A Phase 2 Dose-Finding Study to Assess the Safety and Effectiveness of Tovinontrine in Patients With Chronic Heart Failure With Reduced 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 → 11 Oct 2025

Decision date (initial)

2024-05-15

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Cardurion Pharmaceuticals, Inc.

External identifiers

EU CT number

2023-508736-62-00

WHO UTN

U1111-1298-0901

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Dose response, Pharmacokinetic, Efficacy

To evaluate the effect of the 2 highest doses (twice daily [BID]) of tovinontrine on N-terminal pro b-type natriuretic peptide (NT-proBNP) at 12 weeks compared to placebo in adult patients with HFrEF

Secondary objectives 6

1. To evaluate the safety and tolerability of each tovinontrine dose under investigation in adult patients with HFrEF.
2. To evaluate the dose-response relationship for the reduction of NT proBNP at Week 12 compared to baseline in adult patients with HFrEF
3. To evaluate the effect of each tovinontrine dose under investigation compared to placebo on urine and plasma cyclic guanosine monophosphate (cGMP) over 12 weeks in adult patients with HFrEF
4. To assess the effect of each tovinontrine dose under investigation compared to placebo on b type natriuretic peptide (BNP) at Week 12 in adult patients with HFrEF
5. To assess the effect of each tovinontrine dose under investigation compared to placebo on urine and plasma cGMP to NT-proBNP ratio at Week 12 in adult patients with HFrEF
6. To evaluate the effect of Dose 1 compared to placebo on plasma NT-proBNP at Week 12 in adults with HFrEF

Conditions and MedDRA coding

Heart failure (HF) with reduced ejection fraction (HFrEF)

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 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% % by transthoracic echocardiogram (TTE) performed and interpreted locally at the time of Screening
4. 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
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 ≥40% by TTE within 6 months of the time of Screening or during the Screening Period
2. Has known bleeding diathesis
3. 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
4. Has a requirement for routine, scheduled outpatient IV infusions for HF (ie, inotropes, vasodilators, IV iron, or diuretics) or routinely scheduled ultrafiltration.
5. 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.
6. 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.
7. 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
8. 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
9. Has had prior or planned orthotopic heart transplantation
10. Has the presence of or plan for mechanical circulatory support
11. 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
12. Other protocol-defined criteria apply

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 for Doses 2 and 3 at Week 12

Secondary endpoints 6

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 at Week 12 and the post-baseline NYHA classification at Week 12
6. The percent change from baseline (pre-dose on Day 1) in plasma NT proBNP at Week 12 for Dose 1

Investigational products

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

Test 3

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 2

Locations

12 EU/EEA countries · 92 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 199 files

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

Application history

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