Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT02191839 |
| Other study ID # |
SOR 133-13 ctil |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 1/Phase 2
|
| First received |
July 7, 2014 |
| Last updated |
July 15, 2014 |
| Start date |
July 2014 |
| Est. completion date |
July 2015 |
Study information
| Verified date |
July 2014 |
| Source |
Soroka University Medical Center |
| Contact |
DAN ABRAHAMOV, DR |
| Phone |
972504506205 |
| Email |
danab3[@]clalit.org.il |
| Is FDA regulated |
No |
| Health authority |
Israel: Ministry of Health |
| Study type |
Interventional
|
Clinical Trial Summary
Protocol Summary STUDY DESIGN A pilot, prospective, double blind, randomized, placebo
controlled study.
STUDY POPULATION Patients assigned to elective CABG with cardiopulmonary bypass (CPB) at the
Department of Cardiothoracic Surgery, Soroka University Medical Center.
OBJECTIVE To evaluate anti-inflammatory effects, effects on organ function preservation, and
postoperative blood loss reduction following AAT-1 administration in patients undergoing
CABG with CPB.
PRIMARY ENDPOINT Postoperative organ function preservation and blood loss following
preoperative single-dose AAT-1 administration.
SAMPLE SIZE CONSIDERATIONS A cohort of 20 patients will be recruited. Patients will be
randomized to receive either AAT-1 or placebo prior to surgery. Whereas this is a proof of
concept pilot study, statistical significance is not the primary objective.
INCLUSION CRITERIA 1. The study population will comprise patients between 40 and 70 years of
age, irrespective of gender, at low or intermediate operative risk (calculated Logistic
Euroscore stratification of 5% or less), assigned to elective CABG with CPB. Recruitment
depending on patients informed consent.
EXCLUSION CRITERIA Co-existing conditions including:
1. Coagulation abnormalities
2. Severe pulmonary disease defined by blood oxygen saturation of 90% or less or FEV1 of
less than 60% of predicted.
3. Renal dysfunction defined be serum creatinine levels higher or equal to 1.8 mg%,
4. Abnormal liver function tests
5. Uncontrolled diabetes mellitus,
6. Severe peripheral vascular disease
7. Prior cerebrovascular neurological event.
8. Abnormal left or right ventricular function.
9. Treatment with warfarin or thienopyridine class of anti platelet agents.
Description:
3 Background The use of cardiopulmonary bypass (CPB) during cardiac surgery elicits
generalized non-specific systemic inflammatory response syndrome (SIRS) and subsequent
activation of the cytokine, complement, and coagulation-fibrinolytic cascades (1). In
approximately 11% of the patients SIRS may deteriorate to severe multi-organ failure (MOF)
resulting in mortality rate of 40-98%.
Inflammatory modulation by intraoperative administration of anti-inflammatory substances has
been advocated to attenuate the effects of SIRS. Attempts have subsequently focused on
aprotinin which inhibits proteases that are key mediators in the complement, coagulation,
and fibrinolytic system. Related anti-inflammatory properties of aprotinin include the
inhibition of platelets, neutrophils and kallikrein activation. Reduction in blood loss and
reduced need for allogenic blood transfusions have been proposed as additional mechanisms by
which aprotinin limits the inflammatory response (2). The use of aprotinin during cardiac
surgery, however, was discontinued following alarming results in terms of higher rate of
bypass graft occlusion and overall inferior postoperative outcome.
AAT-1 mechanism of action:
Similar to aprotinin, α1-Antitrypsin (AAT) is a 52-kDa circulating serine protease inhibitor
classified as a SERPIN protein. Besides its ability to inhibit serine proteases,
accumulating data suggest that AAT-1 possesses independent anti-inflammatory and
tissue-protective effects (3). AAT-1 modifies dendritic cell maturation and promotes
regulatory T-cell differentiation, induces interleukin (IL)-1 receptor antagonist and IL-10
release, protects various cell types from cell death, inhibits caspases-1 and -3 activities
and inhibits IL-1 production and activity (4). Contradictory to classic immunosuppressants,
AAT-1 allows undeterred isolated T-lymphocyte responses (5).These effects have been
repeatedly corroborated.
