Cardiac REperfusion With Intralipid® at Reperfusion (CREW-I)

Randomised Control Study on Cardiac Protection With Intralipid® in Patients Undergoing Coronary Artery Bypass Grafting on Cardiopulmonary Bypass

This study will evaluate the benefit of Intralipid® or placebo administered prior to reperfusion to limit ischemia reperfusion injury as measured by the geometric mean difference of the release of troponin I over 72 hours after coronary artery bypass.

Study Overview

• Status: Unknown
• Conditions: Reperfusion Injury
• Intervention / Treatment: Drug: Intralipid 20%; Drug: Modified Ringers Lactate

Detailed Description

A single center randomised control study on cardiac protection with INTRALIPD in patients undergoing coronary artery bypass grafting on cardiopulmonary bypass.

Purpose and objectives:

Reperfusion after coronary artery bypass grafting is associated with a modifiable leak in cardiac Troponin I (cTnI) secondary to ischemia reperfusion injury. The purpose of the study is to test whether INTRALIPID administered at reperfusion can limit myocardial reperfusion injury as measured by cTnI release in patients undergoing coronary artery bypass grafting.

Trial design:

This study is a prospective single centre double blind placebo controlled randomised trial.

Sample size: 30 Adult Male and Female Patients

Investigational drug(s):

INTRALIPID 20% Fresenius Kabi (SA) Registration Number: K/25.2/316 Formulation: IV Solution Strength: 20% (200mg/ml) Modified Ringer's Lactate Fresenius Kabi (SA) Registration Number: C/24/218 Formulation: IV Solution Dose for both drugs: 1.5 ml/kg Administration: IV Bolus through CVP Blood sampling and tissue biopsies: cTnI will be sampled at fixed time points, baseline 1, 6, 9, 12, 24, 48, and 72 hours after surgery. The first biopsy will be done prior to cardioplegic arrest and the second biopsy will be done 5 minutes after reperfusion.

Safety assessments:

The safety of the interventions will be monitored routinely for all patients and these will focus on:

1. Changes in the lipid profile after Intralipid
2. Coagulation as measured by ACT, TEG and PFA
3. Oxygenation with Arterial Blood Gas monitoring
4. Hemodynamic monitoring and echocardiography
5. Lipid interference with laboratory measurements. The laboratory will be informed on specimen preparation to avoid interference with instruments
6. Post operative hemodynamic Intensive Care Unit Monitoring Measurement will be reported on all safety monitoring and will be considered adverse events where the measured parameter results are out of range from the laboratory references.

Efficacy assessments. Primary endpoint: The efficacy of the drug will be determined by the geometric mean (95% CI) difference in the AUC of the cTnI concentration calculated according to the trapezoid rule.

Secondary End Point: Exploring the molecular mechanism involved in cardiac protection by analyzing tissue sample differences in the phosphorylation cytoplasmic protein kinase.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• South Africa
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7925
      • Recruiting
      • Department of Anaesthesia, Groote Schuur Hospital
      • Contact: Nkanyiso E Hadebe, MBBCh; Phone Number: 0769154990; Email: nkanyiso.hadebe@uct.ac.za

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• First time elective isolated CABG
• Ejection Fraction greater the 40 by echocardiography or subjectively judged as preserved or good by ventriculography.
• Male and female adults between 18 and 65 years of age.
• Women must have a negative serum pregnancy test at screening.
• Body mass Index (BMI) between 21 and 35 kg/m2.
• Baseline clinical laboratory tests at screening within the reference ranges

Exclusion Criteria:

• Received an investigational drug or participated in another research trial within 30 days before the first dose of trial drug or at any time throughout the trial.

  • Evidence of current or history of clinically significant oncologic, pulmonary, hepatic with elevated liver functions enzymes 1.5* Upper Limit of Normal (ULN), cardiovascular, haematologic, metabolic, neurological, immunologic, nephrologic, endocrine particularly Diabetes Mellitus as defined by the American Diabetic Association, psychiatric disease, or clinically significant current infection.
  • Patients with renal impairment with a creatinine greater than 200 μmol/L
  • Evidence of current or history of clinically significant gastrointestinal (excluding appendectomy, cholecystectomy) disease.
  • Myocardial infarction within the previous 2 weeks.
  • Patients who require inotropic or mechanical cardiac support prior to anaesthesia.
  • Contraindication to the trial drugs Previous Hypertriglyceridemia pancreatitis. Hypertriglyceridemia with plasma triglyceride levels > 5.7mmol/L Egg, peanut and soybean allergy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intralipid 20%; Intravenous single bolus of 1.5 ml/kg of Intralipid 20% over 3 minutes.	Drug: Intralipid 20%; Single intravenous bolus dose of 1.5 ml/kg over 3 minutes; Other Names: Lipid Emulsion 20%
Placebo Comparator: Modified Ringers Lactate; Intravenous single bolus of 1.5 ml/kg of MRL over 3 minutes.	Drug: Modified Ringers Lactate; Single intravenous bolus dose of 1.5 ml/kg over 3 minutes; Other Names: MRL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of the serum Troponin I Leak over 72 hours	The primary endpoint will be assessed by the geometric mean (95% CI) difference between the protocol and control groups of the area under the curve for the cTnI concentration in serum over 72 hours (sampled at 1, 6, 12, 24, 48 and 72 hours) calculated according to the trapezoid rule.	Over 72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Signaling Pathways of intralipid induced cardiac protection	Two right atrial and two left ventricular biopsies will be collected before cardioplegia and the second will be collected 5 minutes prior to reperfusion. These will be used to compare the activation of signalling protein between the groups.	5 minutes after reperfusion

Collaborators and Investigators

• Sponsor: Nkanyiso Hadebe
• Investigators: Study Chair: Nkanyiso E Hadebe, MBBCh, University of Cape

Study record dates

Study Major Dates

• Study Start: January 1, 2017
• Primary Completion (Anticipated): June 1, 2018
• Study Completion (Anticipated): June 1, 2018

Study Registration Dates

• First Submitted: June 13, 2016
• First Submitted That Met QC Criteria: June 16, 2016
• First Posted (Estimate): June 21, 2016

Study Record Updates

• Last Update Posted (Actual): December 12, 2017
• Last Update Submitted That Met QC Criteria: December 11, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Reperfusion Injury; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; Soybean oil, phospholipid emulsion
• Other Study ID Numbers: CREW-I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: The individual participant data will not be shared