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Protection of the Heart With Doxycycline During Coronary Artery Bypass Grafting

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ClinicalTrials.gov Identifier: NCT00246740
Recruitment Status : Completed
First Posted : October 30, 2005
Results First Posted : December 15, 2017
Last Update Posted : December 15, 2017
Sponsor:
Information provided by (Responsible Party):
Barry Finegan, University of Alberta

Study Description
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Brief Summary:
The purpose of this study is to determine whether doxycycline (Periostat) at a sub-antimicrobial dose will decrease reperfusion injury after coronary artery bypass grafting (CABG) surgery with cardiopulmonary bypass (CPB).

Condition or disease Intervention/treatment Phase
Coronary Artery Bypass Grafting Cardiopulmonary Bypass Reperfusion Injury Drug: Periostat Drug: Placebo Oral Tablet Phase 2

Detailed Description:

This proposal is for a randomized, placebo-controlled, double-blinded study of the use of doxycycline in patients requiring CABG surgery. Patients will be randomized 1:1 to receive either doxycycline or placebo.

This study will be conducted in a blinded manner. The pharmacy will randomize patients and will have the randomization code. The code will only be broken in the case of an emergency and the event will be fully documented.

In addition to standard care, patients will receive oral administration of 20 mg of doxycycline or placebo twice a day at least 2 days prior to surgery, on the day of surgery, and on postoperative days 1, 2, and 3.

Myocardial atrial biopsies will be taken at 2 time points during the CABG procedure: during cannulation of the right atrium and 10 minutes after cross-clamp release. Tissue will be analyzed for MMP-2 and -9 activity and TnI and MLC-1 levels.

A Swan-Ganz-Catheter will be placed in the pulmonary artery over 24 hours to measure hemodynamics (LVSWI).

A coronary sinus catheter will be placed under echocardiographic guidance prior to initiation of CPB (will be removed 20 minutes after cross-clamp release).

Patients will have an additional ECG on post-operative days 1 and 3.

Additional blood will be drawn to determine doxycycline plasma levels, MMP-2 and -9 activity, total gelatinolytic activity, and levels of troponin I and T products at the following time points: pre-induction, prior to initiation of CPB, 10 and 20 minutes following the release of the aortic cross clamp (arterial and venous) and 3, 6, 24 and 72 hours post aortic cross clamp removal (venous). Each of the above samples will require 6 mL of blood for a study total of 72 mL. At the time of each blood draw we will measure and record the hematocrit value.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 56 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Protection of the Heart With Doxycycline During Coronary Artery Bypass Grafting: A Pilot Study
Study Start Date : October 2005
Actual Primary Completion Date : May 2008
Actual Study Completion Date : May 2009

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Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Placebo oral tablet
Patients received oral administration of matching placebo pills, twice a day at least 2 days prior to surgery, on the day of surgery, and for the first 3 postoperative days (via a nasogastric tube or orally when patients tolerated it).
 Drug: Placebo Oral Tablet
In addition to standard care, patients received oral administration of placebo twice a day at least 2 days prior to surgery, on the day of surgery, and on postoperative days 1, 2, and 3.
Other Name: Placebo
Experimental: Periostat
Patients received oral administration of 20 mg of doxycycline, twice a day at least 2 days prior to surgery, on the day of surgery, and for the first 3 postoperative days (via a nasogastric tube or orally when patients tolerated it).
 Drug: Periostat
In addition to standard care, patients received oral administration of 20 mg of doxycycline twice a day at least 2 days prior to surgery, on the day of surgery, and on postoperative days 1, 2, and 3.
Other Name: Doxycycline


Outcome Measures
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Primary Outcome Measures :
  1. Left Ventricular Stroke Work Index (LVSWI) [ Time Frame: Before surgery up to 24h of reperfusion ]
    Measure of global left ventricular function. The formula used for calculation is: LVSWI= SI x MAP x 0.0144 LVSWI = Left Ventricular Stroke Work Index (g*m/m2) SI = Stroke Index (mL/beat/m2) MAP = Mean Arterial Pressure (mmHg) 0.0144 is a conversion term to equalize units.


