A Study to Assess Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Reduced Ejection Fraction (Cycle-1-REF) (Cycle-1-REF)

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose Finding Study to Assess the Safety and Effectiveness of Tovinontrine in Patients With Chronic Heart Failure With Reduced 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 reduced ejection fraction.

Study Overview

• Status: Completed
• Conditions: Heart Diseases; Cardiovascular Diseases; Heart Failure; Heart Failure With Reduced Ejection Fraction
• Intervention / Treatment: Drug: Placebo; Drug: Tovinontrine (CRD-750)

• Study Type: Interventional
• Enrollment (Actual): 557
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Chermside, Australia, 4032
    • Cardurion Investigative Site
  • Perth, Australia
    • Cardurion Investigative Site
  • Queensland
    • Southport, Queensland, Australia, 4222
      • Cardurion Investigative Site
• Belgium
  • Bruges, Belgium, 8000
    • Cardurion Investigational Site
  • Brussels, Belgium
    • Cardurion Investigative Site
  • Brussels, Belgium, 1070
    • Cardurion Investigative Site
  • Genk, Belgium
    • Cardurion Investigative Site
  • Ghent, Belgium, 9000
    • Cardurion Investigative Site
  • Hasselt, Belgium, 3500
    • Cardurion Investigative Site
  • Kortrijk, Belgium, 8500
    • Cardurion Investigative Site
  • Sint-Niklaas, Belgium, 9100
    • Cardurion Investigative Site
• Bulgaria
  • Burgas, Bulgaria, 8008
    • Cardurion Investigative Site
  • Gabrovo, Bulgaria, 5300
    • Cardurion Investigative Site
  • Pazardzhik, Bulgaria, 4400
    • Cardurion Investigative Site
  • Plovdiv, Bulgaria, 4002
    • Cardurion Investigative Site
  • Plovdiv, Bulgaria, 4003
    • Cardurion Investigative Site
  • Rousse, Bulgaria, 7000
    • Cardurion Investigative Site
  • Sofia, Bulgaria, 1000
    • Cardurion Investigative Site
  • Sofia, Bulgaria, 1233
    • Cardurion Investigative Site 2
  • Sofia, Bulgaria, 1233
    • Cardurion Investigative Site
  • Stara Zagora, Bulgaria, 6000
    • Cardurion Investigative Site
  • Veliko Tarnovo, Bulgaria, 5006
    • Cardurion Investigative Site
• Canada
  • Sherbrooke, Canada, J1G 2E8
    • Cardurion Investigative Site
  • Trois-Rivières, Canada, G9B 2N3
    • Cardurion Investigative Site
  • Ontario
    • Cambridge, Ontario, Canada, N1R 6V6
      • Cardurion Investigative Site
    • Hamilton, Ontario, Canada, L8L 2X2
      • Cardurion Investigative Site
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Cardurion Investigative Site
    • Montreal, Quebec, Canada
      • Cardurion Investigative Site
• Czechia
  • Hradec Králové, Czechia, 500 02
    • Cardurion Investigative Site
  • Hradec Králové, Czechia, 500 05
    • Cardurion Investigative Site
  • Prague, Czechia, 128 08
    • Cardurion Investigative Site
• Georgia
  • Tbilisi, Georgia, 0102
    • Cardurion Investigative Site
  • Tbilisi, Georgia, 0131
    • Cardurion Investigative Site
  • Tbilisi, Georgia, 0141
    • Cardurion Investigative Site
  • Tbilisi, Georgia, 0159
    • Cardurion Investigative Site 2
  • Tbilisi, Georgia, 0159
    • Cardurion Investigative Site
  • Tbilisi, Georgia, 0160
    • Cardurion Investigative Site
  • Tbilisi, Georgia, 0186
    • Cardurion Investigative Site
• Germany
  • Dresden, Germany, 01067
    • Cardurion Investigative Site
  • Magdeburg, Germany, 39120
    • Cardurion Investigative Site
  • Brandenburg
    • Berlin, Brandenburg, Germany, 10787
      • Cardurion Investigative Site
    • Elsterwerda, Brandenburg, Germany, 04910
      • Cardurion Investigative Site
  • Lower Saxony
    • Papenburg, Lower Saxony, Germany, 26871
      • Cardurion Investigative Site
• Hungary
  • Balatonfüred, Hungary, 8230
    • Cardurion Investigative Site
  • Budapest, Hungary, H-1122
    • Cardurion Investigative Site
  • Budapest, Hungary, 1148
    • Cardurion Investigative Site
  • Gyöngyös, Hungary, 3200
    • Cardurion Investigative Site
  • Hatvan, Hungary, 3000
    • Cardurion Investigative Site
  • Kaposvár, Hungary, 7400
    • Cardurion Investigative Site
  • Orosháza, Hungary, 5900
    • Cardurion Investigative Site
  • Zalaegerszeg, Hungary, 8900
    • Cardurion Investigative Site
• Italy
  • Bergamo, Italy
    • Cardurion Investigative Site
  • Milan, Italy, 20138
    • Cardurion Investigative Site
  • Napoli, Italy
    • Cardurion Investigative Site
  • Rozzano, Italy
    • Cardurion Investigative Site
• Latvia
  • Riga, Latvia
    • Cardurion Investigative Site
• Lithuania
  • Kaunas, Lithuania
    • Cardurion Investigative Site
