Heart Failure, Left Sided, Myocardial Infarction, Acute
Conditions
Brief summary
This is a Phase 2, multicenter, randomized, parallel, 3-arm, placebo-controlled study to assess efficacy and safety of CDR132L in patients with reduced Left Ventricular Ejection Fraction (LVEF) (≤ 45%) after myocardial infarction (MI). This study consists of a screening period (to occur at least 3 days after MI diagnosis), a 6-month double-blind period, and a 6-month extension period with the End of Study (EOS) Visit at Day 360/Month 12. Two dosages of CDR132L will be tested against placebo on their effects on patients, who just had a heart attack in addition to standard care. The aim of the study is to show that CDR132L is safe and effective to improve heart failure in such patients.
Interventions
DRUGCDR132L
CDR132L is a synthetic antisense oligonucleotide (ASO) and a selective inhibitor of microRNA-132-3p (miR-132). miR-132 in cardiomyocytes is a central switch affecting the expression of genes that are crucially involved in maladaptive cardiac remodeling, transformation, and pathological cardiac growth (hypertrophy), contributing to adverse cardiac remodeling and heart failure (HF).1-5 Aberrant expression of miR-132 in cardiac cells is causally associated with cardiac remodeling and HF progression.
DRUGPlacebo to CDR132L
Placebo to CDR132L
Sponsors
Cardior Pharmaceuticals GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Pharmacy staff is unblinded. They will hand-over prepared investigational medicinal product (IMP) in light-protected syringe.
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: 1. Male or female patients, aged ≥ 30 to ≤ 80 years at the date of signing informed consent which is defined as the beginning of the Screening Period. 2. Spontaneous acute mycardial infarction (AMI) (type I) based on the universal MI definition with randomization to occur no later than 14 days after index event diagnosis. 3. Patient with a LVEF ≤ 45% as measured by ECHO after MI diagnosis (STEMI or NSTEMI). 4. Patient with previous MI events in history can be included. 5. Patient with body weight of ≤ 120 kg. 6. N-terminal pro B-type natriuretic peptide level ≥ 125 pg/ml and \< 8000 pg/ml at screening. 7. Patient with STEMI/NSTEMI who underwent percutaneous coronary intervention for this event.
Exclusion criteria
1. A woman of childbearing potential (WOCBP). 2. Patient with HF of non-ischemic origin; e.g., myocarditis, alcoholic cardiomyopathy. 3. Patient with New York Heart Association (NYHA) class IV at screening or randomization. 4. Patient has any planned cardiac intervention (angiogram without angioplasty is acceptable) or any other planned surgery after the Screening Period. 5. Patient has severe valvular heart disease. 6. Patient has systolic BP \< 90 mmHg or \> 180 mmHg, diastolic BP \< 50 mmHg or \> 110 mmHg, and/or heart rate \< 50 or \> 100 beats/minute at screening or randomization. 7. Patient with an estimated glomerular filtration rate \< 30 mL/min/1.73 m2 or on dialysis. 8. Patient with hepatic insufficiency classified as Child-Pugh B or C. 9. Patient has medical history of disease(s) affecting the blood-brain-barrier, e.g., stroke within 6 months or multiple sclerosis. 10. Patient has medical history of bleeding disorders or has thrombocytopenia (platelets \< 100,000/μL). 11. Patient has poorly controlled diabetes as determined by the Investigator. 12. Patient has a history or presence of any of the following cardiac conditions: known structural cardiac abnormalities beyond HF, family history of long QT syndrome, cardiac syncope, or recurrent, idiopathic syncope. 13. Any clinically significant abnormalities, at the discretion of the Investigator, in rhythm, conduction, or morphology of resting ECG that pose an additional safety risk to patients. 14. Patient with active "severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)" infection confirmed as per the local testing guidelines at screening. 15. Patient is not to be enrolled into the study if they received any prohibited therapy within 3 months of screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in LVESVI (Left Ventricular End-systolic Volume Index) at Month 6 | Baseline (Day 1), Month 6 | Percent change from baseline in LVESVI at Month 6 is presented. LVESVI is considered one of the standard echocardiography (ECHO) markers for assessing risks in ischemic heart failure (HF). The ECHO was performed to assess LVESVI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Emergent Adverse Events (TEAEs) | Up to 12 months | Number of TEAEs were presented. TEAEs were defined as AEs that first occurred or worsened in severity after the first administration of study treatment and prior to 30 days after the last administration of study treatment. |
