Coronary Artery Disease
Conditions
Brief summary
This is a randomized, single-blind, placebo-controlled, parallel-group, multicentre study in patients with CAD. The study will be conducted at approximately 10 centres in 3 countries. Approximately 138 CAD patients will be randomized to AZD5718 or placebo (treatment duration 12 weeks).
Detailed description
This is a randomized, single-blind, placebo-controlled, parallel-group, multicentre study in patients with CAD. The study will be conducted at approximately 10 centres in 3 countries (Denmark, Finland and Sweden). Patients suitable for the study will be identified and screened for eligibility after being hospitalized for Acute Coronary Syndrome (ACS) (Visit 1) comprising ST Elevation Myocardial Infarction (STEMI) or Non-ST Elevation Myocardial Infarction (non-STEMI). At Visit 1, after signing informed consent, study measurements will take place at days 1, 2, 3 and 5 post ACS, where feasible. It is planned that approximately 138 CAD patients will be randomized to ensure at least 66 evaluable patients receiving AZD5718 Dose B or placebo are included with 12 weeks treatment. For supporting dose selection in future studies, a treatment arm with 28 randomized patients receiving AZD5718 Dose A is included in the study. The study was originally designed to be a 4-week study and was amended to be a 12-week study. Therefore, the total number of patients is greater than required for a 12 weeks study (about 100), since some patients will only have 4 weeks of treatment. An evaluable patient is defined as a patient with a valid Coronary Flow Velocity Reserve (CFVR) measurement at Visit 2 and one post baseline visit as judged by the CFVR Core lab. On Day 1 (Visit 2), 7 to 28 days after the ACS event, patients willing to participate in the study will complete the screening procedure and, if eligible, be randomized. Treatment duration will be 12 weeks. During the treatment phase, patients will come in to the clinic for study measurements at 2 weeks (visit 3), 4 weeks (visit 4), 8 weeks (visit 4b) and 12 weeks (visit 4c). A follow-up visit (Visit 5) will be performed at 4 weeks (±4 days) after last dose in order to ensure safety and well-being of the patients
Interventions
DRUGPlacebo
Matching placebo (tablet)
DRUGAZD5718
Oral dose of AZD5718 (tablet)
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Males and females of non-childbearing potential * Age ≥18 to ≤75 * Body Mass Index (BMI) ≥18 to ≤35 kg/m2 * CAD patients, here defined as: ACS 7-28 days prior to study randomization (ACS defined as STEMI, non STEMI event documented by Electrocardiogram (ECG), cardiac enzymes \[troponin\] and angiogram) Provision of signed and dated, written informed consent prior to any study specific procedures
Exclusion criteria
* Uncontrolled Type 1 or Type 2 diabetes defined as haemoglobin A1c (HbA1c) Diabetes * Control and Complications Trial (DCCT)\> 9% or International Federation of Clinical Chemistry (IFCC) \>74.9 mmol/mol * Patients with atrial fibrillation (chronic or current) or history of ventricular tachycardia requiring therapy for termination, or symptomatic sustained ventricular tachycardia or sick sinus syndrome or Atrioventricular blockage degree 2-3 * Prior coronary artery by-pass graft (Coronary artery bypass grafting) to Left Anterior Descending artery (LAD) * Left ventricle ejection fraction \< 30% * Unacceptable level of angina despite maximal medical therapy or unstable angina at entry * Canadian Cardiovascular Society (CCS) ≥ 3 (Visit 1 or Visit 2) * Stroke within the previous 6 months from ACS or ongoing treatment with Persantin or Asasantin * Chronic use of anticoagulants on therapeutic dose (not including thrombosis prophylaxis) during the study * Planned additional cardiac intervention (e.g., Percutaneous coronary intervention (PCI), Coronary artery bypass grafting (CABG) within next 6 months * New York Heart Association (NYHA) class III-IV heart failure or decompensated heart failure at discharge or hospitalization for exacerbation of chronic heart failure within the previous 3 months from ACS * Previously known severe renal disease (Chronic Kidney Disease (CKD) stage 4 or 5) or previously known creatinine clearance calculated by Cockcroft Gault equation \<30 ml/min\*m2 * Known allergy to adenosine and mannitol, or experience of previous adverse effects of adenosine stress testing. * Participation in another interventional clinical study with an investigational pharmaceutical product during the last 3 months also including drug eluting stents.