Study to Evaluate Sex Differences in the Acute Effects of PL-3994 in Heart Failure Subjects

Study Overview
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Brief Summary
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A Multi-Center, Unblinded, Single-Arm Study to Evaluate Sex Differences in the Acute Effects of PL-3994 on Myocardial cGMP Enhancement and Hemodynamics in Heart Failure with Preserved Ejection Fraction

Detailed Description
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Multi-center, unblinded, dose ascending, two-part pilot study involving Part A, up to 15 subjects for dose ascension and optimization (N=3 per dose level, up to 5 dose levels) and Part B, 40 patients (n=20 women, n=20 men), with a single dose of PL-3994 after which hemodynamics will be measured by pulmonary artery catheter and pulmonary artery (mixed venous) and coronary sinus blood sampling will be performed to measure cGMP levels during a 15-minute observation period. The objective of this study is to evaluate the acute effects of a single dose of intravenous PL-3994 on hemodynamics and myocardial cGMP expression. The following endpoints will be assessed: Hemodynamics (including blood pressure, right atrial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output) Myocardial cGMP expression via coronary sinus sampling

Official Title
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A Multi-Center, Unblinded, Single-Arm Study to Evaluate Sex Differences in the Acute Effects of PL-3994 on Myocardial cGMP Enhancement and Hemodynamics in Heart Failure With Preserved Ejection Fraction

Conditions
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Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: PL-3994 Aqueous Intravenous Solution Dose Ascention
* Drug: PL-3994 Aqueous Intravenous Solution Single Dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject has provided written informed consent. Pre- or post-menopausal female or male age > 21 years LVEF ≥ 45% by echocardiography within prior 6 months Symptoms of HF requiring treatment with diuretics for ≥ 30 days prior to enrollment Current symptoms of HF (NYHA class II-IV) at time of enrollment 6. The subject has clinical indication for right heart catheterization for evaluation of HFpEF Negative pregnancy test in a female of childbearing potential Exclusion Criteria: A subject who meets ANY of the following exclusion criteria must not be enrolled. Orthostatic hypotension, systolic blood pressure <100 mm Hg, diastolic blood pressure < 50 mmHg. Any prior echocardiogram with LVEF < 40% Hemoglobin < 9 g/dl eGFR < 30 mL/min/1.73 m2 Hemodynamically significant arrhythmias within prior 4 weeks Acute coronary syndrome, cardiac surgery, or percutaneous coronary intervention within prior 3 months Any of the following cardiac diagnoses: active myocarditis, hypertrophic cardiomyopathy, > moderate regurgitant valvular disease, any valvular stenosis, restrictive cardiomyopathy (including amyloid, sarcoid, or hemochromatosis), constrictive pericarditis, complex congenital heart disease, or pulmonary arterial hypertension Current need for IV inotropic medication Currently taking nitrates or having stopped nitrates within 24 hours of visit Currently taking antihistamines, antipsychotics, tri-cyclic antidepressants, catecholamines/related compounds, monoamine oxidase inhibitors, stimulants (including caffeine and nicotine), sympathomimetics, dopamine agonists. Additionally, medications that inhibit PDE activity will be prohibited during the study and for 5 half- lives prior to Day 1 so that cGMP measurements will not be affected Currently hospitalized for HF Any prior need for mechanical circulatory support Previous adverse reaction to the study drug Inability to comply with planned study procedures Pregnant or nursing mothers Participation in another study with an investigational drug or device within 30 days or a biologic study within 90 days prior to signing consent. Study participants must use method of birth control that has been approved by the Study Doctor and males must not donate sperm during the study and for 30 days after the last dose of study drug.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Part A: Single dose per subject, dose level ascension every 3 subjects. 5 dose levels are planned. An intermediate dose between planned doses may be chosen by the Sponsor/Investigator upon discussion after MTD is reached. Part B: Single dose, dose chosen from Part A.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: PL-3994 Dose Ascension<br>Dose ascension: up to 15 subjects with HFpEF. N = 3 per dose level, up to 5 dose levels. | Drug: PL-3994 Aqueous Intravenous Solution Dose Ascention<br>* Following appropriate dilution, PL-3994 will be injected intravenously by site personnel as a bolus dose followed by continuous infusion<br>* Other names: PL-3994;|
| Experimental: Part B: PL-3994 Single Dose<br>Up to 40 subjects with HFpEF (20 Females, 20 Males) will receive a single dose of PL-3994. | Drug: PL-3994 Aqueous Intravenous Solution Single Dose<br>* Following appropriate dilution, PL-3994 will be injected intravenously by site personnel as a bolus dose followed by continuous infusion<br>* Other names: PL-3994;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Dose Ascension | Reaching the maximum tolderated dose (MTD) as defined by meeting stopping criteria. | 1 day | 
| Part B: Coronary Sinus Levels | Coronary sinus levels of cGMP post PL-3994 infusion as compared to baseline. | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Blood pressure measured in mmHg | Measured at baseline (t=0) and at t=3, 6, 9, 12, and 15 minutes after the infusion of study drug. | 1 day | 
| Part B: Heart rate measured in beats per minute | Measured at baseline (t=0) and at t=3, 6, 9, 12, and 15 minutes after the infusion of study drug. | 1 day | 
| Part B: Right atrial pressure measured in mmHg | Measured at baseline (t=0) and at t=3, 6, 9, 12, and 15 minutes after the infusion of study drug. | 1 day | 
| Part B: Pulmonary artery pressure measured in mmHg | Measured at baseline (t=0) and at t=3, 6, 9, 12, and 15 minutes after the infusion of study drug. | 1 day | 
| Part B: Pulmonary capillary wedge pressure measured in mmHg | Measured at baseline (t=0) and at t=3, 6, 9, 12, and 15 minutes after the infusion of study drug. | 1 day | 
| Part B: Cardiac output measured in L/min. | Measured at baseline (t=0) and at t=3, 6, 9, 12, and 15 minutes after the infusion of study drug. | 1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Ejection Fraction