Evaluation of Tovinontrine on NT-proBNP Levels in Adults with Chronic Heart Failure with Preserved Ejection Fraction: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-508737-13-00
- Protocol
- CRD-750-202
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2, randomized, double-blind, placebo-controlled clinical study is to evaluate the effect of **tovinontrine** on N-terminal pro b-type natriuretic peptide (NT-proBNP) at 12 weeks compared to placebo in adult patients with chronic heart failure with preserved ejection fraction (HFpEF). This objective is clinically relevant as NT-proBNP is a biomarker used to assess the severity and prognosis of heart failure, and its reduction could indicate an improvement in cardiac function and patient outcomes.
Secondary objectives include: - Evaluating the safety and tolerability of tovinontrine versus placebo in adult patients with HFpEF. - Assessing the effect of tovinontrine on urine and plasma cyclic guanosine monophosphate (cGMP) versus placebo at Week 12. - Evaluating the effect of tovinontrine on b-type natriuretic peptide (BNP) compared to placebo at Week 12. - Assessing the effect of tovinontrine on urine and plasma cGMP to NT-proBNP ratio compared to placebo at Week 12. - Evaluating the effect of tovinontrine on urine and plasma cGMP to BNP ratio compared to placebo at Week 12. - Other protocol-defined objectives apply.
Participants
The clinical trial involves a total of **112 participants** diagnosed with **chronic heart failure**. The study population comprises adult male and female patients aged 18 years and older, as per country guidelines. Participants are required to have a medical history of clinical heart failure syndrome, classified as NYHA functional class II to III, with a duration of at least six months prior to screening. The trial includes individuals with an ejection fraction greater than 40% and left atrial enlargement, as determined by a transthoracic echocardiogram. Additionally, participants must have an NT-proBNP level of at least 300 pg/mL, or 500 pg/mL for those with atrial fibrillation or flutter at screening. All participants are on stable, optimized doses of guideline-directed heart failure therapy, with no recent additions to their treatment regimen, except for diuretics. The trial does not include a vulnerable population, and the selection process ensures that participants meet these specific health criteria to evaluate the effect of tovinontrine on NT-proBNP levels over a 12-week period compared to a placebo.
Plans and Procedures
The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled study designed to evaluate the safety and effectiveness of **Tovinontrine** in patients with **chronic heart failure** with preserved ejection fraction (HFpEF). The primary objective is to assess the effect of Tovinontrine on N-terminal pro b-type natriuretic peptide (NT-proBNP) levels at 12 weeks compared to placebo. The trial is expected to commence recruitment on May 1, 2024, and conclude by November 1, 2025, with a total duration of approximately 18 months.
Participants will be randomly assigned to receive either Tovinontrine or a matching placebo, administered orally in tablet form. The maximum daily dose of Tovinontrine is 100 mg, with a total treatment period of 12 weeks. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, medical history, and NT-proBNP levels; baseline assessments on Day 1; and follow-up visits at regular intervals to monitor safety and efficacy endpoints. The end-of-study visit will occur at Week 12, where final assessments will be conducted.
Inclusion criteria require participants to be adults aged 18 years or older with a documented history of heart failure syndrome, NYHA functional class II to III, and an ejection fraction greater than 40%. Exclusion criteria are not explicitly detailed in the provided data. Participants are expected to remain on stable, optimized doses of heart failure therapy throughout the study. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent.
The primary endpoint is the percent change from baseline in plasma NT-proBNP at Week 12. Secondary endpoints include changes in urine and plasma cGMP, BNP levels, and quality of life assessments using the KCCQ-23 questionnaire. The study aims to provide valuable insights into the potential benefits of Tovinontrine for patients with HFpEF, contributing to the understanding of its therapeutic role in managing chronic heart failure.
Treatment
The clinical trial involves the administration of **Tovinontrine**, a small molecule inhibitor of phosphodiesterase type 9 (PDE9), developed by Cardurion Pharmaceuticals Inc. Tovinontrine is provided in the form of a **tablet** and is intended for oral administration. The maximum daily dose is 100 mg, with a total maximum dose of 8.4 grams over the course of the study. The treatment period is set for 12 weeks. The primary objective is to evaluate the effect of Tovinontrine on N-terminal pro b-type natriuretic peptide (NT-proBNP) levels in patients with chronic heart failure with preserved ejection fraction (HFpEF).
