A study of aficamten (CK-3773274) in a Pediatric Population with Symptomatic Obstructive Hypertrophic Cardiomyopathy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cytokinetics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

23 Jan 2025 → ongoing

Decision date (initial)

2024-12-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Cytokinetics Inc.

External identifiers

EU CT number

2024-511377-30-00

ClinicalTrials.gov

NCT06412666

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

P1: To assess the effect of aficamten compared with placebo on change from baseline in Valsalva LVOT-G

P2: To determine the safety of aficamten in pediatric participants with symptomatic oHCM

Secondary objectives 6

1. P1: To assess the effect of aficamten compared with placebo on change from baseline in resting LVOT-G
2. P1: To evaluate the PK of aficamten
3. P1: To evaluate the effect of aficamten compared with placebo on cardiac biomarker levels
4. P1: To evaluate the effect of aficamten compared with placebo on NYHA Functional Classification
5. P2: Assess long-term effects of aficamten on LVOT-G
6. P2: Assess the effect of aficamten on functional outcomes

Conditions and MedDRA coding

SYMPTOMATIC OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY

Study design 3 periods

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002958-PIP01-21

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. P1: Males and females between 12 and < 18 years of age at screening and at Day 1.
2. P1: Body weight ≥ 45 kg for the initial cohort and then body weight ≥ 35 kg after at least 10 participants in the initial cohort have undergone dose titration up to Week 4 without observed events of LVEF < 50% at the starting dose of 5 mg qd.
3. P1: Diagnosed with oHCM per the following criteria, confirmed at the time of screening: Left ventricular (LV) hypertrophy with nondilated LV chamber in the absence of other cardiac disease. Core laboratory confirmation of LV end -diastolic wall thickness that meets a threshold of: Z-score (Ommen 2020)>2.5 in the absence of family history or Z-score (Ommen 2020)>2 in the presence of positive family history or positive genetic test. Core laboratory confirmation of LVEF ≥60% AND Valsalva LVOT-G ≥50mmHg.
4. P1: oHCM of sarcomeric origin confirmed by genetic testing or, if unable to confirm by genetic testing, oHCM of sarcomeric origin may be presumed in the absence of history of metabolic disorders, mitochondrial cardiomyopathies, neuromuscular disease, malformation syndromes, infiltrative diseases/inflammation, and endocrine disorders (such as Fabry’s disease, Noonan syndrome with left ventricular hypertrophy, and amyloid-cardiomyopathy).
5. P1: New York Heart Association (NYHA) Class ≥ II at screening.
6. P1: Adequate acoustic windows for echocardiography.
7. P1: Participants on beta blockers, verapamil, diltiazem, or disopyramide should have been on stable doses or more than 4 weeks prior to randomization.
8. P2: Completed Period 1. If unable to complete Period 1 due to circumstances not related to compliance or safety, the Medical Monitor may review and determine eligibility.
9. P2: LVEF ≥ 55% after washout.
10. P3: completed period 2