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Creatinine-normalized u-LTE4 at Week 4 | Baseline and 4 weeks | Creatinine-normalized u-LTE4 is calculated as uLTE4/creatinine |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CFVR at Week 12 | Baseline and 12 weeks | CFVR = Coronary Flow Velocity Reserve = LAD(hyperaemic)/LAD(rest) |
| Change From Baseline in CFVR at Week 4 | Baseline and 4 weeks | CFVR = Coronary Flow Velocity Reserve = LAD(hyperaemic)/LAD(rest) |
| Summary of Plasma Concentrations of AZD5718 | 16 weeks | — |
| Change From Baseline in LAD Hypereamic Flow at 4 Weeks | Baseline and 4 weeks | LAD=Left Anterior Descending |
| Change From Baseline in Creatinine-normalized u-LTE4 at Week 12 | Baseline and 12 weeks | Creatinine-normalized u-LTE4 is calculated as uLTE4/creatinine |
| Change From Baseline in LV Longitudinal Early Diastolic Strain Rate at 4 Weeks | Baseline and 4 weeks | LV=Left Ventricular |
| Change From Baseline in LV-GLS at Rest at Week 4 | Baseline and 4 weeks | LV-GLS = Left Ventricular Global Longitudinal Strain |
| Change From Baseline in LV-GCS at Rest at Week 4 | Baseline and 4 weeks | LV-GCS = Left Ventricular Global Circumferential Strain |
| Change From Baseline in LAD Resting Mean Diastolic Flow Velocity at 4 Weeks | Baseline and 4 weeks | LAD=Left Anterior Descending |
| Change From Baseline in LVEF at 4 Weeks | Baseline and 4 weeks | LVEF=Left Ventricular Ejection Fraction |
Countries
Denmark, Finland, Sweden
Participant flow
Recruitment details
The study was conducted in 3 countries at 9 sites; 3 in Denmark, 2 in Finland and 4 in Sweden.
Pre-assignment details
Participants underwent a screening visit between 2 and within 27 days before receiving the first dose of IP.
Participants by arm
| Arm | Count |
|---|---|
| AZD5718 (200 mg) AZD5718 (200 mg) | 52 |
| AZD5718 (50 mg) AZD5718 (50 mg) | 25 |
| Placebo Placebo | 51 |
| Total | 128 |
Baseline characteristics
| Characteristic | AZD5718 (200 mg) | AZD5718 (50 mg) | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 61.9 Years STANDARD_DEVIATION 8.21 | 61.4 Years STANDARD_DEVIATION 8.12 | 61.1 Years STANDARD_DEVIATION 8.51 | 61.5 Years STANDARD_DEVIATION 8.26 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants | 25 Participants | 51 Participants | 127 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 52 Participants | 25 Participants | 50 Participants | 127 Participants |
| Sex: Female, Male Female | 7 Participants | 0 Participants | 10 Participants | 17 Participants |
| Sex: Female, Male Male | 45 Participants | 25 Participants | 41 Participants | 111 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 52 | 0 / 25 | 0 / 51 |
| other Total, other adverse events | 27 / 52 | 12 / 25 | 22 / 51 |
| serious Total, serious adverse events | 4 / 52 | 3 / 25 | 4 / 51 |
Outcome results
Primary
Change From Baseline in Creatinine-normalized u-LTE4 at Week 4
Creatinine-normalized u-LTE4 is calculated as uLTE4/creatinine
Time frame: Baseline and 4 weeks
Population: Number of participants analysed differs from participant flow module due to missing data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD5718 (200 mg) | Change From Baseline in Creatinine-normalized u-LTE4 at Week 4 | 0.04 Ratio | Geometric Coefficient of Variation 92.55 |
| AZD5718 (50 mg) | Change From Baseline in Creatinine-normalized u-LTE4 at Week 4 | 0.09 Ratio | Geometric Coefficient of Variation 84.32 |
| Placebo | Change From Baseline in Creatinine-normalized u-LTE4 at Week 4 | 1.09 Ratio | Geometric Coefficient of Variation 44.38 |
p-value: <0.001Mixed Models Analysis
p-value: 0.001Mixed Models Analysis
Secondary
Change From Baseline in CFVR at Week 12
CFVR = Coronary Flow Velocity Reserve = LAD(hyperaemic)/LAD(rest)
Time frame: Baseline and 12 weeks
Population: Number of participants analysed differs from participant flow module due to missing data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD5718 (200 mg) | Change From Baseline in CFVR at Week 12 | 0.93 Ratio | Geometric Coefficient of Variation 23.64 |
