Heart Failure study with Danicamtiv in patients with reduced heart function caused by gene mutation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Myokardia Inc., Myokardia Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

6 Oct 2020 → 22 Feb 2024

Decision date (initial)

2023-08-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Myokardia Inc.

External identifiers

EU CT number

2023-505492-68-00

EudraCT number

2019-003626-24

WHO UTN

U1111-1292-3662

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Pharmacodynamic, Pharmacogenetic

To establish preliminary safety and tolerability of treatment with danicamtiv in participants with myosin heavy chain 7 (MYH7) dilated cardiomyopathy (DCM) or titin (TTN)-DCM, or DCM by other causalities for Part A

Secondary objectives 1

1. To establish preliminary effect, compared with baseline, of treatment with danicamtiv on cardiac PD as determined by TTE in participants with MYH7-DCM or TTN-DCM or DCM by other causalities

Conditions and MedDRA coding

Primary Dilated Cardiomyopathy Due to Either MYH7 o TTN Variants

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Part A_I1. Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent according to federal, local, and institutional guidelines before the first study-specific procedure
2. I3_(g). Documented left ventricular ejection fraction (LVEF) 15-45% (on 2 occasions), including at least once during Screening and confirmed by the Echo Core Laboratory. If a participant's most recent prior TTE (within past 12 months) documents a LVEF ≤45%, then only a single screening visit confirming LVEF ≤45% by the Echo Core Laboratory is required. If no prior documented LVEF ≤45% by TTE within past 12 months is available, then 2 screening TTEs are needed at least one week (7 days) apart. In addition, the absolute difference between the 2 LVEF values qualifying the subject should <12%.
3. I3_(h). Participant receives chronic medication for the treatment of heart failure reflecting current guidelines, including at least one of the following, unless not tolerated or contraindicated: β-blocker, angiotensin converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor. Such treatments should have been given at stable doses for ≥ 2 weeks with no plan to modify during the study
4. Part A_I4. Sinus rhythm or stable atrial or ventricular pacing or persistent atrial fibrillation that is adequately rate-controlled to allow PD assessments by TTE.
5. Part A_I5. If multiple members of a family meet eligibility criteria, a maximum of 3 eligible subjects per family may enroll in the study
6. Part A_I6. Female of childbearing potential (Appendix 6) must not be pregnant or lactating and, if sexually active, must use one of the following highlyeffective birth control methods from the Screening visit through 3 months after the last dose of study drug: -combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation or progestogenonly hormonal contraception associated with inhibition of ovulation by oral, implantable, or injectable route of administration -intrauterine device (IUD) -intrauterine system (IUS)-Female participant is surgically sterile (includes documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy, and/or bilateral tubal occlusion or ligation prior to Screening). -Female participant postmenopausal for 1 year - considered postmenopausal if they have had amenorrhea for at least 1 year or more following cessation of all exogenous hormonal treatments, and follicle stimulating hormone (FSH) levels are in the postmenopausal range. Male partners of female participants must also use a contraceptive (eg, barrier, condom, or vasectomy)
7. Part A_I2. Men or women 18 to 80 years of age (inclusive) at the Screening visit.
8. Part A_I3. For MYH7 and TTN cohorts, diagnosis of primary DCM, clinically stable and associated with probably disease-causing variant MYH7 or TTN as defined by (a) through (f) of the following, All study participants, regardless of the cohort, must meet (g) and (h) criteria
9. I3_(a). Primary DCM participants that have no identified etiology other than variant in MYH7 or TTN as determined by the Investigator.Participants with a diagnosis of heart failure with reduced ejection fraction should be on Guideline Directed Medical Therapy as tolerated.
10. I3_(b). Pathogenic or likely pathogenic variants submitted in the form of final official genetic laboratory reports will be reviewed centrally by the Sponsor and coordinating investigator for eligibility. Some variants designated VUS may also be permitted upon central review.
11. I3_(c). DCM is not secondary to long-standing MYH7 or TTN-related hypertrophic cardiomyopathy (HCM) or left ventricle noncompaction cardiomyopathy, as determined by the Investigator.
12. I3_(d). Participants with DCM related to pathogenic or likely pathogenic variants of TTN must not also have a diagnosis of peripartum DCM (DCM diagnosed initially in the last month of pregnancy or the 6 months following delivery).
13. I3_(e). In participants with DCM related to pathogenic or likely pathogenic variants of TTN, DCM must not be secondary to significant exposure to cardiotoxic chemotherapy agents as determined by the investigator.
14. I3_(f). In participants with DCM related to pathogenic or likely pathogenic variants of TTN, DCM must not be due to a history of significant alcohol abuse as determined by the investigator
15. Part A_I7. Male participants must use barrier method of contraception (whether or not the participant had vasectomy)
16. Part A_I8. I8. For the cohort of primary DCM due to other causalities than MYH7 and TTN, participant must meet the following criteria in addition to I1, I2, I3 (g) and (h), I4, I5, I6, and I7. a. The cause of DCM is not related to MYH7 or TTN variants b. The cause of primary DCM is by variants of the other genes except MYH7 and TTN, or non-genetic cause.

