Tovinontrine for Heart Failure

(Cycle-2-PEF Trial)

No longer recruiting at 99 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 called tovinontrine to determine if it can safely reduce levels of the heart-related protein NT-proBNP in people with chronic heart failure who have preserved ejection fraction (a measure of heart function). It compares tovinontrine's effects with a placebo, a substance with no active treatment. The trial seeks participants who have experienced heart failure symptoms like breathlessness or fatigue that limit activity for at least six months and have been on stable heart failure medication. Participants should also have a history of certain heart failure signs, such as leg swelling or a recent hospital visit for heart failure. As a Phase 2 trial, this 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 stable doses of your current heart failure medications 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 is generally safe for humans. In studies involving individuals with chronic heart failure, most participants did not experience serious side effects. Some reported mild to moderate issues, such as headaches or nausea, but these were uncommon. Tovinontrine is also undergoing tests for other conditions, like sickle cell disease, which further supports its safety profile. As this treatment is in Phase 2 trials, researchers have gathered sufficient safety data to continue testing it with more participants. This indicates it is considered safe enough for further study, although not all side effects may be known yet. ^{1 2 3 4 5}

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

Unlike the standard treatments for heart failure, which typically include medications like ACE inhibitors, beta-blockers, and diuretics, Tovinontrine (CRD-750) works differently by targeting a novel mechanism. Researchers are excited about Tovinontrine because it leverages a unique approach to modulate cyclic nucleotide signaling, which plays a crucial role in heart function and could lead to improved heart performance. This mechanism offers a fresh perspective on managing heart failure, potentially providing benefits beyond what current therapies can achieve.

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

Research has shown that tovinontrine, which participants in this trial may receive, could be a promising treatment for heart failure. It targets a specific enzyme called PDE9, linked to heart failure. Earlier studies with similar treatments have lowered a blood marker called NT-proBNP. High levels of NT-proBNP often appear in people with heart failure, so reducing it can be beneficial. While researchers are still gathering direct human data on tovinontrine, its unique method offers potential hope for those with long-term heart failure. ^{1 2 4 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 over 18 with chronic heart failure who have symptoms like shortness of breath or fatigue, signs such as swelling or lung crackles, and a recent history of heart-related hospital visits. They must have certain levels of NT-proBNP in their blood and be on stable heart medication without changes planned post-randomization.

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% 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 of ≥500 pg/mL at the time of Screening; Is on stable optimized doses of guideline-directed HF therapy, per Investigator's clinical judgment, for a minimum of 4 weeks prior to the time of Screening and during the Screening Period, 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 documented EF ≥ 60% 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 monitoring and assessments

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 the safety and effectiveness of Tovinontrine (CRD-750) against a placebo in reducing NT-proBNP levels among patients with chronic heart failure who still have normal or near-normal heart pumping function.

How Is the Trial Designed?

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

Group II: 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

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]

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]

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]

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]

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. synapse.patsnap.com synapse.patsnap.com/drug/96974202ecaa4a058acd8a52c5a4fa95

Tovinontrine - Drug Targets, Indications, Patents ... Safety and Effectiveness of Tovinontrine in Patients With Chronic Heart Failure With Reduced Ejection Fraction. 100 Clinical Results associated with ...

7. medchemexpress.com medchemexpress.com/tovinontrine.html?srsltid=AfmBOoo6-H-_RE1TTn7ZdMFJxUvxtVc8PB9pLtGlcOlr-Fm1u8ufYFOX

Tovinontrine (IMR-687) | PDE9 Inhibitor Tovinontrine (IMR-687) is a highly potent and selective phosphodiesterase-9 (PDE9) inhibitor specifically for the treatment of sickle cell disease.