Primary Objective; To investigate safety and tolerability of AZD8601 following epicardial injection in patients undergoing Coronary Artery Bypass Grafting (CABG) surgery with moderately impaired systolic function. In addition, exploratory objectives…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To investigate safety and tolerability of AZD8601 following epicardial
injection in patients undergoing Coronary Artery Bypass Grafting (CABG) surgery
with moderately impaired systolic function.
Outcome measures:
- Adverse Events/Serious Adverse Events (AEs/SAEs)
- Vital signs (blood pressure, pulse)
- Electrocardiogram (ECG)
- Left Ventricular Ejection Fraction (LVEF)
- Physical examination
- Laboratory assessments (hematology, clinical chemistry and urinalysis)
Secondary outcome
NA
Background summary
Coronary artery disease (CAD) is characterized by constrictions in the coronary
arteries of the heart causing insufficient oxygen-rich blood to flow to the
heart muscle. This causes damage to the heart muscle, which prevents the heart
from functioning properly. In addition, CAD is a primary cause of heart
failure. This is due to a reduced squeezing force of the left ventricle causing
less blood to be pumped out of the heart.
Despite all possible treatments (revascularization, medication, new devices
such as resynchronization therapy) there remains an unmet medical need because
these treatments are usually unable to restore the full physiological
functionality and that makes innovative treatments essential for this
population.
The study will investigate the safety and tolerability of AZD8601 (versus
placebo). AZD8601 is VEGF-A165 modRNA under development as a novel modality for
local production of human VEGF-A protein and is developed for the treatment of
ischemic heart disease through stimulation of angiogenesis. The study examines
the effects of AZD8601 given as epicardial injections in patients with stable
CAD with decreased left ventricular ejection fraction (LVEF) going through
elective CABG.
Primarily the safety and tolerability of AZD8601 in increasing doses in
patients going through CABG will be assessed. In addition, exploratory
objectives that address the capabilities of AZD8601 to improve global and local
myocardial perfusion and/or left ventricle function in the studied patient
cohort will be explored.
Study objective
Primary Objective; To investigate safety and tolerability of AZD8601 following
epicardial injection in patients undergoing Coronary Artery Bypass Grafting
(CABG) surgery with moderately impaired systolic function.
In addition, exploratory objectives that address the capabilities of AZD8601 to
improve global and local myocardial perfusion and/or left ventricle function in
the studied patient cohort will be explored (patients with stable CAD with
decreased left ventricular ejection fraction (LVEF) going through elective
CABG).
Study design
This is a randomized, double-blind, placebo-controlled, sequential design,
multicentre study in patients with moderately impaired systolic function
undergoing CABG surgery.
The study will include two cohorts of 12 patients each, which will receive
either a low or high dose of AZD8601 (see Section 7.2 of the protocol) in a
sequential, dose ascending fashion. Within each cohort 8 patients will be
randomized to receive AZD8601 and 4 to placebo.
Each cohort will be divided into 3 sentinel dosing cohorts. See Figure 1
section 1.4. The two first will include 2 patients each * 1 patient randomized
to placebo and 1 to AZD8601. The third sentinel cohort will include the 8
remaining patients on that dose level; 2 placebo, 6 AZD8601. After each
sentinel cohort, before proceeding dosing the next, safety data from up to 1
month post dose (Visit 5) from the current cohort and the available data from
previous cohorts, will be reviewed. The same applies before continuing to the
high dose cohort. The procedure will be repeated in the same way within the
high dose cohort.
Intervention
subjects will receive either AZD8601 or placebo. AZD8601 will be administered
as epicardial injections. Thirty injections of either 0.1 mg (3 mg per subject)
or 1 mg (30 mg per subject) will be given on a single occasion with
approximately 1 cm injection distance and 200 *L per injection.
Placebo for AZD8601 will be administered in the same manner as AZD8601 and in a
volume and injection distance to match AZD8601.
Study burden and risks
The subject is asked to visit the site at least 6 times. 5 visits time will
last maximally 5 hours, 1 visit will be the hospitalization for elective CABG.
The subject will be contacted by telephone 1 time. This telephone contact will
last maximally 10 minutes. Blood samples will be taken in this study. The total
volume of blood that will be collected is approximately 450 ml. The subject
will undergo physical examinations at every hospital visit. The subject will
undergo 3 times a 15O PET/CT Scan. The subject will be asked to fill out 2
questionnaires at 4 hospital visits. Women must be non-child bearing potential
confirmed at screening. The subject will undergo 5 times an echography. The
subject will undergo 2 times a stress echocardiography. The subject will
receive the studymedication 1 time on a single occasion. The taking of
bloodsamples may cause some discomfort. The administration by epicardial
injections may cause some side effects as cardiac arrhythmia.
In a ongoing phase 1 trial where AZD8601 is administered as intradermal
injections, AZD8601 was well tolerated without SAE`s. In terms of AE`s the most
common was local transient injection site reaction which is completely
reversible.
Riskreduction:After each sentinel cohort, before proceeding dosing the next,
safety data from up to 1 month post dose (Visit 5) from the current cohort and
the available data from previous cohorts, will be reviewed. The same applies
before continuing to the high dose cohort. The procedure will be repeated in
the same way within the high dose cohort.
Two parallel safety reviews will be done:
* Blinded safety review board (SRB) consisting of study investigators and AZ
personnel
* Study independent unblinded safety review committee (SRC) consisting of
internal AZ expertise
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Listed location countries
Age
Inclusion criteria
1. Provision of signed and dated informed consent prior to any study specific
procedures
2. Males and females:
a. Males must be surgically sterile or using an acceptable method of
contraception (see Section 3.8.5)
b. 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
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)
7. 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.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR201700269019-NL |
| ClinicalTrials.gov | NCT03370887 |
| CCMO | NL67762.056.18 |