  • Klaipėda, Lithuania
    • Cardurion Investigative Site
  • Panevezys, Lithuania
    • Cardurion Investigative Site
• Netherlands
  • Goes, Netherlands, 4462 RA
    • Cardurion Investigative Site
  • Groningen, Netherlands, 9713 GZ
    • Cardurion Investigative Site
  • Hardenberg, Netherlands, 7772 SE
    • Cardurion Investigative Site
  • Sneek, Netherlands, 8601 ZR
    • Cardurion Investigative Site
  • The Hague, Netherlands, 2545 AA
    • Cardurion Investigative Site
  • Utrecht, Netherlands, 3582 KE
    • Cardurion Investigative Site
  • Veldhoven, Netherlands, 5504 DB
    • Cardurion Investigative Site
  • Zutphen, Netherlands, 7207 AE
    • Cardurion Investigative Site
• New Zealand
  • Christchurch, New Zealand
    • Cardurion Investigative Site
  • Dunedin, New Zealand
    • Cardurion Investigative Site
• Poland
  • Grodzisk Mazowiecki, Poland, 05-825
    • Cardurion Investigative Site
  • Krakow, Poland, 31-216
    • Cardurion Investigative Site
  • Lodz, Poland, 92-213
    • Cardurion Investigative Site
  • Lodz, Poland, 94-255
    • Cardurion Investigative Site
  • Lodz, Poland
    • Cardurion Investigative Site
  • Lublin, Poland, 20-011
    • Cardurion Investigative Site
  • Lublin, Poland, 20-049
    • Cardurion Investigative Site
  • Sopot, Poland, 81-717
    • Cardurion Investigative Site
  • Szczecin, Poland
    • Cardurion Investigative Site
  • Torun, Poland, 87-100
    • Cardurion Investigative Site
  • Warsaw, Poland, 04-628
    • Cardurion Investigative Site
  • Wroclaw, Poland, 50-556
    • Cardurion Investigative Site
  • Wroclaw, Poland, 50-981
    • Cardurion Investigative Site
• Slovakia
  • Bardejov, Slovakia
    • Cardurion Investigative Site
  • Bratislava, Slovakia
    • Cardurion Investigative Site
  • Handlová, Slovakia, 972 51
    • Cardurion Investigative Site
  • Košice, Slovakia, 040 022
    • Cardurion Investigative Site
  • Košice, Slovakia
    • Cardurion Investigative Site
  • Nitra, Slovakia, 949 01
    • Cardurion Investigative Site
  • Prešov, Slovakia, 080 01
    • Cardurion Investigative Site
  • Žilina, Slovakia
    • Cardurion Investigative Site
• Spain
  • Alicante, Spain, 03010
    • Cardurion Investigative Site
  • Córdoba, Spain, 14004
    • Cardurion Investigative Site
  • Madrid, Spain, 28041
    • Cardurion Investigative Site
  • Málaga, Spain, 29010
    • Cardurion Investigative Site
  • Santiago de Compostela, Spain, 15706
    • Cardurion Investigative Site
  • Seville, Spain, 41009
    • Cardurion Investigative Site
  • Valencia, Spain, 46026
    • Cardurion Investigative Site
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Cardurion Investigative Site
• Taiwan
  • Kaohsiung City, Taiwan, 80756
    • Cardurion Investigative Site
  • New Taipei City, Taiwan, 243
    • Cardurion Investigative Site
  • Taichung, Taiwan, 407219
    • Cardurion Investigative Site
  • Taipei, Taiwan, 100225
    • Cardurion Investigative Site
  • Taipei, Taiwan, 10507
    • Cardurion Investigative Site
• United Kingdom
  • Bridgend, United Kingdom, CF31 1RQ
    • Cardurion Investigative Site
  • Chichester, United Kingdom, PO19 6SE
    • Cardurion Investigative Site
  • Dundee, United Kingdom, DD1 9SY
    • Cardurion Investigative Site
  • Glasgow, United Kingdom, G81 4DY
    • Cardurion Investigative Site
  • Harrow, United Kingdom, HA1 3UJ
    • Cardurion Investigative Site
  • Isleworth, United Kingdom, TW7 6AF
    • Cardurion Investigative Site
  • London, United Kingdom, SE5 9RS
    • Cardurion Investigative Site
  • London, United Kingdom, NW1 2BU
    • Cardurion Investigative Site
  • Southampton, United Kingdom, SO16 6YD
    • Cardurion Investigative Site
  • Manchester
    • Wythenshawe, Manchester, United Kingdom, M23 9QZ
      • Cardurion Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Cardurion Investigative Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72204
      • Cardurion Investigative Site
  • California
    • Beverly Hills, California, United States, 90211
      • Cardurion Investigative Site
    • Orange, California, United States, 92868
      • Cardurion Investigative Site
    • Torrance, California, United States, 90502
      • Cardurion Investigative Site
    • Van Nuys, California, United States, 91405
      • Cardurion Investigative Site
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Cardurion Investigative Site
    • Miami, Florida, United States, 33137
      • Cardurion Investigative Site
  • Illinois
    • Hazel Crest, Illinois, United States, 60429
      • Cardurion Investigative Site
    • Peoria, Illinois, United States, 61636
