A Phase 2 Clinical Study to Assess the Safety and Effectiveness of Tovinontrine in Patients With Chronic Heart Failure With Preserved Ejection Fraction

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cardurion Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

8 Aug 2024 → 3 Sep 2025

Decision date (initial)

2024-05-30

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Cardurion Pharmaceuticals Inc.

External identifiers

EU CT number

2023-508737-13-00

WHO UTN

U1111-1298-0977

ClinicalTrials.gov

NCT06215586

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacodynamic, Pharmacokinetic

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 HFpEF.

Secondary objectives 6

1. To evaluate the safety and tolerability of tovinontrine versus placebo in adult patients with HFpEF
2. To evaluate the effect of tovinontrine on urine and plasma cyclic guanosine monophosphate (cGMP) versus placebo at Week 12 in adult patients with HFpEF
3. To assess the effect of tovinontrine on b-type natriuretic peptide (BNP) compared to placebo at Week 12 in adult patients with HFpEF
4. To assess the effect of tovinontrine on urine and plasma cGMP to NT-proBNP ratio compared to placebo at Week 12 in adult patients with HFpEF
5. To assess the effect of tovinontrine on urine and plasma cGMP to BNP ratio compared to placebo at Week 12 in adult patients with HFpEF
6. Other protocol-defined objectives apply

Conditions and MedDRA coding

chronic heart failure

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Is an adult male or female patient ≥18 years of age, or adult age as per country guidelines, at the time of Screening.
2. 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
3. Has ejection fraction (EF) > 40% and left atrial enlargement by transthoracic echocardiogram (TTE) performed and interpreted locally at the time of Screening
4. 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
5. Is on stable optimized doses of guideline-directed HF therapy, per Investigator’s clinical judgment.
6. 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
7. Other protocol-defined criteria apply

Exclusion criteria 12

1. Has documented EF ≥60% by TTE within 6 months of the time of Screening or during the Screening Period
2. Has known bleeding diathesis
3. Other protocol-defined criteria apply
4. 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
5. Has a requirement for routine, scheduled outpatient IV infusions for HF (ie, inotropes, vasodilators, IV iron, or diuretics) or routinely scheduled ultrafiltration
6. 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.
7. 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.
8. 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
9. 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
10. Has had prior or planned orthotopic heart transplantation
11. Has the presence of or plan for mechanical circulatory support
12. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The percent change from baseline (pre-dose on Day 1) in plasma NT-proBNP at Week 12.

Secondary endpoints 7

1. The percent change from baseline (pre-dose on Day 1) in urine and plasma cGMP at Week 12
2. The percent change from baseline (pre-dose on Day 1) in BNP at Week 12
3. The percent change from baseline (pre-dose on Day 1) in urine and plasma cGMP to NT-proBNP ratio at Week 12
4. The percent change from baseline (pre-dose on Day 1) in urine and plasma cGMP to BNP ratio at Week 12
5. The change from baseline (pre-dose on Day 1) in the KCCQ-23-CSS, KCCQ-23-OSS, and 8 domains (physical limitation, symptom stability, symptom frequency, symptom burden, total symptom score, quality of life, self-efficacy, and social limitation) at Week 12
6. The change from baseline (pre-dose on Day 1) of the proportion of patients with ≥5, 10, and 20-point improvement in the KCCQ-23-CSS at Week 12
7. The post-baseline NYHA classification at Week 12

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cardurion Pharmaceuticals Inc.

Sponsor organisation

Cardurion Pharmaceuticals Inc.

Address

78 Blanchard Road Suite 200

City

Burlington

Postcode

01803-6014

Country

United States

Scientific contact point

Organisation

Cardurion Pharmaceuticals Inc.

Contact name

Regulatory Affairs

Public contact point

Organisation

Cardurion Pharmaceuticals Inc.

Contact name

Regulatory Submissions

Third parties 3

Locations

9 EU/EEA countries · 50 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 159 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

12 submissions — initial application plus substantial / non-substantial modifications