Exploratory Evaluation of Danicamtiv Safety and Efficacy in Ambulatory Patients with Primary Dilated Cardiomyopathy Due to MYH7 or TTN Variants
- Trial ID
- 2023-505492-68-00
- Protocol
- CV028-005
- Sponsor
- Myokardia Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to establish the preliminary **safety** and tolerability of treatment with **danicamtiv** in participants with **dilated cardiomyopathy** (DCM) due to either **MYH7** or **TTN** variants, or other causalities. This is clinically relevant as it aims to assess the potential of danicamtiv to be a safe therapeutic option for patients with these specific genetic mutations, which are known to contribute to the development of DCM, a condition characterized by reduced heart function and associated with significant morbidity and mortality.
Secondary objectives include:
- To establish the preliminary effect, compared with baseline, of treatment with danicamtiv on cardiac pharmacodynamics as determined by transthoracic echocardiography (TTE) in participants with MYH7-DCM, TTN-DCM, or DCM by other causalities. This objective is important for understanding the potential efficacy of danicamtiv in improving cardiac function in these patients.
Participants
The clinical trial involves a total of **three participants** diagnosed with **Primary Dilated Cardiomyopathy** due to either MYH7 or TTN variants. The study population includes both male and female subjects, aged between **18 to 80 years**. Participants were selected based on their ability to understand and comply with study procedures, and they provided written informed consent. The trial does not include a vulnerable population. Participants are required to have a documented left ventricular ejection fraction between 15-45% and must be on stable doses of chronic medication for heart failure, reflecting current guidelines. Lifestyle considerations such as significant alcohol use or exposure to cardiotoxic chemotherapy agents are exclusionary. The study ensures that participants are clinically stable and have no secondary causes for their condition, such as hypertrophic cardiomyopathy or peripartum cardiomyopathy. The trial population is not selected from a vulnerable group, and both genders are represented. The sponsor has not provided additional information regarding specific lifestyle factors such as diet or physical activity.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and preliminary efficacy of **Danicamtiv** in participants with primary dilated cardiomyopathy due to MYH7 or TTN variants or other causalities. This is an open-label, exploratory study classified as a Phase 2 trial. The trial employs a non-randomized, open-label design, allowing for the direct observation of the effects of the investigational product. The trial is expected to run from April 2020 to October 2025, with a maximum treatment period of 730 days for some participants.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific inclusion criteria, such as age, genetic variants, and left ventricular ejection fraction. Following the screening, eligible participants will enter the treatment phase, where they will receive **Danicamtiv** orally in the form of coated or uncoated tablets. The maximum daily dose is set at 150 mg, with a total dose not exceeding 108.3 g over the treatment period.
Study visits will include regular follow-up assessments to monitor safety and efficacy parameters. These visits will involve evaluations such as vital signs, ECG recordings, and echocardiographic assessments to measure changes in left ventricular function and dimensions. The primary endpoint focuses on the frequency of treatment-emergent adverse events and clinically significant abnormalities. Secondary endpoints include changes in left ventricular systolic and diastolic function, as well as left atrial volume and function.
The expected length of participant involvement varies, with some participants receiving treatment for up to 730 days. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or clinically significant abnormalities that compromise participant safety. The end-of-study visit will conclude the trial for each participant, ensuring all necessary data is collected and any remaining safety concerns are addressed.
Treatment
The clinical trial involves the administration of **Danicamtiv**, an investigational medication developed by Bristol-Myers Squibb International Corporation. Danicamtiv is formulated as both **coated tablets** and **uncoated tablets**. The active substance in Danicamtiv is of chemical origin, identified as **danicamtiv**. The pharmaceutical form of the medication is primarily a coated tablet, although uncoated tablets are also utilized in the study. The maximum daily dose of Danicamtiv is 150 mg, with a total maximum dose of 107.1 g for the coated tablet form and 108.3 g for the uncoated tablet form. The treatment period varies, with a maximum duration of 102 days for the coated tablets and up to 730 days for the uncoated tablets. The route of administration for Danicamtiv is oral use.
