A Study to Assess Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Reduced Ejection Fraction (Cycle-1-REF)
- Conditions
- Heart FailureHeart Failure With Reduced Ejection FractionCardiovascular DiseasesHeart Diseases
- Interventions
- Drug: Placebo
- Registration Number
- NCT06215911
- Lead Sponsor
- Cardurion Pharmaceuticals, Inc.
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 400
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Is an adult male or female patient 18 years of age
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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.
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Has ejection fraction (EF) ≤ 40% by transthoracic echocardiogram (TTE) performed and interpreted locally at the time of Screening;
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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;
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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.
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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;
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Tovinontrine (CRD-750) - high dose Tovinontrine (CRD-750) - Tovinontrine (CRD-750) - medium dose Tovinontrine (CRD-750) - Tovinontrine (CRD-750) - low dose Tovinontrine (CRD-750) - Placebo Placebo -
- Primary Outcome Measures
Name Time Method Change in biomarkers from Baseline to Week 12 - NT-proBNP Baseline to Week 12 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.
- Secondary Outcome Measures
Name Time Method Change in biomarkers at Week 12 by treatment group - NT-proBNP Baseline to Week 12 The percent change in plasma NT-proBNP will be calculated by treatment group from Baseline to Week 12. The correlation of plasma concentration with percent change in plasma NT-proBNP will be evaluated using Pearson's correlation coefficient.
Changes in vital sign measurement: body temperature Baseline to Week 12 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.
Changes in physical examination Baseline to Week 12 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.
Change in biomarkers at week 12 by treatment group - BNP Baseline to Week 12 The percent change in BNP from Baseline to Week 12 will be analyzed using an ANCOVA model to evaluate individual dose comparisons.
Kansas City Cardiomyopathy Questionnaire 23- Overall Summary Score Baseline to Week 12 Scaled 0 to 100 where lower scores represent worse health status than higher scores
Treatment Emergent Adverse Events (TEAEs) Baseline to Week 12 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.
Changes in 12-lead electrocardiogram (ECG) measurements Baseline to Week 12 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.
Change in the biomarker ratio at Week 12 - NT-proBNP Baseline to Week 12 The change in the urine and plasma cGMP to NT-proBNP ratio at week 12 will be calculated for each treatment group
Assessment of pharmacokinetics (PK): PK effect on NT-proBNP Baseline to Week 12 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.
Change in biomarkers at week 12 by treatment group - cGMP Baseline to Week 12 The percent change in urine and plasma cGMP from Baseline to Week 12 will be analyzed using ANCOVA and MMRM models by treatment group.
Change in the biomarker ratio at Week 12 - BNP Baseline to Week 12 The percent change in the urine and plasma cGMP to BNP ratio from Baseline to Week 12 will be calculated for each treatment group
Kansas City Cardiomyopathy Questionnaire-23-Clinical Summary Score Baseline to Week 12 Scaled 0 to 100 where lower scores represent worse health status than higher scores
Changes in vital sign measurement: systolic and diastolic blood pressure Baseline to Week 12 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.
Changes in vital sign measurement: respiratory rate Baseline to Week 12 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.
New York Heart Association Classification Baseline to Week 12 Class I to IV are possible with a higher classification representing worsening heart failure status
Changes in laboratory assessments Baseline to Week 12 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.
Changes in vital sign measurement: pulse rate Baseline to Week 12 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.
Assessment of pharmacokinetics (PK): PK effect on plasma cGMP Baseline to Week 12 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.
Trial Locations
- Locations (3)
Cardurion Investigative Site
🇬🇧Southampton, United Kingdom
Cardurion Investigational Site
🇧🇪Brugge, Belgium
Cardurion Investigative Site 2
🇬🇪Tbilisi, Georgia