Exclusion criteria 25

1. Part A_E1. Inadequate echocardiographic acoustic windows.
2. Part A_E4. HFrEF considered to be caused primarily by ischemic heart disease, chronic valvulopathy, or another condition, as determined by the Investigator
3. Part A_E5. Recent (< 90 days) acute coronary syndrome or angina pectoris
4. Part A_E6. Coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft) within prior 90 days
5. Part A_E7. Recent (< 90 days) hospitalization for heart failure, use of intravenous diuretic or chronic intravenous inotropic therapy or other cardiovascular event (eg, cerebrovascular accident)
6. Part A_E8. Known aortic stenosis of moderate or greater severity
7. Part A_E9. Presence of disqualifying cardiac rhythms that would preclude echocardiographic assessments, as determined by the Investigator, including: (a) rapid, inadequately rate-controlled atrial fibrillation or (b) frequent premature ventricular contractions that might interfere with reliable echocardiographic measurements of left ventricular function
8. Part A_E16. History or evidence of any other clinically significant disorder, condition, or disease (including substance abuse) that, in the opinion of the investigator or the Sponsor physician would pose a risk to participant safety or interfere with the study evaluation, procedures, completion, or lead to premature withdrawal from the study
9. Part A_E17. A life expectancy of < 6 months
10. Part A_E18. Prior/Concurrent Clinical Study Experience: Participated in a clinical trial in which the participant received any investigational drug (or is currently using an investigational device) within 30 days prior to Screening, or at least 5 times the respective elimination half-life (whichever is longer).
11. Part A_E19. WOCBP with a positive pregnancy test
12. Part A_E10. Hypersensitivity to danicamtiv or any of the components of the danicamtiv formulation
13. Part A_E20. Is employed by or is a first-degree relative of someone employed by the Sponsor, the investigator, or his/her staff or family
14. Part A_E21. Currently placed in hospital or facility due to legal or administrative order
15. Part A_E11. Active infection, indicated clinically as determined by the investigator. In the case of SARS-CoV-2 (COVID-19) infection within 4 weeks prior to and during Screening, symptoms must have completely resolved and based on Investigator assessment in consultation with the Clinical Trial Physician, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment. The methods to assess SARS-CoV-2 (COVID-19) infection include PCR, antigen test and serology tests. Each study site should follow requirements per local institutional or regulatory guidance if any.
16. Part A_E12. History of malignancy of any type within 5 years prior to Screening, with the exception of the following surgically excised cancers occurring more than 2 years prior to Screening: in situ cervical cancer, nonmelanomatous skin cancers, ductal carcinoma in situ, and nonmetastatic prostate cancer
17. Part A_E13. Severe renal insufficiency (defined as current estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2 by simplified Modification of Diet in Renal Disease equation [sMDRD])
18. Part A_E14. Serum potassium < 3.5 or > 5.5 mEq/L
19. Part A_E15. Any persistent (2 or more) out-of-range laboratory parameters (chemistry, hematology) at Screening, considered by the investigator and the medical monitor to be clinically significant.
20. Part A_E2. A participant has a QTcF interval > 480 msec (not attributable to ventricular pacing or prolonged QRS duration ≥ 120 msec, average of triplicate electrocardiograms (ECGs)
21. Part A_E3. (a) For MYH7 and TTN cohorts, participants with known pathogenic variant of another gene implicated in DCM at screening (b) For the cohort of participants with primary DCM due to other causalities than MYH7 and TTN, known in MYH7 or TTN variants implicated in DCM at Screening.
22. Part B_E1. Recent (< 90 days) acute coronary syndrome or angina pectoris
23. Part B_E2. Coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft) within prior 90 days
24. Part B_E3. Recent (< 90 days) hospitalization for heart failure, use of intravenous diuretic or chronic intravenous inotropic therapy or other cardiovascular event (eg, cerebrovascular accident)
25. Part B_E4. Active infection, indicated clinically as determined by the Investigator. In the case of SARS-CoV-2 (COVID-19) infection within 4 weeks prior to Part B Baseline Visit or Rescreening (if required), symptoms must have completely resolved and based on Investigator assessment in consultation with the Clinical Trial Physician, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment. The methods to assess SARS-CoV-2 (COVID-19)infection include PCR, antigen test and serology tests. Each study site should follow requirements per local institutional or regulatory guidance if any. Due to character limitation, for other exclusion criteria, please refer to the protocol