The study also includes a **placebo** group, which receives a tovinontrine-matching placebo in the form of an immediate-release tablet. The placebo is designed to mimic the appearance and administration route of the active treatment to maintain the double-blind nature of the trial. The placebo is administered orally, following the same dosing schedule as the active treatment group. This ensures that any observed effects can be attributed to the active substance, Tovinontrine, rather than other variables.
Efficacy
The efficacy of Tovinontrine in patients with **Chronic Heart Failure with Preserved Ejection Fraction (HFpEF)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percent change from baseline in plasma N-terminal pro b-type natriuretic peptide (NT-proBNP) at Week 12. Secondary endpoints include the percent change from baseline in urine and plasma cyclic guanosine monophosphate (cGMP) and brain natriuretic peptide (BNP) at Week 12, as well as the ratios of these biomarkers to NT-proBNP and BNP. Additionally, changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) scores, including the clinical summary score (CSS), overall summary score (OSS), and eight domains, will be evaluated. The proportion of patients achieving improvements of 5, 10, and 20 points in the KCCQ-23-CSS at Week 12 will also be assessed, along with post-baseline New York Heart Association (NYHA) classification at Week 12.
Measurements will be collected at baseline (pre-dose on Day 1) and at Week 12. The analysis will focus on the percent change from baseline for the specified biomarkers and the change in KCCQ-23 scores. These assessments will provide a comprehensive evaluation of the efficacy of Tovinontrine in improving clinical outcomes for patients with HFpEF over the 12-week treatment period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Is an adult male or female patient ≥18 years of age, or adult age as per country guidelines, at the time of Screening.
- Has a medical history supporting a diagnosis of clinical heart failure (HF) syndrome, NYHA functional class II to III, with the duration of at least 6 months prior to the time of Screening
- 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 ≥500 pg/mL at the time of Screening
- Is on stable optimized doses of guideline-directed HF therapy, per Investigator’s clinical judgment.
- Has had no addition of new guideline-directed HF therapy (with the exception of diuretics) within the 3 months prior to the time of Screening or during the Screening Period and is on stable optimized doses of all HF therapies, including diuretics, for a minimum of 4 weeks prior to the time of Screening and during the Screening Period, with no planned changes after randomization
- Other protocol-defined criteria apply
Exclusion Criteria
- Has documented EF ≥60% by TTE within 6 months of the time of Screening or during the Screening Period
- Has known bleeding diathesis
- Other protocol-defined criteria apply
- 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, IV iron, or diuretics) or routinely scheduled ultrafiltration
- Has any clinically significant abnormal findings on physical examination as judged by the Investigator (or designee), AND/OR vital signs recorded at Screening of the following: - Average systolic blood pressure after a triplicate recording of <90 mmHg or ≥180 mmHg; - Average diastolic blood pressure after a triplicate recording of >90 mmHg; or - Heart rate <45 or >90 beats per minute.
- Has elective interventions (eg, percutaneous coronary intervention, de novo device implantations, percutaneous structural heart disease interventions, or major cardiac or non-cardiac surgery) planned to occur during study participation or has undergone this elective procedure <12 weeks prior to Screening.
- 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 clinical suspicion of infiltrative cardiomyopathy (eg, amyloid, sarcoid), hypertrophic cardiomyopathy (obstructive or non-obstructive), or HF secondary to severe valvular disease, active myocarditis, active pericarditis, or clinically significant congenital heart disease
- Has had prior or planned orthotopic heart transplantation
- Has the presence of or plan for mechanical circulatory support
- Has any of the following findings at Screening: A clinically significant abnormal finding on electrocardiogram (ECG) considered by the Investigator to pose a risk to the safety of the patient; and/or oPersonal or family history of Long QT syndrome; and/or A QTcF interval of >500 msec; and/or oUtilization of concomitant therapies known to increase the risk of torsade de pointe
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 May 2024 | 7 |
 Bulgaria | Not Recruiting | 01 May 2024 | 31 |
 Czechia | Not Recruiting | 01 May 2024 | 9 |
 Germany | Not Recruiting | 01 May 2024 | 12 |
 Hungary | Not Recruiting | 01 May 2024 | 15 |
 Italy | Not Recruiting | 01 May 2024 | 6 |
 The Netherlands | Not Recruiting | 01 May 2024 | — |
 Poland | Not Recruiting | 01 May 2024 | 24 |
 Spain | Not Recruiting | 01 May 2024 | 13 |
| Netherlands | — | — | 11 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
tovinontrine-matching placebo, immediate-release tablet | Placebo | N/A | — | — | — | N/A |
Tovinontrine | Test | TABLET | ORAL | 100 | 12 | PRD10875373 |