002
29	Cardioxyl Study Site	Moscow		Russian Federation	111539
30	Cardioxyl Study Site	Moscow		Russian Federation	121309
31	Cardioxyl Study Site	Moscow		Russian Federation	12134
32	Cardioxyl Study Site	Moscow		Russian Federation	127644
33	Cardioxyl Study Site	St. Petersburg		Russian Federation	19242
34	Cardioxyl Study Site	St. Petersburg		Russian Federation	199106
35	Cardioxyl Study Site	Tomsk		Russian Federation	634012

Sponsors and Collaborators

• Bristol-Myers Squibb
• Cardioxyl Pharmaceuticals, Inc

Investigators

• Study Director: ShiYin Foo, M.D., Ph D., Cardioxyl Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02157506
• Other Study ID Numbers: CXL-1427-02; CV013-006
• First Posted: Jun 6, 2014
• Last Update Posted: Jul 31, 2019
• Last Verified: Jul 1, 2019

• Keywords provided by Bristol-Myers Squibb: Acute Heart failure; Hemodynamics; Pharmacokinetics; Renal Function
• Additional relevant MeSH terms: Heart Failure

Study Results

Participant Flow

Pre-assignment Detail	A total of 70 participants were enrolled of which only 46 participants received treatment. 24 were not treated due to screen failures, 3 of the 24 were randomized but not dosed due to other reasons.

Arm/Group Title	Placebo	CXL-1427 3μg/kg/Min	CXL-1427 5μg/kg/Min	CXL-1427 7μg/kg/Min	CXL-1427 12μg/kg/Min
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.	Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.	Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.	Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.	Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.
Period Title: Overall Study
STARTED	12	6	9	12	7
COMPLETED	12	5	8	12	7
NOT COMPLETED	0	1	1	0	0

Baseline Characteristics

Arm/Group Title	Placebo	CXL-1427 3μg/kg/Min	CXL-1427 5μg/kg/Min	CXL-1427 7μg/kg/Min	CXL-1427 12μg/kg/Min	Total
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.	Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.	Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.	Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.	Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.	Total of all reporting groups
Overall Participants	12	6	9	12	7	46
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.7 (9.25)	63.5 (3.51)	61.1 (11.36)	61.6 (10.26)	48.3 (17.49)	60.0 (11.10)
Sex: Female, Male (Count of Participants)
Female	2 16.7%	2 33.3%	1 11.1%	0 0%	2 28.6%	7 15.2%
Male	10 83.3%	4 66.7%	8 88.9%	12 100%	5 71.4%	39 84.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events
Description	A treatment-emergent adverse event (TEAE) was defined as an AE with onset after the start of the study drug infusion at Hour 00:00 through 30 days after the stop of the study drug infusion. All TEAEs and pertinent subsets of TEAEs (e.g., TEAEs with onset during the infusion of study drug, serious TEAEs, etc.) were summarized by system organ class (SOC), preferred term (PT) and treatment group
Time Frame	30 days following the initiation of treatment

Outcome Measure Data

Analysis Population Description

The safety analysis set consists of all randomized participants who received all or part of the infusion of the study drug.

Arm/Group Title	Placebo	CXL-1427 3μg/kg/Min	CXL-1427 5μg/kg/Min	CXL-1427 7μg/kg/Min	CXL-1427 12μg/kg/Min
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.	Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.	Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.	Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.	Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.
Measure Participants	12	6	9	12	7
At least one TEAE	3 25%	5 83.3%	5 55.6%	7 58.3%	3 42.9%
At least one Severe TEAE	0 0%	4 66.7%	0 0%	2 16.7%	1 14.3%
At least one Drug-related severe TEAE	0 0%	0 0%	0 0%	0 0%	0 0%
At least one Serious TEAE	1 8.3%	3 50%	1 11.1%	3 25%	1 14.3%
At least one Drug-related serious TEAE	0 0%	0 0%	0 0%	0 0%	0 0%
At least one Fatal TEAE	0 0%	1 16.7%	0 0%	0 0%	0 0%
At least one Drug-related fatal TEAE	0 0%	0 0%	0 0%	0 0%	0 0%
At least one TEAE leading to drug interruption	0 0%	0 0%	0 0%	0 0%	0 0%
At least one TEAE leading to drug discontinuation	0 0%	0 0%	0 0%	0 0%	1 14.3%