Unlike aprotinin, AAT-1 is produced from human plasma, and does not have strong pro
coagulant characteristics.
AAT-1 in different clinical settings:
Circulating AAT-1 levels increase by 4-fold during acute-phase response (3). Patients with
low circulating levels of AAT-1 are at increase risk for lung, liver and pancreatic
destructive diseases, particularly emphysema (3). Preclinical and clinical studies have
shown that AAT-1 therapy for non-deficient individuals is safe, and may modify disease
progression in type 1 and type 2 diabetes, acute myocardial infarction, rheumatoid
arthritis, inflammatory bowel disease, cystic fibrosis, transplant rejection, graft versus
host disease and multiple sclerosis (6-17, 32,33,37,38) . AAT-1 treatment has subsequently
advanced from replacement therapy to potential treatment for a broad spectrum of
inflammatory and immune-mediated diseases. AAT-1 also appears to be antibacterial and an
inhibitor of viral infections, such as influenza and human immunodeficiency virus (HIV)
(18).
Human pharmacokinetic data:
In patients with AAT-1 deficiency, intravenous administration of AAT-1 in a dose of 60 mg
per kg body weight maintain plasma levels resembling acute phase response immediately after
administration, and retain an appropriate level of serum AAT above the protective threshold
(50 mg/dl) a week afterwards (39).
Rational of AAT-1 dosage:
Based on previous studies and clinical practice, the administration of multiple intravenous
dosage of 60 mg per kg body weight of AAT-1 is safe and is associated with low incidence of
benign side-effects.
Derived from pharmacokinetic studies (39), AAT-1 plasma levels immediately following the
administration of this external dosage resembles acute phase response. A 30% reduction in
AAT-1 plasma levels is anticipated with gradual return to preoperative levels after
termination of CPB (40).
Risk/ benefit of the study:
The role of AAT-1 in mitigating inflammatory response has been established. CPB is a potent
stimulator of inflammatory cascades and associated with bleeding diatheses, coagulation
abnormalities, potentially leading to organ dysfunction. To date, the administration of
AAT-1 in patients undergoing cardiac surgery with CPB has not been explored. It may be
postulated that inherent AAT-1 effects may offset deleterious CPB effects. This may
clinically result in improved preservation of organ function, reduced postoperative bleeding
and reduced hospital stay. The benefits of other protease inhibitors in corresponding
settings have been recently demonstrated (41-43).
As mentioned above, administration of AAT-1 in various clinical settings is considered safe
with low rate of side effects (see section 6.1 - potential risks).
4 Methods 4.1 Primary Objective
1. To evaluate the efficacy and safety of preoperative AAT-1 administration in patients
undergoing CABG with CPB.
2. Postoperative blood loss and organ function will be assessed.
To date, no data exists with regard to AAT-1 effects in the settings of CPB. The primary
goals of this study are to evaluate anti-inflammatory effects, organ function preservation
(1-2) and postoperative blood loss reduction following AAT-1 administration in patients
undergoing cardiac surgery with CPB.
4.2 Determination of Study Eligibility 4.2.1 Inclusion Criteria
1. Male/female patients 40-70 years of age.
2. Candidates for isolated CABG with CPB.
3. Calculated logistic Euroscore risk stratification of 5% or less.
4. Signed patient's written informed consent.
4.2.2 Exclusion Criteria
Co-existing conditions including:
10. Coagulation abnormalities 11. Severe pulmonary disease defined by blood oxygen
saturation of 90% or less or FEV1 of less than 60% of predicted.
12. Renal dysfunction defined be serum creatinine levels higher or equal to 1.8 mg%, 13.
Abnormal liver function tests 14. Uncontrolled diabetes mellitus, 15. Severe peripheral
vascular disease 16. Prior cerebrovascular neurological event. 17. Abnormal left or right
ventricular function. 18. Treatment with warfarin or thienopyridine class of anti-platelet
agents. 4.2.3 Withdrawal Criteria Patients will preserve the right to withdraw from the
study at any time during treatment without prejudice.
If medically indicated, the principal investigator or the surgeon poses the right to
discontinue patient enrollment at any stage of the study.
Discontinuation (failure to complete the study) will be documented. The reason for
discontinuation will be recorded.