| Absolute Change From Baseline in NT-proBNP at Month 3 | Baseline (Day 1), Month 3 | Absolute change from baseline in NT-proBNP at month 3 is presented. |
| Absolute Change From Baseline in NT-proBNP at Month 6 | Baseline (Day 1), Month 6 | Absolute change from baseline in NT-proBNP at month 6 is presented. |
| Absolute Change From Baseline in NT-proBNP at Month 12 | Baseline (Day 1), Month 12 | Absolute change from baseline in NT-proBNP at month 12 is presented. |
| Relative Change From Baseline in NT-proBNP at Month 1 | Baseline (Day 1), Month 1 | Relative change from baseline in NT-proBNP at month 1 is presented. |
| Relative Change From Baseline in NT-proBNP at Month 2 | Baseline (Day 1), Month 2 | Relative change from baseline in NT-proBNP at month 2 is presented. |
| Relative Change From Baseline in NT-proBNP at Month 3 | Baseline (Day 1), Month 3 | Relative change from baseline in NT-proBNP at month 3 is presented. |
| Relative Change From Baseline in NT-proBNP at Month 6 | Baseline (Day 1), Month 6 | Relative change from baseline in NT-proBNP at month 6 is presented. |
| Relative Change From Baseline in NT-proBNP at Month 12 | Baseline (Day 1), Month 12 | Relative change from baseline in NT-proBNP at month 12 is presented. |
| Absolute Change From Baseline in Mean KCCQ Score (Overall Summary Score) at Month 6 | Baseline (Day 1), Month 6 | Absolute change from baseline in mean Kansas City Cardiomyopathy Questionnaire (KCCQ) score (overall summary score) at month 6 is presented. The KCCQ is a 23-item, self-administered ques-tionnaire developed to independently measure the participant's perception of their health status. Scores range from 0 to 100, with 0 as lowest score and 100 as the highest score. Higher scores indi-cate better health status, fewer symptoms, and greater disease-specific health-related quality of life. The calculation is following the KCCQ scoring manual that states: "Overall Summary Score is defined as mean of the following available summary scores: Physical Limitation Score, Total Symptom Score, Quality of Life Score and Social Limitation Score". Because the manual states that the Overall Sum-mary Score should be calculated on available scores, then if physical limitation score is missing, but other sub scores are available the Overall Summary Score will be calculated anyhow based on other sub scores. |
| Absolute Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) at Month 1 | Baseline (Day 1), Month 1 | Absolute change from baseline in NT-proBNP at month 1 is presented. |
| Absolute Change From Baseline in NT-proBNP at Month 2 | Baseline (Day 1), Month 2 | Absolute change from baseline in NT-proBNP at month 2 is presented. |
| Number of Treatment Emergent Serious Adverse Events (TESAEs) | Up to 12 months | Number of TESAEs are presented. TEAEs were defined as AEs that first occurred or worsened in severity after the first administration of study treatment and prior to 30 days after the last administration of study treatment. A SAE is defined as any untoward medical occurrence that, at any dose: a) results in death, b) is life-threatening, c) requires inpatient hospitalization or prolongation of existing hospitalization, d) results in persistent disability/incapacity, e) is a congenital anomaly/birth defect, f) other situations where medical or scientific judgement should be excercised. |
| Number of Participants With Abnormalities in Clinically Relevant Laboratory Assessments | At month 6 | Number of participants with abnormalities in clinically relevant laboratory assessments up to month 6 is presented. Laboratory investigation included hematology, chemistry, coagulation and urinalysis parameters. Clinical relevance was decided by the investigator. |
