A trial to compare the efficacy and safety of aficamten (CK-3773274) compared with metoprolol succinate in adults with symptomatic hypertrophic cardiomyopathy and left ventricular outflow obstruction

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cytokinetics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

7 Feb 2024 → 28 Mar 2025

Decision date (initial)

2023-12-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Cytokinetics, Inc.

External identifiers

EU CT number

2023-504809-37-00

ClinicalTrials.gov

NCT05767346

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy

To evaluate the effect of aficamten compared with metoprolol on exercise capacity in participants with symptomatic oHCM

Secondary objectives 5

1. To evaluate the effect of aficamten compared with metoprolol on New York Heart Association (NYHA) Functional Classification
2. To evaluate the effect of aficamten compared with metoprolol on participant health status
3. To evaluate the effect of aficamten compared with metoprolol on structural remodeling
4. To evaluate the effect of aficamten compared with metoprolol on N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels
5. To evaluate the effect of aficamten compared with metoprolol on post -Valsalva left ventricular outflow tract gradients (LVOT-G)

Conditions and MedDRA coding

Symptomatic Obstructive Hypertrophic Cardiomyopathy

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Males and females between 18 to 85 years of age, inclusive, at the signing of informed consent
2. Body mass index < 35 kg/m2, Qualification of BMI for study eligibility is only required at the participant’s first screening visit.
3. "Diagnosed with oHCM per the following criteria by cardiac magnetic resonance imaging (CMR) or echocardiography: a. Has LV hypertrophy with non-dilated LV chamber in the absence of other cardiac disease and b. Has an end-diastolic LV wall thickness as measured by the echocardiography core laboratory: • ≥ 15 mm in one or more myocardial segments OR • ≥ 13 mm in one or more wall segments and a known-disease-causing gene mutation or positive family history of HCM"
4. KCCQ score ≤90 at Screening Visit 2
5. "Has a screening echocardiogram with the following as determined by the echocardiography core laboratory: a. Resting LVOT-G > 30 mm Hg and/or post-Valsalva LVOT-G ≥ 50 mmHg at screening AND b. LVEF ≥ 60% at screening"
6. Hemoglobin ≥ 10g/dL at screening
7. Patients previously exposed to mavacamten are allowed to participate but must be off mavacamten for at least 8 weeks

Exclusion criteria 15

1. Medical indication for either beta blocker or calcium-channel blockers prohibiting drug discontinuation other than oHCM
2. Resting SBP of > 160 mmHg at the time of screening
3. Resting heart rate of > 100 beats per minute (bpm) at the time of screening
4. Inability to exercise on a treadmill or bicycle (eg, orthopedic limitations)
5. "Significant valvular heart disease a. Moderate-severe valvular aortic stenosis or fixed subaortic obstruction b. Mitral regurgitation not due to systolic anterior motion of the mitral valve (per Investigator judgment)"
6. Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis)
7. History of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy at any time during their clinical course
8. Documented room air oxygen saturation reading < 90% at screening
9. Planned septal reduction treatment that cannot be deferred during the trial period
10. History of septal reduction therapy (surgical myectomy or alcohol septal ablation) within 6 months of screening
11. History of paroxysmal or persistent atrial fibrillation or atrial flutter. Atrial flutter treated with radio frequency ablation without recurrence within the last 6 months prior to screening is allowed.
12. Current or recent (< 4 weeks prior to signing of informed consent) therapy with disopyramide
13. History of syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening
14. History of intolerance or medical contraindication to beta blocker therapy
15. Has received prior treatment with aficamten or previously intolerant (reduced LVEF requiring permanent drug discontinuation) to mavacamten

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET) from baseline to Week 24

Secondary endpoints 5

1. Proportion of participants with ≥ 1 class improvement in NYHA Functional Class from baseline to Week 24
2. Change in Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score (KCCQ-CSS) from baseline to Week 24
3. "• Change in left ventricular mass index (LVMI) from baseline to Week 24 • Change in left atrial volume index (LAVI) from baseline to Week 24"
4. Change from baseline values in NT-proBNP from baseline to Week 24
5. Change in post-Valsalva LVOT-G from baseline to Week 24

Investigational products

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

Test 1

Comparator 1

Placebo 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cytokinetics Inc.

Sponsor organisation

Cytokinetics Inc.

Address

350 Oyster Point Boulevard

City

South San Francisco

Postcode

94080-1912

Country

United States

Scientific contact point

Organisation

Cytokinetics Inc.

Contact name

Cytokinetics MD

Public contact point

Organisation

Cytokinetics Inc.

Contact name

Cytokinetics MD

Third parties 12

Locations

7 EU/EEA countries · 22 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 97 files

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

Application history

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