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

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

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

Study Overview

• Status: Recruiting
• Conditions: Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: PL-3994 Aqueous Intravenous Solution Dose Ascention; Drug: PL-3994 Aqueous Intravenous Solution Single Dose

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 Type: Interventional
• Enrollment (Anticipated): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Evanston, Illinois, United States, 60208
      • Recruiting
      • Northwestern University
      • Contact: Sanjiv J Shah, MD; Phone Number: 312-695-0993; Email: sanjiv.shah@northwestern.edu
      • Contact: Ryan Sisk; Email: r-sisk@northwestern.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: PL-3994 Dose Ascension; 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; Following appropriate dilution, PL-3994 will be injected intravenously by site personnel as a bolus dose followed by continuous infusion; Other Names: PL-3994
Experimental: Part B: PL-3994 Single Dose; 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; Following appropriate dilution, PL-3994 will be injected intravenously by site personnel as a bolus dose followed by continuous infusion; Other Names: PL-3994

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Palatin Technologies, Inc
• Investigators: Principal Investigator: Sangiv J. Shah, MD, Northwestern University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2020
• Primary Completion (Anticipated): March 31, 2022
• Study Completion (Anticipated): March 31, 2023

Study Registration Dates

• First Submitted: March 16, 2020
• First Submitted That Met QC Criteria: March 20, 2020
• First Posted (Actual): March 23, 2020

Study Record Updates

• Last Update Posted (Actual): December 14, 2021
• Last Update Submitted That Met QC Criteria: December 13, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Heart Failure, Ejection Fraction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Pharmaceutical Solutions
• Other Study ID Numbers: PL-3994-701

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No