AZD8601 Study in CABG Patients

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, sequential design, multicentre study in patients with moderately impaired systolic function undergoing CABG surgery. Twenty four (24) patients scheduled for elective bypass surgery will be randomized (up to approximately 33 patients if replacements are needed). The objective is to investigate safety and tolerability of AZD8601 following epicardial injection in patients undergoing Coronary Artery Bypass Grafting (CABG) surgery with moderately impaired systolic function. At Visit 3 patients will receive either AZD8601 or placebo as epicardial injections and will then be followed up at 14 days (telephone visit) and 1, 3 and 6 months (on-site) post-surgery.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multi-centre, Sequential Design, Phase IIa Study to Evaluate Safety and Tolerability of Epicardial Injections of AZD8601 During Coronary Artery Bypass Grafting Surgery

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: AZD8601
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For inclusion in the study patients should fulfil the following criteria at Visit 1 and/or 2: 1. Provision of signed and dated informed consent prior to any study specific procedures Males and females: Males must be surgically sterile or using an acceptable method of contraception Females must be of non-childbearing potential confirmed at screening by fulfilling one of the following criteria a) postmenopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the postmenopausal range, b) documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 3. Age >18 years 4. Indication for elective CABG surgery enrolled at least 15 days before the planned surgery 5. Moderately reduced global LVEF at rest (30% ≤ LVEF ≤ 50%) from medical records 6. If patient is on statin, ACE inhibitor/ARB, and/or beta-blocker, the dose should be stable at least 2 weeks prior to Visit 1 7. Patients who are blood donors should not donate blood during the study and for 3 months following their last dose of AZD8601. Exclusion Criteria: Patients should not enter the study if any of the following exclusion criteria are fulfilled: 1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) 2. Previous randomisation in the present study 3. Participation in another clinical study with an investigational product during the last 3 months 4. BMI > 35 kg/m2 OR poor image window for echocardiography 5. Need for CABG emergency operation. (Emergency operation is defined as significant symptom status worsening in CAD, such as crescendo angina, unstable angina or ACS requiring rescheduling the revascularization. CAD should be stable at least 3 months prior to Visit 3.) 6. History of ventricular arrhythmia (≥ Lown III) without Implantable Cardiac Defibrillator (ICD) History of any clinically significant disease or disorder which, in the opinion of the PI, may either put the patient at risk because of participation in the study, or influence the results or the patient's ability to participate in the study 8. Severe co-morbidities that can interfere with the execution of the study, interpretation of study results or affect the safety of the patient, in judgement of the investigator 9. eGFR ≤ 30 mL/min (derived from creatinine clearance, calculated by local lab) 10. For CFVR (Visit 1) and sMBF (Visit 2) measurement: Known severe adverse reactions to adenosine Known elevated intracranial pressure AV block ≥ second degree and/or sick sinus syndrome in patient without pacemaker Heart rate < 40 bpm (ECG verified) Systolic blood pressure < 90 mmHg Asthma or COPD with strong reactive component in judgement of investigator Treatment with dipyridamole (e.g. Persantin or Asasantin), theophyllamine or fluvoxamine that cannot be paused 11. Inability to comply with the protocol 12. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity to drugs with a similar chemical structure or class as study drugs 13. Patients unable to give their consent or communicate reliably with the investigator or vulnerable patients e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order 14. Positive hepatitis C antibody hepatitis B virus surface antigen or hepatitis B virus core antibody or human immunodeficiency virus, at Visit 1 15. Known history of drug or alcohol abuse 16. Any concomitant medications that are known to be associated with Torsades de Pointes 17. History of QT prolongation associated with other medications that required discontinuation of that medication 18. Congenital long QT syndrome 19. History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3). 20. Current atrial fibrillation as well as paroxysmal atrial fibrillation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose AZD8601 (3 mg)<br>8 patients will be randomised to receive 3 mg AZD8601 | Drug: AZD8601<br>* AZD8601 solution for injection, 0,5 mg/mL and 5 mg/mL will be given as 30 injections of 0.1 mg (3 mg per patient), or 1 mg (30 mg per patient) respectively on a single occasion<br>|
| Experimental: High dose AZD8601 (30 mg)<br>8 patients will be randomised to receive 30 mg AZD8601 | Drug: AZD8601<br>* AZD8601 solution for injection, 0,5 mg/mL and 5 mg/mL will be given as 30 injections of 0.1 mg (3 mg per patient), or 1 mg (30 mg per patient) respectively on a single occasion<br>|
| Placebo Comparator: Placebo<br>8 patients will be randomised to receive placebo injections | Drug: Placebo<br>* Placebo for AZ8601 injection for solution will be given as 30 injections per patient on a single occasion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious Adverse Events | To assess safety and tolerability of AZD8601 given as epicardial injections | Up to 9 months; from signing of ICF at Visit 1, maximum 90 days before investigational product (IP) administration, until 6 months after receiving IP. | 
| Adverse event | To assess safety and tolerability of AZD8601 given as epicardial injections | 6 months, from receiving IP at Visit 3 until 6 months after receiving IP. | 
| Electrocardiogram (ECG, number of patients with ECG results exceeding ICH reference ranges) | To assess safety and tolerability of AZD8601 given as epicardial injections | Up to 9 months; from Visit 1, maximum 90 days before investigational product (IP) administration, until 6 months after receiving IP. | 
| Left ventricular ejection fraction (LVEF) change from baseline (%) | To assess safety and tolerability of AZD8601 given as epicardial injections | Up to 9 months; from Visit 1, maximum 90 days before investigational product (IP) administration, until 6 months after receiving IP. | 
| Changes in physical examination (number of abnormal findings in physical examination) | To assess safety and tolerability of AZD8601 given as epicardial injections | Up to 9 months; from Visit 1, maximum 90 days before investigational product (IP) administration, until 6 months after receiving IP. | 
| Changes in vital signs - blood pressure (mmHg) | To assess safety and tolerability of AZD8601 given as epicardial injections | Up to 9 months; from Visit 1, maximum 90 days before investigational product (IP) administration, until 6 months after receiving IP. | 
| Changes in vital signs - pulse (bpm) | To assess safety and tolerability of AZD8601 given as epicardial injections | Up to 9 months; from Visit 1, maximum 90 days before investigational product (IP) administration, until 6 months after receiving IP. | 
| Changes in laboratory values - hematology | To assess safety and tolerability of AZD8601 given as epicardial injections | Up to 9 months; from Visit 1, maximum 90 days before investigational product (IP) administration, until 6 months after receiving IP. | 
| Changes in laboratory values - clinical chemistry | To assess safety and tolerability of AZD8601 given as epicardial injections | Up to 9 months; from Visit 1, maximum 90 days before investigational product (IP) administration, until 6 months after receiving IP. | 
| Changes in laboratory values - urinalysis | To assess safety and tolerability of AZD8601 given as epicardial injections | Up to 9 months; from Visit 1, maximum 90 days before investigational product (IP) administration, until 6 months after receiving IP. |