| AZD5718 (50 mg) | Change From Baseline in CFVR at Week 12 | 0.98 Ratio | Geometric Coefficient of Variation 39.53 |
| Placebo | Change From Baseline in CFVR at Week 12 | 1.16 Ratio | Geometric Coefficient of Variation 33.46 |
Secondary
Change From Baseline in CFVR at Week 4
CFVR = Coronary Flow Velocity Reserve = LAD(hyperaemic)/LAD(rest)
Time frame: Baseline and 4 weeks
Population: Number of participants analysed differs from participant flow module due to missing data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD5718 (200 mg) | Change From Baseline in CFVR at Week 4 | 1.03 Ratio | Geometric Coefficient of Variation 28.34 |
| AZD5718 (50 mg) | Change From Baseline in CFVR at Week 4 | 1.15 Ratio | Geometric Coefficient of Variation 31.47 |
| Placebo | Change From Baseline in CFVR at Week 4 | 1.08 Ratio | Geometric Coefficient of Variation 33.16 |
Secondary
Change From Baseline in Creatinine-normalized u-LTE4 at Week 12
Creatinine-normalized u-LTE4 is calculated as uLTE4/creatinine
Time frame: Baseline and 12 weeks
Population: Number of participants analysed differs from participant flow module due to missing data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD5718 (200 mg) | Change From Baseline in Creatinine-normalized u-LTE4 at Week 12 | 0.04 Ratio | Geometric Coefficient of Variation 92.55 |
| AZD5718 (50 mg) | Change From Baseline in Creatinine-normalized u-LTE4 at Week 12 | 0.09 Ratio | Geometric Coefficient of Variation 84.32 |
| Placebo | Change From Baseline in Creatinine-normalized u-LTE4 at Week 12 | 1.09 Ratio | Geometric Coefficient of Variation 44.38 |
p-value: <0.001Mixed Models Analysis
p-value: 0.001Mixed Models Analysis
Secondary
Change From Baseline in LAD Hypereamic Flow at 4 Weeks
LAD=Left Anterior Descending
Time frame: Baseline and 4 weeks
Population: Number of participants analysed differs from participant flow module due to missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD5718 (200 mg) | Change From Baseline in LAD Hypereamic Flow at 4 Weeks | 0.02 m/sec | Standard Deviation 0.16 |
| AZD5718 (50 mg) | Change From Baseline in LAD Hypereamic Flow at 4 Weeks | 0.04 m/sec | Standard Deviation 0.16 |
| Placebo | Change From Baseline in LAD Hypereamic Flow at 4 Weeks | 0.03 m/sec | Standard Deviation 0.17 |
Secondary
Change From Baseline in LAD Resting Mean Diastolic Flow Velocity at 4 Weeks
LAD=Left Anterior Descending
Time frame: Baseline and 4 weeks
Population: Number of participants analysed differs from participant flow module due to missing data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD5718 (200 mg) | Change From Baseline in LAD Resting Mean Diastolic Flow Velocity at 4 Weeks | 1.01 m/sec | Geometric Coefficient of Variation 23.31 |
| AZD5718 (50 mg) | Change From Baseline in LAD Resting Mean Diastolic Flow Velocity at 4 Weeks | 0.92 m/sec | Geometric Coefficient of Variation 23.68 |
| Placebo | Change From Baseline in LAD Resting Mean Diastolic Flow Velocity at 4 Weeks | 0.99 m/sec | Geometric Coefficient of Variation 20.14 |
Secondary
Change From Baseline in LVEF at 4 Weeks
LVEF=Left Ventricular Ejection Fraction
Time frame: Baseline and 4 weeks
Population: Number of participants analysed differs from participant flow module due to missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD5718 (200 mg) | Change From Baseline in LVEF at 4 Weeks | -0.23 percent LVEF | Standard Deviation 5.3 |
| AZD5718 (50 mg) | Change From Baseline in LVEF at 4 Weeks | 2.70 percent LVEF | Standard Deviation 6.39 |
| Placebo | Change From Baseline in LVEF at 4 Weeks | 0.48 percent LVEF | Standard Deviation 5 |
Secondary
Change From Baseline in LV-GCS at Rest at Week 4
LV-GCS = Left Ventricular Global Circumferential Strain
Time frame: Baseline and 4 weeks
Population: Number of participants analysed differs from participant flow module due to missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD5718 (200 mg) | Change From Baseline in LV-GCS at Rest at Week 4 | 0.34 Percent | Standard Deviation 7.24 |
| AZD5718 (50 mg) | Change From Baseline in LV-GCS at Rest at Week 4 | 1.71 Percent | Standard Deviation 5.4 |