      • Cardurion Investigative Site
  • Louisiana
    • Alexandria, Louisiana, United States, 71301
      • Cardurion Investigative Site
    • Covington, Louisiana, United States, 70433
      • Cardurion Investigative Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Cardurion Investigative Site
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Cardurion Investigative Site
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Cardurion Investigative Site
  • New York
    • Buffalo, New York, United States, 14215
      • Cardurion Investigative Site
    • New York, New York, United States, 10025
      • Cardurion Investigative Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cardurion Investigative Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73135
      • Cardurion Investigative Site
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Cardurion Investigative Site
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Cardurion Investigative Site
  • Texas
    • Dallas, Texas, United States, 75226
      • Cardurion Investigative Site
    • McKinney, Texas, United States, 75069
      • Cardurion Investigative Site
  • Vermont
    • Burlington, Vermont, United States, 05401
      • Cardurion Investigative Site
  • Washington
    • Seattle, Washington, United States, 98195
      • Cardurion Investigative Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • 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% by transthoracic echocardiogram (TTE) performed and interpreted locally at the time of Screening;
• Has NT-proBNP level ≥ 600 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 ≥ 1000 pg/mL at the time of Screening;
• Is on stable optimized doses of guideline-directed HF therapy, per Investigator's clinical judgement, for a minimum of 4 weeks prior to the time of Screening and during Screening, 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 a documented EF >40% 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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Tablets administered orally
Experimental: Tovinontrine (CRD-750) - low dose	Drug: Tovinontrine (CRD-750); Tablets administered orally
Experimental: Tovinontrine (CRD-750) - medium dose	Drug: Tovinontrine (CRD-750); Tablets administered orally
Experimental: Tovinontrine (CRD-750) - high dose	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 by treatment group	The percent change in plasma NT-proBNP from Baseline to Week 12.	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.	Baseline to Week 12
Change in biomarkers at week 12 by treatment group - BNP	The percent change in BNP from Baseline to Week 12.	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.	Baseline to Week 12
Change in biomarkers at Week 12 - NT-proBNP	The percent change in plasma NT-proBNP will be calculated from Baseline to Week 12. The correlation of plasma concentration with percent change in plasma NT-proBNP will be evaluated.	Baseline to Week 12
Change in the biomarker ratio at Week 12 - NT-proBNP	The percent change in the urine and plasma cGMP to NT-proBNP ratio at week 12	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	Baseline to Week 12
The change from baseline in the 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
The change from baseline in the Kansas City Cardiomyopathy Questionnaire 23- Overall Summary Score	Scaled 0 to 100 where lower scores represent worse health status than higher scores	Baseline to Week 12
The change from baseline in the Kansas City Cardiomyopathy Questionnaire-23-CSS - Categorical	The proportion of patients with >=5, 10 and 20-point improvement in the KCCQ-23-CSS.	Week 12
New York Heart Association Classification	Class I to IV are possible with a higher classification representing worsening heart failure status.	Week 12

Collaborators and Investigators

• Sponsor: Cardurion Pharmaceuticals, Inc.
• Investigators: Study Director: Gail Berman, Senior VP Head, Clinical Development Cardurion

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2024
• Primary Completion (Actual): October 10, 2025
• Study Completion (Actual): October 10, 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): November 17, 2025
• Last Update Submitted That Met QC Criteria: November 14, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Heart Failure; HFrEF; PDE9; PED9 Inhibitor; CRD-750; Tovinontrine
• Additional Relevant MeSH Terms: Heart Failure; Cardiovascular Diseases; Heart Diseases
• Other Study ID Numbers: CRD-750-201; 2023-508736-62 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No