| Number of Participants With Clinically Relevant Laboratory Abnormalities in Vital Signs Parameters | At month 12 | Number of participants with clinically relevant laboratory abnormalities in vital signs parameters on month 12 is presented. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Clinical relevance was decided by the investigator. |
| Number of Participants With Clinically Relevant Laboratory Abnormalities in ECG Parameters | At month 12 | Number of participants with clinically relevant laboratory abnormalities in ECG parameters at month 12 is presented. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Pulse Rate, QRS, QT interval. Clinical relevance was decided by the investigator. |
| Absolute Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Month 3 | Baseline (Day 1), Month 3 | Absolute change from baseline in LVEF at month 3 is presented. LVEF is an established method for evaluation of left ventricular systolic function. A 2D echocardiography (ECHO) was performed in the ECHO central laboratory by trained personnel to assess LVEF. Contrast ECHO was available as an option to enhance image quality. |
| Absolute Change From Baseline in LVEF at Month 6 | Baseline (Day 1), Month 6 | Absolute change from baseline in LVEF at month 6 is reported. LVEF is an established method for evaluation of left ventricular systolic function. A 2D ECHO was performed in the ECHO central laboratory by trained personnel to assess LVEF. Contrast ECHO was available as an option to enhance image quality. |
| Absolute Change From Baseline in LVEF at Month 12 | Baseline (Day 1), Month 12 | Absolute change from baseline in LVEF at month 12 is reported. LVEF is an established method for evaluation of left ventricular systolic function. A 2D ECHO was performed in the ECHO central laboratory by trained personnel to assess LVEF. Contrast ECHO was available as an option to enhance image quality. |
| Relative Change From Baseline in LVEF at Month 3 | Baseline (Day 1), Month 3 | Relative change from baseline in LVEF at month 3 is presented. LVEF is an established method for evaluation of left ventricular systolic function. A 2D ECHO was performed in the ECHO central laboratory by trained personnel to assess LVEF. Contrast ECHO was available as an option to enhance image quality. |
| Relative Change From Baseline in LVEF at Month 6 | Baseline (Day 1), Month 6 | Relative change from baseline in LVEF at month 6 is presented. LVEF is an established method for evaluation of left ventricular systolic function. A 2D ECHO was performed in the ECHO central laboratory by trained personnel to assess LVEF. Contrast ECHO was available as an option to enhance image quality. |
| Relative Change From Baseline in LVEF at Month 12 | Baseline (Day 1), Month 12 | Relative change from baseline in LVEF at month 12 is presented. LVEF is an established method for evaluation of left ventricular systolic function. A 2D ECHO was performed in the ECHO central laboratory by trained personnel to assess LVEF. Contrast ECHO was available as an option to enhance image quality. |
| Absolute Change From Baseline in LVESVI at Month 3 | Baseline (Day 1), Month 3 | Absolute change from baseline in LVESVI at month 3 is presented. LVESVI is considered one of the standard ECHO markers for assessing risks in ischemic HF. The ECHO was performed to assess LVESVI. |
| Absolute Change From Baseline in LVESVI at Month 6 | Baseline (Day 1), Month 6 | Absolute change from baseline in LVESVI at month 6 is presented. LVESVI is considered one of the standard ECHO markers for assessing risks in ischemic HF. The ECHO was performed to assess LVESVI. |
| Absolute Change From Baseline in LVESVI at Month 12 | Baseline (Day 1), Month 12 | Absolute change from baseline in LVESVI at month 12 is presented. LVESVI is considered one of the standard ECHO markers for assessing risks in ischemic HF. The ECHO was performed to assess LVESVI. |
| Relative Change From Baseline in LVESVI at Month 3 | Baseline (Day 1), Month 3 | Relative change from baseline in LVESVI at month 3 is presented. LVESVI is considered one of the standard ECHO markers for assessing risks in ischemic HF. The ECHO was performed to assess LVESVI. |
