Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Preserved Ejection Fraction (Cycle-2-PEF) (Cycle-2-PEF)

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Study to Assess the Safety and Effectiveness of Tovinontrine in Patients With Chronic Heart Failure With Preserved Ejection Fraction

The purpose of this study is to evaluate the safety and effectiveness of tovinontrine compared to placebo to lower NT-proBNP in patients with chronic heart failure with preserved ejection fraction

Study Overview

• Status: Recruiting
• Conditions: Heart Diseases; Cardiovascular Diseases; Heart Failure; Heart Failure Preserved Ejection Fraction
• Intervention / Treatment: Drug: Placebo; Drug: Tovinontrine (CRD-750

• Study Type: Interventional
• Enrollment (Estimated): 240
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Elizabeth Moore, DNP; Phone Number: 617-941-5130; Email: info@cardurion.com

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Recruiting
      • Cardurion Investigative Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72204
      • Recruiting
      • Cardurion Investigative Site
  • California
    • Van Nuys, California, United States, 91405
      • Recruiting
      • Cardurion Investigative Site
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Recruiting
      • Cardurion Investigative Site
    • Miami, Florida, United States, 33137
      • Recruiting
      • Cardurion Investigative Site
  • Illinois
    • Hazel Crest, Illinois, United States, 60429
      • Recruiting
      • Cardurion Investigative Site
    • Peoria, Illinois, United States, 61636
      • Recruiting
      • Cardurion Investigative Site
  • Louisiana
    • Covington, Louisiana, United States, 70433
      • Recruiting
      • Cardurion Investigative Site
  • Texas
    • McKinney, Texas, United States, 75069
      • Recruiting
      • Cardurion Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Is an adult male or female patient ≥ 18 years of age

• Has evidence in the medical history supporting a diagnosis of clinical HF syndrome, NYHA functional class II to III, with the duration of at least 6 months prior to the time of Screening. The HF syndrome is defined by documentation of 1 or more of the following:

  • At least 1 of the typical symptoms due to HF such as dyspnea and/or fatigue limiting exercise capacity;
  • At least 1 of the typical signs of HF such as peripheral edema, elevated jugular venous pressure, pulmonary crackles; or
  • Hospitalization, emergency department visit, or outpatient visit for HF requiring intravenous (IV) or subcutaneous (SQ) diuresis within the past 12 months.
• Has ejection fraction (EF) >40% and left atrial enlargement by transthoracic echocardiogram (TTE) performed and interpreted locally at the time of Screening;
• Has NT-proBNP level ≥ 300 pg/mL at the time of Screening. Patients with atrial fibrillation or flutter at the time of Screening are required to have an NT proBNP level of ≥500 pg/mL at the time of Screening;
• Is on stable optimized doses of guideline-directed HF therapy, per Investigator's clinical judgment, for a minimum of 4 weeks prior to the time of Screening and during the Screening Period, with no planned changes after randomization; Has had no addition of new guideline-directed HF therapy within the 3 months prior to the time of Screening or during the Screening Period;

Exclusion Criteria:

• Has documented EF ≥ 60% by TTE within 6 months of the time of Screening or during the Screening Period;
• Has evidence of recent HF exacerbation defined by hospitalization or requirement for IV or SQ diuretics within 60 days of the time of Screening or during the Screening Period;
• Has a requirement for routine, scheduled outpatient IV infusions for HF (ie, inotropes, vasodilators, or diuretics) or routinely scheduled ultrafiltration;
• Has elective interventions (eg, percutaneous coronary intervention, device implantations, percutaneous structural heart disease interventions, cardiac and non-cardiac surgery) planned to occur during involvement in this study;
• Has acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major cardiovascular surgery, or carotid angioplasty within 60 days of the time of Screening or during the Screening Period;
• Has had a prior or planned orthotopic heart transplantation;
• Has presence of or plan for mechanical circulatory support;

