AZD8601 Study in CABG Patients

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

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: AZD8601; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• Finland
  • Kuopio, Finland, 70210
    • Research Site
  • Tampere, Finland, 33520
    • Research Site
  • Turku, Finland, 20520
    • Research Site
• Germany
  • München, Germany, 81675
    • Research Site
  • München, Germany, 80363
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Research Site
  • Groningen, Netherlands, 9713 GZ
    • Research Site
• Sweden
  • Göteborg, Sweden, 413 45
    • Research Site
  • Uppsala, Sweden, 751 85
    • Research Site
• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low dose AZD8601 (3 mg); 8 patients will be randomised to receive 3 mg AZD8601	Drug: AZD8601; 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
Experimental: High dose AZD8601 (30 mg); 8 patients will be randomised to receive 30 mg AZD8601	Drug: AZD8601; 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
Placebo Comparator: Placebo; 8 patients will be randomised to receive placebo injections	Drug: Placebo; Placebo for AZ8601 injection for solution will be given as 30 injections per patient on a single occasion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
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 Erythrocytes, Particle Concentration	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Diastolic Blood Pressure (Vital Sign)		From baseline to end of follow up at 6 months
Number of Subjects With High Values of Erythrocyte, Volume Fraction	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Erythrocytes, Mean Cell Volume	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Hemoglobin	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Neutrophils	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Lymphocytes	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Monocytes	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Eosinophils	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Basophils	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Platelets	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Reticulocytes	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Prothrombin Complex INR	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Activated Partial Thromboplastin Time	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Fibrinogen	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Sodium	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Potassium	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Urea	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Creatinine	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Albumin	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Calcium	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Phosphate	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Alkaline Phosphatase	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Alanine Aminotransferase	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Aspartate Aminotransferase	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months
Number of Subjects With High Values of Bilirubin, Total	Values are classified as high if they are above the normal reference range, based on local lab reference ranges.	From baseline to end of follow up at 6 months

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Vesa Anttila, MD, PhD, Heart Center, Turku University, Finland

Publications and helpful links

General Publications

• 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.

Helpful Links

• CSP redacted
• SAP redacted
• CSR synopsis redacted

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2018
• Primary Completion (Actual): June 30, 2021
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: November 16, 2017
• First Submitted That Met QC Criteria: December 6, 2017
• First Posted (Actual): December 13, 2017

Study Record Updates

• Last Update Posted (Actual): October 10, 2024
• Last Update Submitted That Met QC Criteria: July 10, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: D9150C00003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No