| Relative Change From Baseline in LVESVI at Month 12 | Baseline (Day 1), Month 12 | Relative change from baseline in LVESVI at month 12 is presented. LVESVI is considered one of the standard ECHO markers for assessing risks in ischemic HF. The ECHO was performed to assess LVESVI. |
| Absolute Change From Baseline in Troponin T at Month 3 | Baseline (Day 1), Month 3 | Absolute change from baseline in troponin T at month 3 is presented. Troponin T levels were measured by high-sensitivity cardiac troponin (hs-cTn) assays. |
| Absolute Change From Baseline in Troponin T at Month 6 | Baseline (Day 1), Month 6 | Absolute change from baseline in troponin T at month 6 is presented. Troponin T levels were measured by hs-cTn assays. |
| Absolute Change From Baseline in Troponin T at Month 12 | Baseline (Day 1), Month 12 | Absolute change from baseline in troponin T at month 12 is presented. Troponin T levels were measured by hs-cTn assays. |
| Relative Change From Baseline in Troponin T at Month 3 | Baseline (Day 1), Month 3 | Relative change from baseline in troponin T at month 3 is presented. Troponin T levels were measured by hs-cTn assays. |
| Relative Change From Baseline in Troponin T at Month 6 | Baseline (Day 1), Month 6 | Relative change from baseline in troponin T at month 6 is presented. Troponin T levels were measured by hs-cTn assays. |
| Relative Change From Baseline in Troponin T at Month 12 | Baseline (Day 1), Month 12 | Relative change from baseline in troponin T at month 12 is presented. Troponin T levels were measured by hs-cTn assays. |
| Absolute Change From Baseline in Mean KCCQ Score (Overall Summary Score) at Month 12 | Baseline (Day 1), Month 12 | Absolute change from baseline in mean KCCQ score (overall summary score) at month 12 is presented. The KCCQ is a 23-item, self-administered ques-tionnaire developed to independently measure the participant's perception of their health status. Scores range from 0 to 100, with 0 as lowest score and 100 as the highest score. Higher scores indi-cate better health status, fewer symptoms, and greater disease-specific health-related quality of life. The calculation is following the KCCQ scoring manual that states: "Overall Summary Score is defined as mean of the following available summary scores: Physical Limitation Score, Total Symptom Score, Quality of Life Score and Social Limitation Score". Because the manual states that the Overall Summary Score should be calculated on available scores, then if physical limitation score is missing, but other sub scores are available the Overall Summary Score will be calculated anyhow based on other sub scores. |
| Absolute Change From Baseline in KCCQ Subdomain Score (Symptom Burden) at Month 6 | Baseline (Day 1), Month 6 | Absolute change from baseline in KCCQ subdomain score (symptom burden) at month 6 is presented. The KCCQ is a 23-item, self-administered questionnaire developed to independently measure the participant's perception of their health status, which includes HF symptoms, impact on physical and social function, and how their HF impacts their quality of life within a 2-week recall period. The 7 domains under KCCQ include: Physical Limitation (6 items), Symptom Stability (1 item), Symptom Frequency (4 items), Symptom Burden (3 items), Self-Efficacy (2 items), Quality of Life (3 items), Social Limitations (4 items). Symptom burden: scores on a scale of 0 to 100, higher scores means better outcome. |
| Absolute Change From Baseline in KCCQ Subdomain Score (Symptom Burden) at Month 12 | Baseline (Day 1), Month 12 | Absolute change from baseline in KCCQ subdomain score (symptom burden) at month 12 is presented. The KCCQ is a 23-item, self-administered questionnaire developed to independently measure the participant's perception of their health status, which includes HF symptoms, impact on physical and social function, and how their HF impacts their quality of life within a 2-week recall period. The 7 domains under KCCQ include: Physical Limitation (6 items), Symptom Stability (1 item), Symptom Frequency (4 items), Symptom Burden (3 items), Self-Efficacy (2 items), Quality of Life (3 items), Social Limitations (4 items). Symptom burden: scores on a scale of 0 to 100, higher scores means better outcome. |
