AZD8601 Study in CABG Patients

NCT03370887 | Completed Phase 2 Results

• 1 other identifier: D9150C00003
• Study Type: interventional
• Target: 11
• Locations: 5 countries
• Sites: 10

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.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (32)

• 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

Study Arms (3)

Low dose AZD8601 (3 mg)

EXPERIMENTAL

8 patients will be randomised to receive 3 mg AZD8601

Drug: AZD8601

High dose AZD8601 (30 mg)

EXPERIMENTAL

8 patients will be randomised to receive 30 mg AZD8601

Drug: AZD8601

Placebo

PLACEBO COMPARATOR

8 patients will be randomised to receive placebo injections

Drug: Placebo

Interventions

AZD8601 DRUG

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

High dose AZD8601 (30 mg); Low dose AZD8601 (3 mg)

Placebo DRUG

Placebo for AZ8601 injection for solution will be given as 30 injections per patient on a single occasion

Placebo

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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.

You may not qualify if:

• \. 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).
• \. Current atrial fibrillation as well as paroxysmal atrial fibrillation.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (10)

Research Site

New Haven, Connecticut, 06510, United States

Location

Research Site

Kuopio, 70210, Finland

Location

Research Site

Tampere, 33520, Finland

Location

Research Site

Turku, 20520, Finland

Location

Research Site

München, 80363, Germany

Location

Research Site

München, 81675, Germany

Location

Research Site

Amsterdam, 1081 HV, Netherlands

Location

Research Site

Groningen, 9713 GZ, Netherlands

Location

Research Site

Gothenburg, 413 45, Sweden

Location

Research Site

Uppsala, 751 85, Sweden

Location

Related Publications (2)

• Anttila V, Saraste A, Knuuti J, Hedman M, Jaakkola P, Laugwitz KL, Krane M, Jeppsson A, Sillanmaki S, Rosenmeier J, Zingmark P, Rudvik A, Garkaviy P, Watson C, Pangalos MN, Chien KR, Fritsche-Danielson R, Collen A, Gan LM. Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting. Mol Ther. 2023 Mar 1;31(3):866-874. doi: 10.1016/j.ymthe.2022.11.017. Epub 2022 Dec 17.

  PMID: 36528793 DERIVED

• 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.

  PMID: 32728595 DERIVED

Related Links

• CSP redacted
• SAP redacted
• CSR synopsis redacted

MeSH Terms

Conditions

Heart Failure

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Global Clinical LEad
• Organization: AstraZeneca

information.center@astrazeneca.com

1-877-240-9479

Study Officials

• Vesa Anttila, MD, PhD

  Heart Center, Turku University, Finland

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 16, 2017
• First Posted: December 13, 2017
• Study Start: February 5, 2018
• Primary Completion: June 30, 2021
• Study Completion: June 30, 2021
• Last Updated: October 10, 2024
• Results First Posted: October 10, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• 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.
• 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.

Locations

FI (3); US (1); SE (2); NL (2); DE (2)