Secondary Outcome Measures :
  1. Cardiac Matrix Metalloproteinase-9 Activity in Right Atrial Biopsies at 10 Minutes Reperfusion [ Time Frame: Before surgery and 10 minutes reperfusion after surgery ]
    Biochemical activity of MMP-9 activity in right atrial biopsies, measured at 10 minutes of reperfusion after surgery. To determine MMP-9 activity, 20 μg of total protein from both myocardial extracts and plasma were analyzed by gelatin zymography. For detailed methodology consult Cheung PY, Sawicki G, Wozniak M, et al: Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart. Circulation 2000; 101:1833-1839

  2. Cardiac Matrix Metalloproteinase-2 Activity in Right Atrial Biopsies at 10 Minutes Reperfusion [ Time Frame: Before surgery and 10 minutes reperfusion after surgery ]
    Biochemical activity of MMP-2 activity in right atrial biopsies, measured at 10 minutes of reperfusion after surgery.

  3. Venous Plasma Cardiac Matrix Metalloproteinase-9 Activity Before and After Reperfusion [ Time Frame: Before surgery and up to 72 h reperfusion after surgery ]
    Biochemical activity of MMP-9 activity in venous plasma, measured before surgery and up to 72h of reperfusion after surgery.

  4. Venous Plasma Cardiac Matrix Metalloproteinase-2 Activity Before and After Reperfusion [ Time Frame: Before surgery and up to 72 h reperfusion after surgery ]
    Biochemical activity of MMP-2 activity in venous plasma, measured before surgery and up to 72h of reperfusion after surgery.

  5. Venous Plasma Concentration of Troponin-I [ Time Frame: Before surgery and 10 minutes reperfusion after surgery ]
    Measurement of levels of TnI (troponin-I), a marker of cardiac cell damage

  6. Cleaved TroponinI/GAPDH Ratios in Right Atrial Biopsy [ Time Frame: Before surgery and 10 minutes reperfusion after surgery ]
    Measurement of the ratios of cleaved TnI (troponin-I) versus GAPDH in biopsies collected from right atria. Measure is the ratio TnI/GAPDH

  7. Venous Plasma Concentration of C-reactive Protein [ Time Frame: Before surgery and up to 72 h reperfusion after surgery ]
    Measurement of inflammation marker C-reactive protein in plasma

  8. Venous Plasma Concentration of IL-6 [ Time Frame: Before surgery and up to 72 h reperfusion after surgery ]
    Measurement of inflammation marker interleukin-6 in plasma


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent
  • Aged 18 through 80 years, inclusive
  • Scheduled for primary CABG surgery with CPB

Exclusion Criteria:

  • Females of childbearing potential
  • Emergency CABG
  • Previous sternotomy
  • Planned simultaneous surgery (i.e. valve repair or carotid endarterectomy)
  • Myocardial infarction within 48 hours
  • Pre-operative atrial fibrillation
  • Pre-operative ventricular pacing or left bundle branch block (LBBB)
  • Known hypersensitivity to tetracycline class antibiotics
  • Renal failure requiring dialysis
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00246740


Locations
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Canada, Alberta
University of Alberta Hospital
Edmonton, Alberta, Canada, T6G 2G3
Sponsors and Collaborators
University of Alberta
Investigators
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Principal Investigator: Barry A Finegan, FFARCS FRCPC Department of Anesthesiology and Pain Medicine, University of Alberta Hospital
More Information
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Additional Information:

Publications of Results:

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Responsible Party: Barry Finegan, Professor, University of Alberta
ClinicalTrials.gov Identifier: NCT00246740    
Other Study ID Numbers: Protect Study Protocol
First Posted: October 30, 2005    Key Record Dates
Results First Posted: December 15, 2017
Last Update Posted: December 15, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Barry Finegan, University of Alberta:
Doxycycline
coronary artery bypass grafting
Additional relevant MeSH terms:
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Reperfusion Injury
Vascular Diseases
Cardiovascular Diseases
Postoperative Complications
Pathologic Processes
Doxycycline
 Anti-Bacterial Agents
Anti-Infective Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents