Tovinontrine for Heart Failure

(Cycle-1-REF Trial)

No longer recruiting at 147 trial locations

Overseen By Gail Berman

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Cardurion Pharmaceuticals, Inc.

Must be taking: Guideline-directed HF therapy

Disqualifiers: Recent HF exacerbation, Acute coronary syndrome, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment, tovinontrine, to determine its safety and effectiveness for people with chronic heart failure. Specifically, the trial aims to lower a certain heart failure marker (NT-proBNP) in those with reduced heart pumping ability. Participants will receive either a low, medium, or high dose of tovinontrine, or a placebo, to compare results. Ideal candidates have experienced heart failure symptoms like shortness of breath or fatigue for at least six months and currently have a reduced ejection fraction, a measure of heart efficiency. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stay on your current heart failure medications at stable doses for at least 4 weeks before and during the screening period, with no planned changes after joining the study.

Is there any evidence suggesting that tovinontrine is likely to be safe for humans?

Research has shown that tovinontrine, a treatment for chronic heart failure, is under study to assess its safety and effectiveness. Earlier studies tested tovinontrine in individuals with chronic heart failure, providing insights into patient tolerance and potential side effects.

This is a Phase 2 study, focusing primarily on ensuring the treatment's safety and determining the appropriate dose. The treatment has already undergone testing in some individuals, but researchers seek additional information to confirm its safety and understand responses to various doses. While some side effects may occur, serious issues are less likely due to prior testing.

In summary, tovinontrine demonstrated promise in earlier tests, and this trial aims to gather more information on its safety for people with heart failure. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for heart failure?

Researchers are excited about Tovinontrine for heart failure because it represents a novel approach to treatment. While most heart failure medications, like ACE inhibitors and beta-blockers, primarily focus on managing symptoms and preventing disease progression, Tovinontrine targets a different pathway. It acts on cyclic nucleotide phosphodiesterase, potentially improving heart function more directly. This unique mechanism could lead to improved outcomes for patients who don't fully benefit from existing therapies.

What evidence suggests that tovinontrine could be an effective treatment for heart failure?

Research shows that tovinontrine is under study as a new treatment for chronic heart failure. It blocks PDE9, an enzyme related to heart function. Early results suggest it might help lower NT-proBNP levels, a substance often elevated in people with heart failure. Specifically, previous patients demonstrated promising reductions in this substance. While more research is needed, early signs offer hope for those with heart failure with reduced ejection fraction. ^{1 2 3 6 7}

Who Is on the Research Team?

Gail Berman

Principal Investigator

Senior VP Head, Clinical Development Cardurion

Are You a Good Fit for This Trial?

This trial is for adults with chronic heart failure who have a reduced ability of the heart to pump blood (ejection fraction ≤ 40%). Participants must show certain levels of NT-proBNP, a marker indicating heart stress, and have symptoms or signs of heart failure. They should be on stable heart failure medication for at least 4 weeks with no recent changes.

Inclusion Criteria

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;

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tovinontrine or placebo to evaluate safety and effectiveness in lowering NT-proBNP

12 weeks

Regular visits for assessments and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Tovinontrine

Trial Overview The study tests Tovinontrine's effectiveness in lowering NT-proBNP levels compared to a placebo in patients with chronic heart failure. The goal is to see if Tovinontrine can improve symptoms by helping the failing heart work better.

How Is the Trial Designed?

Group I: Tovinontrine (CRD-750) - medium dose Experimental Treatment 1 Intervention

Group II: Tovinontrine (CRD-750) - low dose Experimental Treatment 1 Intervention

Group III: Tovinontrine (CRD-750) - high dose Experimental Treatment 1 Intervention

Group IV: Placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Cardurion Pharmaceuticals, Inc.

Lead Sponsor

Trials

6

Recruited

740+

Published Research Related to This Trial

In a study of 254 patients with chronic heart failure, tolvaptan significantly reduced body weight and edema while normalizing serum sodium levels in patients with low sodium, demonstrating its efficacy as a treatment.

Tolvaptan was well tolerated with no significant adverse effects on heart rate, blood pressure, serum potassium, or renal function, indicating a favorable safety profile for patients with chronic heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Gheorghiade, M., Niazi, I., Ouyang, J., et al.[2022]

In the SMILE study, tolvaptan was found to be equally effective in treating congestive heart failure symptoms in patients aged 80 and older compared to those younger than 80, indicating its efficacy across age groups.

The safety profile of tolvaptan was favorable in older patients, with a lower incidence of thirst compared to younger patients, but a recommendation was made to start at lower doses in older patients to avoid the risk of hypernatremia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and adverse events of tolvaptan in octogenarians with heart failure. Interim analyses of Samsca Post-Marketing Surveillance In Heart faiLurE (SMILE study). Kinugawa, K., Inomata, T., Sato, N., et al.[2018]

Tolvaptan, a vasopressin receptor 2 antagonist, effectively improved congestive symptoms in heart failure patients with volume overload within 14 days, regardless of treatment duration (14DS vs. 15DL).

Patients in the longer treatment group (15DL) showed statistically significant further improvements in symptoms like lower limb edema and dyspnea after 2 weeks, although many patients may not have responded well, indicating a need for better identification of effective responders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Who Needs Longer Tolvaptan Treatment? Kinugawa, K., Inomata, T., Sato, N., et al.[2018]

Tolvaptan, a once-daily oral medication, has shown effectiveness in increasing fluid loss and improving serum sodium levels in patients with heart failure without negatively impacting blood pressure, heart rate, or kidney function, based on Phase II clinical trials.

In patients with hyponatremia, tolvaptan is more effective than fluid restriction for raising sodium levels and is generally well tolerated, with side effects primarily related to its intended effects, such as thirst and dry mouth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolvaptan for the treatment of hyponatremia and congestive heart failure. Orlandi, C., Zimmer, CA., Gheorghiade, M.[2009]

Childhood cancer survivors, particularly those treated with anthracyclines, face a significantly increased risk of cardiac dysfunction and heart failure, with a 15-fold higher likelihood of developing late treatment-related heart failure compared to the general population.

Cardio-oncology is emerging as a crucial field to monitor and manage these risks, but there is still a lack of randomized controlled trials specifically addressing treatment for cardiac issues in childhood cancer survivors, highlighting the need for better identification of high-risk patients and timely intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy for Cancer Treatment-Related Cardiac Dysfunction and Heart Failure in Childhood Cancer Survivors. Das, B.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06215586

NCT06215586 | Safety & Effectiveness of Tovinontrine in ... 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 ...

2. cardurion.com cardurion.com/cardurion-pharmaceuticals-completes-enrollment-in-phase-2-cycle-trials-evaluating-crd%E2%80%91750-a-novel-pde9-inhibitor-in-heart-failure/

News and Events Cardurion is the first company to bring a PDE9 inhibitor into clinical development for the treatment of chronic heart failure. The CYCLE-1-REF ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06215586?utm_source=trialradar

Safety & Effectiveness of Tovinontrine in Chronic Heart Failure ... The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

4. clinicaltrials.eu clinicaltrials.eu/inn/tovinontrine/

Tovinontrine: A New Drug for Heart Failure Treatment These trials aim to evaluate the safety and effectiveness of Tovinontrine in patients with chronic heart failure, both with preserved ejection fraction (HFpEF) ...

5. delta.larvol.com delta.larvol.com/Products/?ProductId=112788cd-d42c-4510-82a0-262dcbe3fa60

tovinontrine (IMR-687) / Enliven Therapeutics, Cardurion A Study to Assess Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Reduced Ejection Fraction (Cycle-1-REF) (clinicaltrials.gov) - P2 ...

6. clinicaltrials.eu clinicaltrials.eu/trial/study-on-the-safety-and-effectiveness-of-tovinontrine-for-adults-with-chronic-heart-failure-with-preserved-ejection-fraction/

Study on the Safety and Effectiveness of Tovinontrine ... This study investigates the safety and effectiveness of Tovinontrine, a phosphodiesterase type 9 inhibitor, in treating adults with chronic ...

7. trial.medpath.com trial.medpath.com/clinical-trial/30f1b3b462551910/nct06215911-safety-effectiveness-tovinontrine-chronic-heart-failure

A Study to Assess Safety & Effectiveness of Tovinontrine in Chronic ... 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 ...