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

Phase 2

• Conditions: Heart Failure With Preserved Ejection Fraction
• Interventions: Drug: PL-3994 Aqueous Intravenous Solution Single Dose; Drug: PL-3994 Aqueous Intravenous Solution Dose Ascention

• Registration Number: NCT04318145
• Lead Sponsor: Palatin Technologies, Inc

Brief Summary

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

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

Study Timeline

• Study First Submitted: 2020-03-16
• Study First Submitted QC: 2020-03-20
• Study First Posted: 2020-03-23
• Study Start: 2020-11-12
• Status Verified: 2021-12
• Last Update Submitted: 2021-12-13
• Last Update Posted: 2021-12-14
• Primary Completion: 2022-03-31
• Study Completion: 2023-03-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 55

Inclusion Criteria

1. The subject has provided written informed consent.
2. Pre- or post-menopausal female or male age > 21 years
3. LVEF ≥ 45% by echocardiography within prior 6 months
4. Symptoms of HF requiring treatment with diuretics for ≥ 30 days prior to enrollment
5. Current symptoms of HF (NYHA class II-IV) at time of enrollment
6. 6. The subject has clinical indication for right heart catheterization for evaluation of HFpEF
7. 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.

  1. Orthostatic hypotension, systolic blood pressure <100 mm Hg, diastolic blood pressure < 50 mmHg.
  2. Any prior echocardiogram with LVEF < 40%
  3. Hemoglobin < 9 g/dl
  4. eGFR < 30 mL/min/1.73 m2
  5. Hemodynamically significant arrhythmias within prior 4 weeks
  6. Acute coronary syndrome, cardiac surgery, or percutaneous coronary intervention within prior 3 months
  7. 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
  8. Current need for IV inotropic medication
  9. Currently taking nitrates or having stopped nitrates within 24 hours of visit
  10. 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
  11. Currently hospitalized for HF
  12. Any prior need for mechanical circulatory support
  13. Previous adverse reaction to the study drug
  14. Inability to comply with planned study procedures
  15. Pregnant or nursing mothers
  16. Participation in another study with an investigational drug or device within 30 days or a biologic study within 90 days prior to signing consent.
  17. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Part B: PL-3994 Single Dose	PL-3994 Aqueous Intravenous Solution Single Dose	Up to 40 subjects with HFpEF (20 Females, 20 Males) will receive a single dose of PL-3994.
Part A: PL-3994 Dose Ascension	PL-3994 Aqueous Intravenous Solution Dose Ascention	Dose ascension: up to 15 subjects with HFpEF. N = 3 per dose level, up to 5 dose levels.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Northwestern University; 🇺🇸 Evanston, Illinois, United States