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Tablets administered orally
Experimental: Tovinontrine (CRD-750)	Drug: Tovinontrine (CRD-750; Tablets administered orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in biomarkers from Baseline to Week 12 - NT-proBNP	The percent change in plasma NT-proBNP (Dose Cohort 3 versus placebo) will be calculated from Baseline to Week 12 using an ANCOVA model. If a statistically significant reduction in plasma NT-proBNP is detected (2-sided alpha=0.05), the next analysis will compare Dose 2 versus placebo at the (2-sided alpha = 0.05 level). If statistically significant, the next analysis will compare Dose 1 versus placebo.	Baseline to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in biomarkers at week 12 by treatment group - cGMP	The percent change in urine and plasma cGMP from Baseline to Week 12 will be analyzed using ANCOVA and MMRM models by treatment group.	Baseline to Week 12
Change in biomarkers at week 12 by treatment group - BNP	The percent change in BNP from Baseline to Week 12 will be analyzed using an ANCOVA model to evaluate individual dose comparisons.	Baseline to Week 12
Change in the biomarker ratio at Week 12 - NT-proBNP	The change in the urine and plasma cGMP to NT-proBNP ratio at week 12 will be calculated for each treatment group	Baseline to Week 12
Change in the biomarker ratio at Week 12 - BNP	The percent change in the urine and plasma cGMP to BNP ratio from Baseline to Week 12 will be calculated for each treatment group	Baseline to Week 12
Kansas City Cardiomyopathy Questionnaire-23-Clinical Summary Score	Scaled 0 to 100 where lower scores represent worse health status than higher scores	Baseline to Week 12
New York Heart Association Classification	Class I to IV are possible with a higher classification representing worsening heart failure status	Baseline to Week 12
Treatment Emergent Adverse Events (TEAEs)	The number of participants with TEAEs including drug related AEs, serious AEs (SAEs), and AEs leading to study drug discontinuation will be assessed. The incidence of AEs will be presented by system organ class and preferred term according to the Medical Dictionary of Regulatory Activities.	Baseline to Week 12
Changes in laboratory assessments	Number of participants with normal/ abnormal values at Baseline compared to normal/ abnormal values post-Baseline will be assessed for hematology, serum chemistry and urinalysis. Descriptive statistics of clinical laboratory assessment results and the change from Baseline will be presented by dose cohort and visit.	Baseline to Week 12
Changes in vital sign measurement: systolic and diastolic blood pressure	Change from Baseline to Week 12 will be assessed for systolic and diastolic blood pressure (mmHg). Descriptive statistics of vital signs and the change from Baseline will be presented by dose cohort and visit.	Baseline to Week 12
Changes in vital sign measurement: pulse rate	The change from Baseline to Week 12 will be assessed for pulse rate (bpm). Descriptive statistics of vital signs and the change from Baseline will be presented by dose cohort and visit.	Baseline to Week 12
Changes in vital sign measurement: respiratory rate	The change from Baseline to Week 12 will be assessed for respiratory rate (breaths/min). Descriptive statistics of vital signs and the change from Baseline will be presented by dose cohort and visit.	Baseline to Week 12
Changes in vital sign measurement: body temperature	The change from Baseline to Week 12 will be assessed for body temperature. Descriptive statistics of vital signs and the change from Baseline will be presented by dose cohort and visit.	Baseline to Week 12
Changes in physical examination	General physical exams will be carried out to detect any abnormalities in the cardiovascular, respiratory, and other body systems. Non-pre-existing abnormal physical examinations will be summarized by dose cohort and visit.	Baseline to Week 12
Changes in 12-lead electrocardiogram (ECG) measurements	Number of participants who have normal/abnormal 12-lead ECG measurements at Baseline will be compared to normal/abnormal 12-lead ECG measurement post Baseline. Descriptive statistics of 12-lead ECG data and the change from baseline will be presented by dose cohort and visit.	Baseline to Week 12
Assessment of pharmacokinetics (PK): PK effect on NT-proBNP	The plasma concentrations will be evaluated in the PK Population. The plasma concentration of tovinontrine will be summarized by dose cohort and visit. The correlation of plasma concentration with percent change in plasma NT-proBNP will be evaluated using Pearson's correlation coefficient.	Baseline to Week 12
Assessment of pharmacokinetics (PK): PK effect on plasma cGMP	The plasma concentrations will be evaluated in the PK Population. The plasma concentration of tovinontrine will be summarized by dose cohort and visit. The correlation of plasma concentration with percent change in plasma cGMP will be evaluated using Pearson's correlation coefficient.	Baseline to Week 12

Collaborators and Investigators

• Sponsor: Cardurion Pharmaceuticals, Inc.
• Investigators: Study Director: Elizabeth Moore, DNP, Senior Director, Clinical Research Cardurion

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2024
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: December 13, 2023
• First Submitted That Met QC Criteria: January 19, 2024
• First Posted (Actual): January 22, 2024

Study Record Updates

• Last Update Posted (Actual): May 13, 2024
• Last Update Submitted That Met QC Criteria: May 10, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Heart Failure; HFpEF; PDE9; PED9 Inhibitor; CRD-750; Tovinontrine
• Additional Relevant MeSH Terms: Heart Failure; Heart Diseases; Cardiovascular Diseases
• Other Study ID Numbers: CRD-750-202; 2023-508737-13 (EudraCT Number)

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