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Clinical safety and tolerability as assessed by the following: • Frequency of treatment-emergent adverse events and serious adverse events in Part A • Frequency of clinically significant abnormalities from vital signs, adverse events, physical examination, ECG recordings, and safety labs in Part A

Secondary endpoints 4

1. Change in the following PD parameters as assessed by TTE from Baseline corresponding to Parts A and B of the study: • Left ventricular SET • Parameters of left ventricular systolic function including but not limited to left ventricular stroke volume (LVSV), LVEF, left ventricular strain (LVGLS and LVGCS) and tissue doppler imaging (TDI) of mitral valve annulus peak systolic velocity (s') will be evaluated.
2. Change in the following PD parameters as assessed by TTE from Baseline corresponding to Parts A and B of the study:• Parameters of left ventricular dimensions including left ventricular end-systolic and end-diastolic diameters (LVESD, LVEDD), left ventricular end-systolic and end-diastolic volumes indexed for body surface area (LVEDVI, and LVESVi).
3. Change in the following PD parameters as assessed by TTE from Baseline corresponding to Parts A and B of the study: • Parameters of left atrial volume and function including but not limited to minimum and maximum left atrium (LA) volumes indexed for body surface area (LAmaxVi, LAminVi), left atrial emptying fraction (LAEF), and left atrial function index (LAFI)
4. Change in the following PD parameters as assessed by TTE from Baseline corresponding to Parts A and B of the study: • Parameters of left ventricular diastolic function including but not limited to TDI of mitral valve annulus peak velocity in diastole (e', lateral,septal), ratio of peak inflow velocities in early and late diastole (E/A), ratio of early mitral peak inflow velocity to early mitral peak annulus velocity (TDI) (E/e') lateral, septal, and average

Investigational products

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

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Myokardia Inc.

Sponsor organisation

Myokardia Inc.

Address

1000 Sierra Point Parkway

City

Brisbane

Postcode

94005-1804

Country

United States

Scientific contact point

Organisation

Myokardia Inc.

Contact name

GSM-CT

Public contact point

Organisation

Myokardia Inc.

Contact name

GSM-CT

Third parties 3

Myokardia Inc.

Sponsor organisation

Myokardia Inc.

Address

1000 Sierra Point Parkway

City

Brisbane

Postcode

94005-1804

Country

United States

Locations

2 EU/EEA countries · 5 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 4 files

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

Application history

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