Clinical trial NCT03370887: AZD8601 Study in CABG Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2017-12-13
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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:

1. Males must be surgically sterile or using an acceptable method of contraception
2. 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.

Primary outcomes:
measure: Number of Subjects With Adverse Events
timeFrame: From baseline to end of follow up at 6 months
measure: Pulse Rate (Vital Sign)
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With an ECG Determined to be Abnormal and Clinically Significant
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Leukocytes, Particle Concentration
timeFrame: From baseline to end of follow up at 6 months
measure: Oxygen Saturation (Vital Sign)
timeFrame: From baseline to end of follow up at 6 months
measure: Systolic Blood Pressure (Vital Sign)
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Erythrocytes, Particle Concentration
timeFrame: From baseline to end of follow up at 6 months
measure: Diastolic Blood Pressure (Vital Sign)
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Erythrocyte, Volume Fraction
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Erythrocytes, Mean Cell Volume
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Hemoglobin
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Neutrophils
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Lymphocytes
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Monocytes
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Eosinophils
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Basophils
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Platelets
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Reticulocytes
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Prothrombin Complex INR
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Activated Partial Thromboplastin Time
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Fibrinogen
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Sodium
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Potassium
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Urea
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Creatinine
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Albumin
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Calcium
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Phosphate
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Alkaline Phosphatase
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Alanine Aminotransferase
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Aspartate Aminotransferase
timeFrame: From baseline to end of follow up at 6 months
measure: Number of Subjects With High Values of Bilirubin, Total
timeFrame: From baseline to end of follow up at 6 months
Secondary outcomes:
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Research Site
state: Connecticut
city: Kuopio
country: Finland
facility: Research Site
city: Tampere
country: Finland
facility: Research Site
city: Turku
country: Finland
facility: Research Site
city: München
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Groningen
country: Netherlands
facility: Research Site
city: Göteborg
country: Sweden
facility: Research Site
city: Uppsala
country: Sweden
facility: Research Site
Study officials:
affiliation: Heart Center, Turku University, Finland
name: Vesa Anttila, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Anttila V, Saraste A, Knuuti J, Jaakkola P, Hedman M, Svedlund S, Lagerstrom-Fermer M, Kjaer M, Jeppsson A, Gan LM. Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial. Mol Ther Methods Clin Dev. 2020 Jun 1;18:464-472. doi: 10.1016/j.omtm.2020.05.030. eCollection 2020 Sep 11.