| Absolute Change From Baseline in KCCQ Subdomain Score (Physical Limitation) at Month 6 | Baseline (Day 1), Month 6 | Absolute change from baseline in KCCQ subdomain score (physical limitation) at month 6 is presented. The KCCQ is a 23-item, self-administered questionnaire developed to independently measure the participant's perception of their health status, which includes HF symptoms, impact on physical and social function, and how their HF impacts their quality of life within a 2-week recall period. The 7 domains under KCCQ include: Physical Limitation (6 items), Symptom Stability (1 item), Symptom Frequency (4 items), Symptom Burden (3 items), Self-Efficacy (2 items), Quality of Life (3 items), Social Limitations (4 items). Physical limitation: scores on a scale of 0 to 100, higher scores means better outcome. |
| Absolute Change From Baseline in KCCQ Subdomain Score (Physical Limitation) at Month 12 | Baseline (Day 1), Month 12 | Absolute change from baseline in KCCQ subdomain score (physical limitation) at month 12 is presented. The KCCQ is a 23-item, self-administered questionnaire developed to independently measure the participant's perception of their health status, which includes HF symptoms, impact on physical and social function, and how their HF impacts their quality of life within a 2-week recall period. The 7 domains under KCCQ include: Physical Limitation (6 items), Symptom Stability (1 item), Symptom Frequency (4 items), Symptom Burden (3 items), Self-Efficacy (2 items), Quality of Life (3 items), Social Limitations (4 items). Physical limitation: scores on a scale of 0 to 100, higher scores means better outcome. |
| Absolute Change From Baseline in KCCQ Subdomain Score (Quality of Life) at Month 6 | Baseline (Day 1), Month 6 | Absolute change from baseline in KCCQ subdomain score (quality of life) at month 6 is presented. The KCCQ is a 23-item, self-administered questionnaire developed to independently measure the participant's perception of their health status, which includes HF symptoms, impact on physical and social function, and how their HF impacts their quality of life within a 2-week recall period. The 7 domains under KCCQ include: Physical Limitation (6 items), Symptom Stability (1 item), Symptom Frequency (4 items), Symptom Burden (3 items), Self-Efficacy (2 items), Quality of Life (3 items), Social Limitations (4 items). Quality of life: scores on a scale of 0 to 100, higher scores means better outcome. |
| Absolute Change From Baseline in KCCQ Subdomain Score (Quality of Life) at Month 12 | Baseline (Day 1), Month 12 | Absolute change from baseline in KCCQ subdomain score (quality of life) at month 12 is presented. The KCCQ is a 23-item, self-administered questionnaire developed to independently measure the participant's perception of their health status, which includes HF symptoms, impact on physical and social function, and how their HF impacts their quality of life within a 2-week recall period. The 7 domains under KCCQ include: Physical Limitation (6 items), Symptom Stability (1 item), Symptom Frequency (4 items), Symptom Burden (3 items), Self-Efficacy (2 items), Quality of Life (3 items), Social Limitations (4 items). Quality of life: scores on a scale of 0 to 100, higher scores means better outcome. |
Countries
Czechia, Germany, Greece, Hungary, Netherlands, Poland, Spain, United Kingdom
Contacts
PRINCIPAL_INVESTIGATORJohann Bauersachs, Prof. Dr.
Hannover Medical School
Participant flow
Recruitment details
The trial was conducted in 8 countries (Netherlands, Spain, Germany, Czech Republic, Poland, United Kingdom, Greece, and Hungary).
Pre-assignment details
The study consisted of a 6-month double blind period and a 6-month prolonged follow-up period with the end of study visit at day 360/month 12.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 60.9 Years STANDARD_DEVIATION 10.18 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 269 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 98 | 0 / 98 | 1 / 98 |
| other Total, other adverse events | 3 / 91 | 5 / 94 | 4 / 95 |
| serious Total, serious adverse events | 9 / 91 | 9 / 94 | 8 / 95 |
Outcome results
None listed