| Placebo | Change From Baseline in LV-GCS at Rest at Week 4 | -1.88 Percent | Standard Deviation 6.78 |
Secondary
Change From Baseline in LV-GLS at Rest at Week 4
LV-GLS = Left Ventricular Global Longitudinal Strain
Time frame: Baseline and 4 weeks
Population: Number of participants analysed differs from participant flow module due to missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD5718 (200 mg) | Change From Baseline in LV-GLS at Rest at Week 4 | -0.41 Percent LV-GLS | Standard Deviation 3 |
| AZD5718 (50 mg) | Change From Baseline in LV-GLS at Rest at Week 4 | 0.34 Percent LV-GLS | Standard Deviation 2.47 |
| Placebo | Change From Baseline in LV-GLS at Rest at Week 4 | -0.63 Percent LV-GLS | Standard Deviation 2.61 |
Secondary
Change From Baseline in LV Longitudinal Early Diastolic Strain Rate at 4 Weeks
LV=Left Ventricular
Time frame: Baseline and 4 weeks
Population: Number of participants analysed differs from participant flow module due to missing data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD5718 (200 mg) | Change From Baseline in LV Longitudinal Early Diastolic Strain Rate at 4 Weeks | 1.02 1/s | Geometric Coefficient of Variation 30.61 |
| AZD5718 (50 mg) | Change From Baseline in LV Longitudinal Early Diastolic Strain Rate at 4 Weeks | 0.98 1/s | Geometric Coefficient of Variation 33.55 |
| Placebo | Change From Baseline in LV Longitudinal Early Diastolic Strain Rate at 4 Weeks | 1.03 1/s | Geometric Coefficient of Variation 30.45 |
Secondary
Summary of Plasma Concentrations of AZD5718
Time frame: 16 weeks
Population: Number of participants analysed differs from participant flow module due to missing data
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AZD5718 (200 mg) | Summary of Plasma Concentrations of AZD5718 | Baseline: 1-8 Hours Post-Dose | 611.88 nmol/L | Geometric Coefficient of Variation 234.5 |
| AZD5718 (200 mg) | Summary of Plasma Concentrations of AZD5718 | 2 weeks (Visit 3): 20-28 Hours Post-Dose | 59.36 nmol/L | Geometric Coefficient of Variation 90.97 |
| AZD5718 (200 mg) | Summary of Plasma Concentrations of AZD5718 | 4 weeks (Visit 4): Pre-Dose | 48.00 nmol/L | Geometric Coefficient of Variation 68.17 |
| AZD5718 (200 mg) | Summary of Plasma Concentrations of AZD5718 | 4 weeks (Visit 4): 0-2 Hours Post-Dose | 339.28 nmol/L | Geometric Coefficient of Variation 243.04 |
| AZD5718 (200 mg) | Summary of Plasma Concentrations of AZD5718 | 4 weeks (Visit 4): 2-4 Hours Post-Dose | 919.22 nmol/L | Geometric Coefficient of Variation 51.26 |
| AZD5718 (200 mg) | Summary of Plasma Concentrations of AZD5718 | 4 weeks (Visit 4): 4-8 Hours Post-Dose | 649.09 nmol/L | Geometric Coefficient of Variation 49.89 |
| AZD5718 (200 mg) | Summary of Plasma Concentrations of AZD5718 | 12 weeks (Visit 4c): Pre-Dose | 65.39 nmol/L | Geometric Coefficient of Variation 91.52 |
| AZD5718 (200 mg) | Summary of Plasma Concentrations of AZD5718 | 16 weeks (Visit 5) - FUP 1 month | 0.51 nmol/L | Geometric Coefficient of Variation 16.39 |
| AZD5718 (50 mg) | Summary of Plasma Concentrations of AZD5718 | 16 weeks (Visit 5) - FUP 1 month | 0.50 nmol/L | Geometric Coefficient of Variation 0 |
| AZD5718 (50 mg) | Summary of Plasma Concentrations of AZD5718 | Baseline: 1-8 Hours Post-Dose | 47.88 nmol/L | Geometric Coefficient of Variation 497.86 |
| AZD5718 (50 mg) | Summary of Plasma Concentrations of AZD5718 | 4 weeks (Visit 4): 2-4 Hours Post-Dose | 148.64 nmol/L | Geometric Coefficient of Variation 71.86 |
| AZD5718 (50 mg) | Summary of Plasma Concentrations of AZD5718 | 2 weeks (Visit 3): 20-28 Hours Post-Dose | 16.57 nmol/L | Geometric Coefficient of Variation 127.8 |
| AZD5718 (50 mg) | Summary of Plasma Concentrations of AZD5718 | 12 weeks (Visit 4c): Pre-Dose | 13.97 nmol/L | Geometric Coefficient of Variation 88.12 |
| AZD5718 (50 mg) | Summary of Plasma Concentrations of AZD5718 | 4 weeks (Visit 4): Pre-Dose | 11.01 nmol/L | Geometric Coefficient of Variation 60.7 |
| AZD5718 (50 mg) | Summary of Plasma Concentrations of AZD5718 | 4 weeks (Visit 4): 4-8 Hours Post-Dose | 105.40 nmol/L | Geometric Coefficient of Variation 52.16 |
| AZD5718 (50 mg) | Summary of Plasma Concentrations of AZD5718 | 4 weeks (Visit 4): 0-2 Hours Post-Dose | 38.68 nmol/L | Geometric Coefficient of Variation 159.56 |