2. Primary Outcome

Title	Mean Time Averaged Change From Baseline in Adjudicated Pulmonary Capillary Wedge Pressure (PCWP) During Infusion
Description	The effect of CXL-1427 on PCWP is presented as the mean time-averaged change from baseline over the course of infusion of CXL-1427 or placebo in adjudicated pulmonary capillary wedge pressure (PCWP) on a modified intent-to-treat population
Time Frame	Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion

Outcome Measure Data

Analysis Population Description

Modified Intent-To-Treat Analysis Set: all randomized participants who received all or part of the infusion of the study drug and had at least one baseline and post-baseline invasive hemodynamic assessment.

Arm/Group Title	Placebo	CXL-1427 3μg/kg/Min	CXL-1427 5μg/kg/Min	CXL-1427 7μg/kg/Min	CXL-1427 12μg/kg/Min
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.	Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.	Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.	Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.	Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.
Measure Participants	12	6	9	12	7
Mean (Standard Deviation) [mm Hg]	-0.17 (2.35)	-3.00 (3.06)	-5.06 (3.93)	-4.42 (4.00)	-4.75 (3.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 3μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0059
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 5μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 7μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0062
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 12μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0086
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

3. Primary Outcome

Title	Mean Time-Averaged Change From Baseline in Adjudicated Pulmonary Artery Diastolic Pressure (PAD) During the Infusion
Description	Pulmonary artery diastolic pressure (PAD) was measured by an indwelling PA catheter. Pulmonary artery diastolic pressure (PAD) approximates pulmonary capillary wedge pressure in normal individuals. The effects of CXL-1427 on time-averaged PAD during the course of the infusion are presented.
Time Frame	Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion initiation

Outcome Measure Data

Analysis Population Description

Modified Intent-To-Treat Analysis Set: all randomized patients who received all or part of the infusion of the study drug and had at least one baseline and post-baseline invasive hemodynamic assessment.

Arm/Group Title	Placebo	CXL-1427 3μg/kg/Min	CXL-1427 5μg/kg/Min	CXL-1427 7μg/kg/Min	CXL-1427 12μg/kg/Min
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.	Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.	Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.	Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.	Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.
Measure Participants	12	6	9	12	7
Mean (Standard Deviation) [mm Hg]	-0.21 (3.35)	-3.69 (2.55)	-4.17 (4.02)	-2.67 (3.63)	-3.17 (1.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 3μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0076
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 5μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0052
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 7μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.1064
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 12μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.1151
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

4. Primary Outcome

Title	Mean Time-Averaged Percent Change From Baseline in Cardiac Index (Fick)
Description	Cardiac index is a measure of cardiac function, relating the cardiac output from the left ventricle in one minute to body surface area. It is calculated using the Fick principle, using oxygen consumption measured with a metabolic cart, hemoglobin levels, and the difference between arterial and superior vena cava oxygen saturation measured by co-oximetry. Cardiac index as calculated by the Fick method was performed using an assumed oxygen consumption value of 125 ml/min per m2 of body surface area. i.e., an assumed Fick method.
Time Frame	Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion initiation

Outcome Measure Data

Analysis Population Description

Modified Intent-To-Treat Analysis Set: all randomized participants who received all or part of the infusion of the study drug and had at least one baseline and post-baseline invasive hemodynamic assessment.

Arm/Group Title	Placebo	CXL-1427 3μg/kg/Min	CXL-1427 5μg/kg/Min	CXL-1427 7μg/kg/Min	CXL-1427 12μg/kg/Min
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.	Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.	Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.	Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.	Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.
Measure Participants	12	6	9	12	7
Mean (Standard Deviation) [Percentage of change]	7.95 (16.15)	0.53 (18.12)	13.41 (23.53)	9.59 (11.91)	-9.58 (18.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 3μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.4241
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 5μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.4035
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 7μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.8308
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 12μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.1180
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

5. Secondary Outcome

Title	Mean Time-Averaged Change From Baseline in Adjudicated Pulmonary Artery Systolic Pressure (PAS) During the Infusion
Description	Pulmonary artery systolic pressure (PAS) was measured by an indwelling PA catheter. The effects of CXL-1427 on time-averaged PAS during the course of the infusion are presented
Time Frame	Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion initiation

Outcome Measure Data

Analysis Population Description

Modified Intent-To-Treat Analysis Set: all randomized participants who received all or part of the infusion of the study drug and had at least one baseline and post-baseline invasive hemodynamic assessment.