In this clinical trial, Danicamtiv is classified as a new chemical entity and is not designated as an orphan drug. The study does not involve a pediatric formulation of the medication. The trial aims to evaluate the safety and preliminary efficacy of Danicamtiv in participants with primary dilated cardiomyopathy due to MYH7 or TTN variants or other causalities. The study is open-label and exploratory in nature, focusing on the safety and tolerability of the treatment. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial protocol. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.
Efficacy
The clinical trial aims to assess the efficacy of **Danicamtiv** in participants with primary dilated cardiomyopathy (DCM) due to MYH7 or TTN variants or other causalities. Efficacy will be evaluated through secondary endpoints, which include changes in pharmacodynamic (PD) parameters as assessed by transthoracic echocardiography (TTE) from baseline. These parameters encompass left ventricular systolic function, such as left ventricular stroke volume (LVSV), left ventricular ejection fraction (LVEF), left ventricular strain (LVGLS and LVGCS), and tissue Doppler imaging (TDI) of mitral valve annulus peak systolic velocity (s'). Additionally, left ventricular dimensions, including end-systolic and end-diastolic diameters (LVESD, LVEDD) and volumes indexed for body surface area (LVEDVI, LVESVi), will be measured.
Further assessments will include parameters of left atrial volume and function, such as minimum and maximum left atrium volumes indexed for body surface area (LAmaxVi, LAminVi), left atrial emptying fraction (LAEF), and left atrial function index (LAFI). Left ventricular diastolic function will also be evaluated, focusing on TDI of mitral valve annulus peak velocity in diastole (e', lateral, septal), the ratio of peak inflow velocities in early and late diastole (E/A), and the ratio of early mitral peak inflow velocity to early mitral peak annulus velocity (E/e') lateral, septal, and average. These efficacy parameters will be collected and analyzed at specified timepoints throughout the study to determine the impact of Danicamtiv on cardiac function in the target population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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
- 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%.
- 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
- 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.
- 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
- 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)
- Part A_I2. Men or women 18 to 80 years of age (inclusive) at the Screening visit.
- 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
- 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.
- 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.
- 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.
- 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).
- 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.
- 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
- Part A_I7. Male participants must use barrier method of contraception (whether or not the participant had vasectomy)
- 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
- Part A_E1. Inadequate echocardiographic acoustic windows.
- Part A_E4. HFrEF considered to be caused primarily by ischemic heart disease, chronic valvulopathy, or another condition, as determined by the Investigator
- Part A_E5. Recent (< 90 days) acute coronary syndrome or angina pectoris
- Part A_E6. Coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft) within prior 90 days
- 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)
- Part A_E8. Known aortic stenosis of moderate or greater severity
- 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
- 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
- Part A_E17. A life expectancy of < 6 months
- 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).
- Part A_E19. WOCBP with a positive pregnancy test
- Part A_E10. Hypersensitivity to danicamtiv or any of the components of the danicamtiv formulation
- 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
- Part A_E21. Currently placed in hospital or facility due to legal or administrative order
- 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.
- 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
- 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])
- Part A_E14. Serum potassium < 3.5 or > 5.5 mEq/L
- 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.
- 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)
- 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.
- Part B_E1. Recent (< 90 days) acute coronary syndrome or angina pectoris
- Part B_E2. Coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft) within prior 90 days
- 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)
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 15 Apr 2020 | 17 |
 Spain | Not Recruiting | 15 Apr 2020 | 4 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Danicamtiv | Test | COATED TABLET | ORAL USE | 150 | 102 | PRD10447415 |
Danicamtiv | Test | COATED TABLET | ORAL USE | 150 | 102 | PRD10447389 |
Danicamtiv | Test | UNCOATED TABLETS | ORAL USE | 150 | 730 | PRD10447365 |
Danicamtiv | Test | COATED TABLET | ORAL USE | 150 | 102 | PRD10447391 |
Danicamtiv | Test | UNCOATED TABLETS | ORAL USE | 150 | 730 | PRD10447355 |
Danicamtiv | Test | COATED TABLET | ORAL USE | 150 | 102 | PRD10447402 |