Potential causes that may lead to discontinuation include:
- Adverse event(s)
- Protocol violation
- Patient withdrew consent
- Administrative problems 4.3 Enrollment Prior to participation in this study, the
Investigator will obtain written appropriate approval for the protocol and the informed
consent form the Ethics Committee (EC) and other local regulatory organizations. The
approved consent form will clearly reflect the EC approval date.
Failure to obtain a signed and hand dated informed consent prior to the procedure
constitutes a protocol violation, and subsequently reportable to the EC.
4.4 Subject Screening Patients that have been already scheduled for isolated CABG operation
will be addressed by a member of the research team during the preoperative waiting period
(either in the Department of Cardiothoracic Surgery, the Department of Cardiology or the
Department of Internal Medicine). The goal of the study, procedure and incentive will be
explained by a research staff member to each potential participant. Consenting subjects will
be asked to provide written consent.
4.4.1 Randomization The study participants will be randomized to receive either single dose
AAT-1 60 mg per kg or placebo.
4.4.2 Trial medication administration: Preparation and dosing of AAT-1 will be performed by
an unblinded pharmacist. The medication will be diluted just prior to administration. The
placebo solution will comprise human albumin that resembles the color and consistency of
AAT-1 solution. The medication will be given 3-5 hours prior to surgery (skin incision).
Administration rate of the drug will not exceed 0.04 ml per kg per minute (approximately
60-80 minutes). Vital signs including blood pressure, pulse rate and body temperature will
be correspondingly monitored.
The patients, research staff, laboratory personnel and data analysts will remain blinded to
the identity of the treatment from the time of randomization and until database lock. Data
unblinding will commence in the case of patient's emergency.
A randomization list will be produced by the pharmacist, however, will be secured and
confidential until time of unblinding.
4.4.3 Surgical technique Consistent with our routine policy, fentanyl citrate (20-50mcg/kg),
midazolam (2-3mg) and isoflurane (0.5-2%) will be used for induction and maintenance of
anesthesia.
Standard median sternotomy will be followed by procurement of the conduits. Heparin loading
dose will be administered to achieve a kaolin activated coagulation time (ACT). Ascending
aorta - right atrial cannulation will be performed to institute CPB and ACT will be
monitored at 480 seconds or more. Standard centrifugal pump and a membrane oxygenator will
be used for extracorporeal circulation (cardiopulmonary bypass). Compatible with the
standard technique, systemic active cooling will be avoided and patients core temperature
will remain range between 32 and 37˚C. Distal anastomoses will be performed during single
aortic cross-clamp and blood cardioplegic arrest. Proximal anastomoses will be performed
during aortic cross-clamp. Cold (10˚C) blood cardioplegic solution will be delivered in a
4:1 ratio. Cardioplegia will be delivered antegrade via the aortic root with or without
additional retrograde administration via the coronary sinus. After cardioplegic induction
(10 ml / Kg), intermittent doses (300 - 500 ml) will be administered following completion of
each distal anastomosis. Heparin will be reversed using protamine sulphate in a ratio of 1:1
after weaning from CPB.
4.4.4 Data collection Preoperative data: Demographic, morphological and clinical descriptors
including age, gender, body mass index (BMI), body surface area (BSA) co-morbidity,
Euroscore risk-stratification, medication, etc. will be recorded. Preoperative laboratory
analysis will include complete blood count, coagulation profile, serum creatinine levels and
creatinine clearance, liver function test and arterial blood gases test and serology for
HIV,HCV,HBC. Compatible with our routine policy, all patients will undergo preoperative
echocardiography, coronary angiography, chest x-ray, lung function tests (spirometry) and
carotid artery duplex study.
Study participants will be assigned to undergo preoperative brain MRI; subjected to the
protocol described below.
Intraoperative: The type of surgery will be classified. The following data will be recorded:
heparin dose given prior to bypass initiation; activated clotting time (ACT) counts during
the operation (prior, during and after CPB); operative time, cross-clamp time and CPB time;
number of trials to wean from CPB, type of inotropes and dosage used during weaning from
CPB; blood products utilization during surgery. Allergic reactions or adverse events
observed by the surgeon or anesthesiologist will be documented. The individual surgeon's
impression regarding bleeding tendency will be recorded.