Arm/Group Title	Placebo	CXL-1427 3μg/kg/Min	CXL-1427 5μg/kg/Min	CXL-1427 7μg/kg/Min	CXL-1427 12μg/kg/Min
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.	Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.	Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.	Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.	Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.
Measure Participants	12	6	9	12	7
Mean (Standard Deviation) [mm Hg]	-0.73 (3.73)	-6.42 (2.59)	-5.98 (5.31)	-6.26 (5.09)	-4.24 (5.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 3μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0048
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 5μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0022
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 7μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0045
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 12μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0294
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

6. Secondary Outcome

Title	Mean Time-Averaged Change From Baseline in Adjudicated Right Atrial Pressure (RAP) During the Infusion
Description	The effects of CXL-1427 on time-averaged RAP during the course of the infusion are presented
Time Frame	Baseline, Hour 2, Hour 4, Hour 6, Hour 8 post infusion initiation

Outcome Measure Data

Analysis Population Description

Modified Intent-To-Treat Analysis Set: all randomized participants who received all or part of the infusion of the study drug and had at least one baseline and post-baseline invasive hemodynamic assessment.

Arm/Group Title	Placebo	CXL-1427 3μg/kg/Min	CXL-1427 5μg/kg/Min	CXL-1427 7μg/kg/Min	CXL-1427 12μg/kg/Min
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.	Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.	Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.	Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.	Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.
Measure Participants	12	6	9	12	7
Mean (Standard Deviation) [mm Hg]	-0.03 (2.61)	-1.92 (2.91)	-2.08 (3.10)	-2.17 (2.42)	-4.60 (3.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 3μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.2022
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 5μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0658
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 7μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0741
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 12μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0497
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

7. Secondary Outcome

Title	Mean Time-Averaged Change From Baseline in Mean Arterial Blood Pressure (MAP) During the Infusion
Description	Mean arterial pressure during infusion of CXL-1427 or placebo on a modified intent-to-treat population is presented
Time Frame	Baseline, Hour 24 after infusion, Follow-up visit 1

Outcome Measure Data

Analysis Population Description

Modified Intent-To-Treat Analysis Set: all randomized participants who received all or part of the infusion of the study drug and had at least one baseline and post-baseline invasive hemodynamic assessment.

Arm/Group Title	Placebo	CXL-1427 3μg/kg/Min	CXL-1427 5μg/kg/Min	CXL-1427 7μg/kg/Min	CXL-1427 12μg/kg/Min
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.	Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.	Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.	Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.	Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.
Measure Participants	12	6	9	12	7
Mean (Standard Deviation) [mm Hg]	-1.11 (5.01)	-5.84 (4.46)	-4.75 (10.93)	-7.16 (7.67)	-6.69 (5.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 3μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.1842
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 5μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.3328
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 7μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.1465
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 12μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.2799
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

8. Secondary Outcome

Title	Mean Time-Averaged Change From Baseline in Systolic Blood Pressure (SBP) During the Infusion
Description	Mean Time-Averaged Change from Baseline in Systolic Blood Pressure during infusion of CXL-1427 or placebo on a modified intent-to-treat population is presented
Time Frame	Baseline, Hour 24 after infusion, Follow-up visit 1

Outcome Measure Data

Analysis Population Description

Modified Intent-To-Treat Analysis Set: all randomized participants who received all or part of the infusion of the study drug and had at least one baseline and post-baseline invasive hemodynamic assessment.

