| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Dilated Cardiomyopathy Due to Either MYH7 or TTN Variants. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Heart Failure with reduced heart function caused by gene mutation. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To establish preliminary safety and tolerability of treatment with danicamtiv in participants with myosin heavy chain 7 (MYH7) dilated cardiomyopathy (DCM), with titin (TTN)-DCM, or DCM by other causalities for Part A. |
|
| E.2.2 | Secondary objectives of the trial |
| To establish preliminary effect, compared with Baseline, of treatment with danicamtiv on cardiac pharmacodynamics (PD), as determined by transthoracic echocardiography (TTE) in participants with MYH7-DCM or TTN-DCM, or DCM by other causalities. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants must complete Part A before opting in and starting Part B.
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.
I2. Men or women 18 to 80 years of age (inclusive) at the Screening visit.
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:
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.
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.
c. DCM is not secondary to long-standing MYH7 or TTN-related HCM or left ventricular noncompaction cardiomyopathy, as determined by the Investigator.
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).
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.
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.
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 the 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 participant should be <12%.
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.
I4. Sinus rhythm or stable atrial or ventricular pacing or persistent atrial fibrillation that is adequately rate-controlled to allow PD assessments by TTE.
I5. If multiple members of a family meet eligibility criteria, a maximum of 3 eligible participants per family may enroll in the study.
I6. Female participants of childbearing potential (Appendix 6) must not be pregnant or lactating and, if sexually active, must use one of the following highly-effective 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 progestogen-only 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).
I7. Male participants must use barrier method of contraception (whether or not the participant had vasectomy)
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. |
|
| E.4 | Principal exclusion criteria |
Part A:
E1. Inadequate echocardiographic acoustic windows.
E2. A participants has a QTcF interval >480 msec, not attributable to ventricular pacing or has prolonged QRS duration ≥ 120 msec, average of triplicate electrocardiograms (ECG).
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.
E4. HFrEF considered to be caused primarily by ischemic heart disease, chronic valvulopathy, or another condition, as determined by the Investigator.
E5. Recent (< 90 days) acute coronary syndrome or angina pectoris.
E6. Coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft) within prior 90 days.
E7. Recent (< 90 days) hospitalization for heart failure, use of intravenous diuretic or chronic intravenous inotropic therapy or other cardiovascular event (eg, cerebrovascular accident).
E8. Known aortic stenosis of moderate or greater severity.
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.
E10. Hypersensitivity to danicamtiv or any of the components of the danicamtiv formulation.
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.
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.
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]).
E14. Serum potassium < 3.5 or > 5.5 mEq/L.
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.
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.
E17. A life expectancy of < 6 months.
Prior/Concurrent Clinical Study Experience:
E18. 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).
Other Exclusions:
E19. WOCBP with a positive pregnancy test.
E20. Is employed by or is a first-degree relative of someone employed by the Sponsor, the investigator, or his/her staff or family.
E21. Currently placed in hospital or facility due to legal or administrative order.
Part B:
E1. Recent (< 90 days) acute coronary syndrome or angina pectoris.
E2. Coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft) within prior 90 days.
E3. Recent (< 90 days) hospitalization for heart failure, use of intravenous diuretic or chronic intravenous inotropic therapy or other cardiovascular event (eg, cerebrovascular accident).
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A:
V1.1A (Screening 1, Day -56 to -1); V1.2A (Screening 2, if needed), V2A (Baseline); TH1A (1-3 days before V3A), V3A (End of Period 1); TH2A (1-3 days before V4A); V4A/EoT (End of Period 2); TH3A (2 days after V4A), V5A/EoS (14d ±7d after V4A).
Part B:
V0B (Rescreening, if needed, -28 days), V1B (Baseline, Day 1), V2B (Week 2), V3B (Week 6), V4B (Week 12), V5B (Week 18), V6B (Week 24), TH1B (Week 30), V7B (Week 36), TH2B (Week 42), V8B (Week 48), TH3B (Week 54), V9B (Week 60), TH4B (Week 66), V10B (Week 72), TH5B (Week 78), TH6B (Week 84), EOT (Week 96), FU/EOS (Week 100). |
|
| E.5.2 | Secondary end point(s) |
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’)
• 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).
• 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)
• 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A:
V1.1A (Screening 1, Day -56 to -1); V1.2A (Screening 2, if needed), V2A (Baseline); TH1A (1-3 days before V3A), V3A (End of Period 1); TH2A (1-3 days before V4A); V4A/EoT (End of Period 2); TH3A (2 days after V4A), V5A/EoS (14d ±7d after V4A).
Part B:
V0B (Rescreening, if needed, -28 days), V1B (Baseline, Day 1), V2B (Week 2), V3B (Week 6), V4B (Week 12), V5B (Week 18), V6B (Week 24), TH1B (Week 30), V7B (Week 36), TH2B (Week 42), V8B (Week 48), TH3B (Week 54), V9B (Week 60), TH4B (Week 66), V10B (Week 72), TH5B (Week 78), TH6B (Week 84), EOT (Week 96), FU/EOS (Week 100). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability; Cardiomyopathy genetic testing. |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| 3-cohort, Baseline-controlled, sequential, 2-period, open-label study with an optional extension. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Spain |
| Germany |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 66 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 66 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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