Postoperative organ function and blood loss evaluation:
The occurrence and magnitude of systemic inflammatory response and organ dysfunction will be
recorded and quantified by laboratory markers. Related laboratory markers will be monitored
on a daily basis during the recovery period (in the intensive care unit and at the ward).
The following organs and corresponding markers will be monitored:
Pulmonary function: Pulmonary function will be evaluated by measured overall mechanical
ventilation time, peak inspiratory pressures (PIP), plateau pressures, physiologic dead
space and static and dynamic lung compliance. Bronchoalveolar lavage (BAL) will be performed
3 hours after operation (while the patient is anesthesized and intubated) and extracted
fluid will be analyzed for inflammatory markers. A-a DO2 calculation [AaDO2 = (713 x FiO2) -
(pCO2 / 0.8) - (paO2)] will be measured daily.
Complete pulmonary function test will be performed before and 4 days after the operation.
Chest radiographs will be evaluated and quantified by an independent radiologist for the
occurrence of atelectasis, pulmonary edema, or pleural changes.
Renal function: Daily measurements of urine output, serum creatinine levels, creatinine
clearance and urinary albumin levels. Acute kidney injury (AKI) markers will be sampled in
the ICU.
Brain injury assessment: The degree of insult to the brain will be measured by plasma S-100
proteinlevels. Assessment of damage to the blood-brain barrier (BBB) will be performed by
magnetical resonance imaging (MRI) modality (see technique protocol below).
Hepatic function: Daily measurements of serum hepatic enzymes levels. Cardiac function:
Monitoring of cardiac enzymes levels; need and magnitude of required inotrope treatment;
occurrence of low cardiac output syndrome (defined as systolic blood pressure of 90 mmHg or
less coupled with central venous pressure (CVP) of 15 mmHg or more) and incidence of cardiac
arrhythmias. Transthoracic echocardiography examination will be performed on postoperative
day 5 and assessed by an independent cardiologist.
Blood loss: Operative and postoperative blood loss will be monitored as well as daily
hemoglobin levels. Daily platelet counts and thromboelastograms will be performed. The
distribution of blood products and total administered will be recorded daily. Postoperative
CRP levels will be evaluated daily.
Blood sampling and laboratory analysis methods for cytokine levels:
Ten mL whole blood venous EDTA samples will be collected from radial artery catheter at five
specified occasions: before induction of anaesthesia, 30 minutes after aortic cross-clamp
positioning and 3, 6, and 9 hours after aortic cross clamp positioning. The blood samples
will be subsequently centrifuged at 4 °C for 15 min and the serum stored at −70 °C. Samples
will be analyzed for the following markers: Polimorphonuclear Neutrophil Elastase (PMNE),
Interleukin-1α (IL-1α), Interleukin-1ß (IL-1ß), Interleukin-2 (IL-2), Interleukin-4 (IL-4),
Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-10 (IL-10), Interferon-γ (IFN-γ),
Tumor Necrosis Factor-α (TNF-α), Vascular Endothelial Growth Factor (VEGF), Monocyte
Chemoattractant Protein-1 (MCP-1), and Endothelial Growth Factor (EGF).
Daily blood samples will be collected postoperatively for platelet count, renal function,
liver function, CRP levels S-100 protein and troponin.
Early postoperative adverse events will be documented. These include 30-day mortality, new
neurological events, myocardial infarction, renal dysfunction, need for re-exploration for
bleeding and deep sternal wound infection.
Blood-Brain Barrier (BBB) assessment by MRI The imaging modality used for BBB assessment
will be MRI scanner (Philips 3T or General Electric 1.5T). The examination format will
include 24 cm FOV, 35 contiguous interleaved slices, 3.5-4 mm thick and co-localized across
series. Trace-weighted DWI images will be obtained at b=1000 from a 13-15 direction DTI
sequence with an in-plane resolution of 2.5×2.5mm and TR/TE=10s/58ms at 3T or TR/TE=10s/72ms
at 1.5T. T2-FLAIR images will be obtained with an in-plane resolution of 0.94×0.94 mm,
TR/TE=9000/120 ms and TI=2600 ms at 3T or TR/TE=9000/140 ms and TI=2200 ms at 1.5T. (25)