Arm/Group Title	Placebo	CXL-1427 3μg/kg/Min	CXL-1427 5μg/kg/Min	CXL-1427 7μg/kg/Min	CXL-1427 12μg/kg/Min
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.	Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.	Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.	Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.	Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.
Measure Participants	12	6	9	12	7
Mean (Standard Deviation) [mm Hg]	-3.15 (5.53)	-8.69 (4.43)	-2.41 (12.57)	-6.81 (9.54)	-4.64 (4.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 3μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.2499
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 5μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.8281
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 7μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.4121
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 12μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.8592
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

9. Secondary Outcome

Title	Mean Time-Averaged Change From Baseline in Diastolic Blood Pressure (DBP) During the Infusion
Description	Mean Time-Averaged Change from Baseline in Diastolic Blood Pressure during infusion of CXL-1427 or placebo on a modified intent-to-treat population is presented
Time Frame	Baseline, Hour 24 after infusion, Follow-up visit 1

Outcome Measure Data

Analysis Population Description

Modified Intent-To-Treat Analysis Set: all randomized participants who received all or part of the infusion of the study drug and had at least one baseline and post-baseline invasive hemodynamic assessment.

Arm/Group Title	Placebo	CXL-1427 3μg/kg/Min	CXL-1427 5μg/kg/Min	CXL-1427 7μg/kg/Min	CXL-1427 12μg/kg/Min
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.	Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.	Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.	Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.	Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.
Measure Participants	12	6	9	12	7
Mean (Standard Deviation) [mm Hg]	-0.09 (8.30)	-4.42 (5.22)	-5.93 (11.07)	-7.33 (8.51)	-7.71 (8.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 3μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.1391
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 5μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.1724
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 7μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.1245
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 12μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.1690
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

10. Secondary Outcome

Title	Mean Time-Averaged Change From Baseline in Heart Rate (HR) During the Infusion
Description	Mean Time-Averaged Change from Baseline in Heart Rate during infusion of CXL-1427 or placebo on a modified intent-to-treat population is presented
Time Frame	Baseline, Hour 24 after infusion, Follow-up visit 1

Outcome Measure Data

Analysis Population Description

Modified Intent-To-Treat Analysis Set: all randomized participants who received all or part of the infusion of the study drug and had at least one baseline and post-baseline invasive hemodynamic assessment.

Arm/Group Title	Placebo	CXL-1427 3μg/kg/Min	CXL-1427 5μg/kg/Min	CXL-1427 7μg/kg/Min	CXL-1427 12μg/kg/Min
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.	Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.	Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.	Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.	Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.
Measure Participants	12	6	9	12	7
Mean (Standard Deviation) [Beats/min]	-0.79 (6.34)	1.06 (3.74)	-3.09 (6.84)	1.00 (7.08)	-4.52 (16.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 3μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.4936
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 5μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.9920
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 7μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.2789
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, CXL-1427 12μg/kg/Min
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.9100
	Comments
	Method	Mixed Models Analysis
	Comments	Statistical significance was defined by a P-value < 0.05. No adjustments were made for multiplicity.

