AZD8601 Study in CABG Patients

Phase 2

Completed

Conditions: Heart Failure

Interventions: Drug: Placebo
Drug: AZD8601

Registration Number: NCT03370887

Lead Sponsor: AstraZeneca

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 11

Inclusion Criteria

For inclusion in the study patients should fulfil the following criteria at Visit 1 and/or 2:

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:

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).
1. Current atrial fibrillation as well as paroxysmal atrial fibrillation.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	8 patients will be randomised to receive placebo injections
Low dose AZD8601 (3 mg)	AZD8601	8 patients will be randomised to receive 3 mg AZD8601
High dose AZD8601 (30 mg)	AZD8601	8 patients will be randomised to receive 30 mg AZD8601

Primary Outcome Measures

Name	Time	Method
Number of Subjects With High Values of Urea	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Creatinine	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Albumin	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Calcium	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Phosphate	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Alkaline Phosphatase	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Alanine Aminotransferase	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Aspartate Aminotransferase	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Bilirubin, Total	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Erythrocytes, Particle Concentration	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Potassium	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Diastolic Blood Pressure (Vital Sign)	From baseline to end of follow up at 6 months
Number of Subjects With Adverse Events	From baseline to end of follow up at 6 months
Pulse Rate (Vital Sign)	From baseline to end of follow up at 6 months
Number of Subjects With an ECG Determined to be Abnormal and Clinically Significant	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Leukocytes, Particle Concentration	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Oxygen Saturation (Vital Sign)	From baseline to end of follow up at 6 months
Systolic Blood Pressure (Vital Sign)	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Erythrocyte, Volume Fraction	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Erythrocytes, Mean Cell Volume	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Hemoglobin	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Neutrophils	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Lymphocytes	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Monocytes	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Eosinophils	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Basophils	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Platelets	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Reticulocytes	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Prothrombin Complex INR	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Activated Partial Thromboplastin Time	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Fibrinogen	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.
Number of Subjects With High Values of Sodium	From baseline to end of follow up at 6 months	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.