Exclusion criteria 16

1. P1: Significant valvular heart disease. - Moderate or severe valvular aortic stenosis or fixed subaortic obstruction. - Mitral regurgitation that is greater than mild in severity and not due to systolic anterior motion of the mitral valve (per judgment of Principal Investigator or designee). - Evidence of fixed left-sided obstruction (eg, subaortic membrane, aortic valve stenosis, or coarctation of the aorta).
2. P1: Has received prior treatment with aficamten or mavacamten.
3. P1: Currently listed for heart transplantation or anticipated to be listed for heart transplantation in the next 12 months.
4. P1: Does not assent/consent to participate in the CMR substudy.
5. P1: Inability to tolerate CMR without sedation.
6. P1: Has an ICD or cardiac pacemaker.
7. P1: History of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy at any time during their clinical course.
8. P1: History of congenital heart disease other than oHCM (may be enrolled if not hemodynamically significant in the judgement of the Principal Investigator and study Medical Monitor).
9. P1: Hypersensitivity to aficamten or any of the excipients
10. P1: Has been treated with SRT (surgical myectomy or percutaneous alcohol septal ablation) within the preceding 6 months or has plans for either treatment during the trial period.
11. P1: History of paroxysmal or persistent atrial fibrillation or atrial flutter.
12. P1: History of syncope, symptomatic ventricular arrhythmia, or sustained ventricular tachyarrhythmia within 3 months prior to screening.
13. P1: History or evidence of any other clinically significant disorder, malignancy, active infection, other condition, or disease that, in the opinion of the Principal Investigator (or designee) or the Medical Monitor, would pose a risk to participant safety or interfere with the trial evaluation, procedures, or completion.
14. P1: Current or previous use of drugs known to cause cardiomyopathy (eg, anthracyclines, monoclonal antibodies [trastuzumab], alkylating agents [cyclophosphamide], and tyrosine kinase inhibitors [sunitinib and imatinib]).
15. P1: Currently participating in another investigational device or drug trial or received an investigational device or drug < 1 month (or 5 half-lives for drugs, whichever is longer) prior to screening.
16. P1: Implantable cardioverter defibrillator (ICD) implantation within 6 weeks of screening or planned ICD implantation during the trial period.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. P1: Change in Valsalva LVOT-G from baseline to Week 12
2. P2: Participant incidence of AEs and SAEs through End of Study

Secondary endpoints 13

1. P1: Change in resting LVOT-G from baseline to Week 12
2. P1: All participants: Observed Ctrough and C2h postdose of aficamten over the 12-week treatment period Intensive PK substudy: Observed Cmax, tmax, AUCtau, and Ctrough for aficamten.
3. P1: Change in NT-proBNP from baseline to Week 12 Change in hs-cTnI from baseline to Week 12
4. P1: Change in NYHA Functional Class from baseline to Week 12
5. P1: Proportion of participants with ≥ 1 class improvement in NYHA Functional Class from baseline to Week 12
6. P2: Change in the following measurements at 12-week intervals (Period 2) and 24-week intervals (Period 3) from Week 14 through Week 66 (Period 2) and end of treatment (Period 3): − Peak LVOT-G at rest and with Valsalva provocation.
7. P2: Change in the following measurements at 12-week intervals (Period 2) and 24-week intervals (Period 3) from Week 14 through Week 66 (Period 2) and end of treatment (Period 3): Proportion of participants with resting LVOT-G < 30 mmHg
8. P2: Change in the following measurements at 12-week intervals (Period 2) and 24-week intervals (Period 3) from Week 14 through Week 66 (Period 2) and end of treatment (Period 3): − Proportion of participants with Valsalva LVOT-G < 50 mmHg
9. P2: (Period 2) and 24-week intervals (Period 3) from Week 14 through Week 66 (Period 2) and end of treatment (Period 3): − Proportion of participants with Valsalva LVOT-G < 30 mmHg
10. P2: (Period 2) and 24-week intervals (Period 3) from Week 14 through Week 66 (Period 2) and end of treatment (Period 3):: − Proportion of participants with LVEF ≥ 50%, resting LVOT-G < 30 mmHg, and Valsalva LVOT-G < 50 mmHg
11. P2: Time to the following event through last follow-up: − First resting LVOT-G < 30 mmHg − First Valsalva LVOT-G < 50 mmHg − First Valsalva LVOT-G < 30 mmHg − First LVEF ≥ 50%, resting LVOT-G < 30 mmHg, and Valsalva LVOT-G < 50 mmHg
12. P2: Change in NYHA Functional Class from Week 14 to Week 66 (Period 2) and end of treatment (Period 3)
13. P2: Proportion of participants with ≥ 1 class improvement in NYHA Functional Class from Week 14 to Week 66 (Period 2) and end of treatment (Period 3)

Investigational products

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

Test 1

Placebo 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 Inc. Medical Affairs

Public contact point

Organisation

Cytokinetics Inc.

Contact name

Cytokinetics Inc. Medical Affairs

Third parties 11

Locations

2 EU/EEA countries · 4 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 31 files

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

Application history

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