Adverse Events

Time Frame	All adverse events were reported from signed of informed consent form through 30 days post final infusion of study drug.
Arm/Group Title	Placebo		CXL-1427 3 μg/kg/Min		CXL-1427 5 μg/kg/Min		CXL-1427 7 μg/kg/Min		CXL-1427 12 μg/kg/Min
Arm/Group Description	Subjects received matching placebo intravenous (IV) infusion.		Subjects received CXL-1427 3 microgram per kilogram per minute (μg/kg/min) IV infusion as 90 milliliter (mL) of dosing solution at a rate of 15 milliliter per hour (mL/hour) for six hours.		Subjects received CXL-1427 5 μg/kg/min IV infusion as 90 mL of dosing solution at a rate of 15 mL/hour for six hours.		Subjects received CXL-1427 7 μg/kg/min IV infusion as 150 mL of dosing solution at a rate of 25 mL/hour for six hours.		Subjects received CXL-1427 12 μg/kg/min IV infusion as 180 mL of dosing solution at a rate of 30 mL/hour for six hours.
All Cause Mortality
	Placebo		CXL-1427 3 μg/kg/Min		CXL-1427 5 μg/kg/Min		CXL-1427 7 μg/kg/Min		CXL-1427 12 μg/kg/Min
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		1/6 (16.7%)		0/9 (0%)		0/12 (0%)		0/7 (0%)
Serious Adverse Events
	Placebo		CXL-1427 3 μg/kg/Min		CXL-1427 5 μg/kg/Min		CXL-1427 7 μg/kg/Min		CXL-1427 12 μg/kg/Min
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)		3/6 (50%)		1/9 (11.1%)		3/12 (25%)		1/7 (14.3%)
Cardiac disorders
Atrial flutter	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
Atrioventricular block complete	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1
Cardiac failure	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
Cardiac failure congestive	0/12 (0%)	0	1/6 (16.7%)	1	1/9 (11.1%)	1	0/12 (0%)	0	0/7 (0%)	0
Infections and infestations
Rhinovirus infection	0/12 (0%)	0	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0	0/7 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/12 (8.3%)	1	0/6 (0%)	0	0/9 (0%)	0	0/12 (0%)	0	0/7 (0%)	0
Renal and urinary disorders
Renal failure	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure	0/12 (0%)	0	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0	0/7 (0%)	0
Skin and subcutaneous tissue disorders
Toxic epidermal necrolysis	0/12 (0%)	0	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0	0/7 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		CXL-1427 3 μg/kg/Min		CXL-1427 5 μg/kg/Min		CXL-1427 7 μg/kg/Min		CXL-1427 12 μg/kg/Min
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/12 (25%)		6/6 (100%)		6/9 (66.7%)		7/12 (58.3%)		4/7 (57.1%)
Cardiac disorders
Atrial flutter	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
Atrioventricular block complete	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1
Cardiac failure	0/12 (0%)	0	0/6 (0%)	0	1/9 (11.1%)	1	1/12 (8.3%)	1	0/7 (0%)	0
Cardiac failure congestive	0/12 (0%)	0	1/6 (16.7%)	1	1/9 (11.1%)	1	0/12 (0%)	0	0/7 (0%)	0
Cardiorenal syndrome	0/12 (0%)	0	0/6 (0%)	0	1/9 (11.1%)	1	0/12 (0%)	0	0/7 (0%)	0
Low cardiac output syndrome	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1
Tachycardia	0/12 (0%)	0	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0	0/7 (0%)	0
Ventricular tachycardia	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
General disorders
Catheter site haemorrhage	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
Chest pain	0/12 (0%)	0	0/6 (0%)	0	1/9 (11.1%)	1	0/12 (0%)	0	0/7 (0%)	0
Infections and infestations
Rhinovirus infection	0/12 (0%)	0	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0	0/7 (0%)	0
Urinary tract infection	0/12 (0%)	0	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0	0/7 (0%)	0
Injury, poisoning and procedural complications
Vascular pseudoaneurysm	1/12 (8.3%)	1	0/6 (0%)	0	0/9 (0%)	0	0/12 (0%)	0	0/7 (0%)	0
Investigations
Blood creatinine increased	1/12 (8.3%)	1	0/6 (0%)	0	0/9 (0%)	0	0/12 (0%)	0	0/7 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/12 (8.3%)	1	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
Hypoglycaemia	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign neoplasm of thyroid gland	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
Nervous system disorders
Dizziness	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
Headache	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	2/12 (16.7%)	2	1/7 (14.3%)	1
Syncope	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1
Psychiatric disorders
Psychotic disorder	0/12 (0%)	0	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0	0/7 (0%)	0
Renal and urinary disorders
Renal failure	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
Respiratory failure	0/12 (0%)	0	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0	0/7 (0%)	0
Skin and subcutaneous tissue disorders
Ecchymosis	0/12 (0%)	0	0/6 (0%)	0	0/9 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0
Toxic epidermal necrolysis	0/12 (0%)	0	1/6 (16.7%)	1	0/9 (0%)	0	0/12 (0%)	0	0/7 (0%)	0
Vascular disorders
Hypotension	1/12 (8.3%)	1	0/6 (0%)	0	3/9 (33.3%)	3	0/12 (0%)	0	1/7 (14.3%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.