Phase 2 Randomized Double-Blind Placebo-Controlled Study of Tovinontrine in Adults with Heart Failure with Reduced Ejection Fraction
- Trial ID
- 2023-508736-62-00
- Protocol
- CRD-750-201
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of the two highest doses of **tovinontrine** administered twice daily on N-terminal pro b-type natriuretic peptide (NT-proBNP) levels at 12 weeks compared to placebo in adult patients with heart failure with reduced ejection fraction (HFrEF). This is clinically relevant as NT-proBNP is a biomarker used to assess the severity and prognosis of heart failure, and its reduction could indicate improved cardiac function and patient outcomes.
Secondary objectives include:
- Evaluating the safety and tolerability of each tovinontrine dose in adult patients with HFrEF.
- Assessing the dose-response relationship for the reduction of NT-proBNP at Week 12 compared to baseline.
- Evaluating the effect of each tovinontrine dose compared to placebo on urine and plasma cyclic guanosine monophosphate (cGMP) over 12 weeks.
- Assessing the effect of each tovinontrine dose compared to placebo on b-type natriuretic peptide (BNP) at Week 12.
- Evaluating the effect of each tovinontrine dose compared to placebo on the urine and plasma cGMP to NT-proBNP ratio at Week 12.
- Evaluating the effect of Dose 1 compared to placebo on plasma NT-proBNP at Week 12.
Participants
The clinical trial involves a total of **163 participants** diagnosed with **heart failure (HF) with reduced ejection fraction (HFrEF)**. The study population comprises adult males and females aged 18 years and older, as per country guidelines. Participants are required to have a medical history supporting a diagnosis of clinical HF syndrome, classified as New York Heart Association (NYHA) functional class II to III, with a duration of at least six months prior to screening. The ejection fraction must be 40% or less, as determined by a transthoracic echocardiogram. Additionally, participants must have an N-terminal pro b-type natriuretic peptide (NT-proBNP) level of at least 600 pg/mL, or 1000 pg/mL for those with atrial fibrillation or flutter. All participants are on stable, optimized doses of guideline-directed HF therapy, with no recent additions or planned changes to their treatment regimen. 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.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the safety and effectiveness of Tovinontrine in patients with chronic heart failure with reduced ejection fraction (HFrEF). The trial aims to assess the effect of the two highest doses of Tovinontrine, administered twice daily, on N-terminal pro b-type natriuretic peptide (NT-proBNP) levels over a 12-week period compared to placebo. The study will involve adult participants who meet specific inclusion criteria, such as having a medical history of heart failure syndrome, NYHA functional class II to III, and an ejection fraction of 40% or less. Participants must also have stable, optimized doses of guideline-directed heart failure therapy.
The trial will commence with a screening visit to confirm eligibility based on the inclusion criteria, including NT-proBNP levels and echocardiogram results. Following successful screening, participants will be randomized to receive either Tovinontrine or a matching placebo. The trial will include several follow-up visits to monitor safety, efficacy, and adherence to the treatment regimen. These visits will involve assessments of NT-proBNP, urine and plasma cGMP, and other secondary endpoints such as changes in BNP and quality of life measures. The primary endpoint is the percent change from baseline in plasma NT-proBNP at week 12.
The expected duration of participant involvement is approximately 12 weeks, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The trial is estimated to start recruitment in May 2024 and conclude by November 2025. Participants will be closely monitored throughout the study to ensure their safety and the integrity of the trial data. The study's design and procedures are structured to provide robust data on the efficacy and safety of Tovinontrine in the target population.
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 tablet form and is administered orally. The study evaluates three different dosages of Tovinontrine: 100 mg, 50 mg, and 5 mg. The maximum daily dose for the 100 mg formulation is 100 mg, with a total maximum dose of 8.4 grams over a 12-week period. For the 50 mg formulation, the maximum daily dose is 50 mg, with a total maximum dose of 4.2 grams over the same period. The 5 mg formulation has a maximum daily dose of 5 mg, with a total maximum dose of 420 mg. The treatment period for each dosage is 12 weeks, with the medication administered twice daily (BID).
The trial 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 medication, ensuring the study remains double-blind. The placebo is administered orally, following the same dosing schedule as the active treatment groups, to maintain consistency in the trial design.
Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the prescribed treatment schedule. This monitoring is crucial for maintaining the integrity of the trial results and ensuring accurate assessment of the medication's safety and efficacy in patients with chronic heart failure with reduced ejection fraction (HFrEF).
Efficacy
The efficacy of the investigational product, **Tovinontrine**, in the clinical trial will be assessed primarily through the evaluation of the percent change from baseline in plasma N-terminal pro b-type natriuretic peptide (NT-proBNP) levels at Week 12. This primary endpoint will focus on the two highest doses of Tovinontrine administered twice daily, compared to placebo, in patients with chronic heart failure with reduced ejection fraction (HFrEF).
Secondary endpoints will include the percent change from baseline in urine and plasma cyclic guanosine monophosphate (cGMP) levels, the percent change in brain natriuretic peptide (BNP) levels, and the ratios of urine and plasma cGMP to NT-proBNP and BNP at Week 12. Additionally, changes in the Kansas City Cardiomyopathy Questionnaire-23 Clinical Summary Score (KCCQ-23-CSS) and the New York Heart Association (NYHA) classification will be evaluated at Week 12. The percent change in plasma NT-proBNP for the lowest dose of Tovinontrine will also be assessed as a secondary endpoint.
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 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% % 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 ≥1000 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 ≥40% by TTE within 6 months of the time of Screening or during the Screening Period
- Has known bleeding diathesis
- 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: o Average systolic blood pressure after a triplicate recording of <90 mmHg or ≥180 mmHg; o Average diastolic blood pressure after a triplicate recording of ≥90 mmHg; or o 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: o A clinically significant abnormal finding on ECG considered by the Investigator to pose a risk to the safety of the patient; AND/OR o A QTcF interval of >500 msec AND/OR o A family history of Long QT Syndrome AND/OR o Utilization of concomitant therapies known to increase the risk of torsade de pointes
- Other protocol-defined criteria apply
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 May 2024 | 8 |
 Bulgaria | Not Recruiting | 01 May 2024 | 25 |
 Czechia | Not Recruiting | 01 May 2024 | 13 |
 Germany | Not Recruiting | 01 May 2024 | 17 |
 Hungary | Not Recruiting | 01 May 2024 | 28 |
 Italy | Not Recruiting | 01 May 2024 | 11 |
 Latvia | Not Recruiting | 01 May 2024 | 18 |
 Lithuania | Not Recruiting | 01 May 2024 | 14 |
 The Netherlands | Not Recruiting | 01 May 2024 | — |
 Poland | Not Recruiting | 01 May 2024 | 45 |
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 | Test | TABLET | ORAL | 50 | 12 | PRD10875371 |
Tovinontrine | Test | TABLET | ORAL | 5 | 12 | PRD10875363 |
Tovinontrine | Test | TABLET | ORAL | 100 | 12 | PRD10875373 |
tovinontrine-matching placebo, immediate-release tablet | Placebo | N/A | — | — | — | N/A |