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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo oral tablet | Placebo Comparator | 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). |
|
| Periostat | Experimental | 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Periostat | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Left Ventricular Stroke Work Index (LVSWI) | 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. | Before surgery up to 24h of reperfusion |
| Measure | Description | Time Frame |
|---|---|---|
| Cardiac Matrix Metalloproteinase-9 Activity in Right Atrial Biopsies at 10 Minutes Reperfusion | 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Barry A Finegan, FFARCS FRCPC | Department of Anesthesiology and Pain Medicine, University of Alberta Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alberta Hospital | Edmonton | Alberta | T6G 2G3 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23928836 | Result | Schulze CJ, Castro MM, Kandasamy AD, Cena J, Bryden C, Wang SH, Koshal A, Tsuyuki RT, Finegan BA, Schulz R. Doxycycline reduces cardiac matrix metalloproteinase-2 activity but does not ameliorate myocardial dysfunction during reperfusion in coronary artery bypass patients undergoing cardiopulmonary bypass. Crit Care Med. 2013 Nov;41(11):2512-20. doi: 10.1097/CCM.0b013e318292373c. |
| Label | URL |
|---|---|
| DOI of published results paper | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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). 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. |
| FG001 | 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). 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Initial Enrollment |
|
| |||||||||||||||||||||
| Experimental Phase |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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). 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Left Ventricular Stroke Work Index (LVSWI) | 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. | Posted | Mean | Standard Error | g*m/m2 | Before surgery up to 24h of reperfusion |
|
72 hours
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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). 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. |
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Small sample size. LVSWI does not estimate diastolic dysfunction. Right atrial biopsies may not reflect changes in left ventricular MMP activity. Doxycycline dose- and time-response analyses is required to better assess the protective effects
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Richard Schulz | Departments of Pediatrics and Pharmacology, University of Alberta | 780-492-6581 | richard.schulz@ualberta.ca |
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| ID | Term |
|---|---|
| D015427 | Reperfusion Injury |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D004318 | Doxycycline |
| ID | Term |
|---|---|
| D013754 | Tetracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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|
| Placebo Oral Tablet | Drug | 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. |
|
|
| Before surgery and 10 minutes reperfusion after surgery |
| Cardiac Matrix Metalloproteinase-2 Activity in Right Atrial Biopsies at 10 Minutes Reperfusion | Biochemical activity of MMP-2 activity in right atrial biopsies, measured at 10 minutes of reperfusion after surgery. | Before surgery and 10 minutes reperfusion after surgery |
| Venous Plasma Cardiac Matrix Metalloproteinase-9 Activity Before and After Reperfusion | Biochemical activity of MMP-9 activity in venous plasma, measured before surgery and up to 72h of reperfusion after surgery. | Before surgery and up to 72 h reperfusion after surgery |
| Venous Plasma Cardiac Matrix Metalloproteinase-2 Activity Before and After Reperfusion | Biochemical activity of MMP-2 activity in venous plasma, measured before surgery and up to 72h of reperfusion after surgery. | Before surgery and up to 72 h reperfusion after surgery |
| Venous Plasma Concentration of Troponin-I | Measurement of levels of TnI (troponin-I), a marker of cardiac cell damage | Before surgery and 10 minutes reperfusion after surgery |
| Cleaved TroponinI/GAPDH Ratios in Right Atrial Biopsy | Measurement of the ratios of cleaved TnI (troponin-I) versus GAPDH in biopsies collected from right atria. Measure is the ratio TnI/GAPDH | Before surgery and 10 minutes reperfusion after surgery |
| Venous Plasma Concentration of C-reactive Protein | Measurement of inflammation marker C-reactive protein in plasma | Before surgery and up to 72 h reperfusion after surgery |
| Venous Plasma Concentration of IL-6 | Measurement of inflammation marker interleukin-6 in plasma | Before surgery and up to 72 h reperfusion after surgery |
| Surgery schedule change |
|
| Other |
|
| NOT COMPLETED |
|
| BG001 | 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). 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG001 |
| 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). 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. |
|
|
| Secondary | Cardiac Matrix Metalloproteinase-9 Activity in Right Atrial Biopsies at 10 Minutes Reperfusion | 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 | Posted | Mean | Standard Error | Arbitrary units | Before surgery and 10 minutes reperfusion after surgery |
|
|
|
| Secondary | Cardiac Matrix Metalloproteinase-2 Activity in Right Atrial Biopsies at 10 Minutes Reperfusion | Biochemical activity of MMP-2 activity in right atrial biopsies, measured at 10 minutes of reperfusion after surgery. | Posted | Mean | Standard Error | Arbitrary units | Before surgery and 10 minutes reperfusion after surgery |
|
|
|
| Secondary | Venous Plasma Cardiac Matrix Metalloproteinase-9 Activity Before and After Reperfusion | Biochemical activity of MMP-9 activity in venous plasma, measured before surgery and up to 72h of reperfusion after surgery. | Posted | Mean | Standard Error | Arbitrary units | Before surgery and up to 72 h reperfusion after surgery |
|
|
|
| Secondary | Venous Plasma Cardiac Matrix Metalloproteinase-2 Activity Before and After Reperfusion | Biochemical activity of MMP-2 activity in venous plasma, measured before surgery and up to 72h of reperfusion after surgery. | Posted | Mean | Standard Error | Arbitrary units | Before surgery and up to 72 h reperfusion after surgery |
|
|
|
| Secondary | Venous Plasma Concentration of Troponin-I | Measurement of levels of TnI (troponin-I), a marker of cardiac cell damage | Posted | Mean | Standard Error | pg/ml | Before surgery and 10 minutes reperfusion after surgery |
|
|
|
| Secondary | Cleaved TroponinI/GAPDH Ratios in Right Atrial Biopsy | Measurement of the ratios of cleaved TnI (troponin-I) versus GAPDH in biopsies collected from right atria. Measure is the ratio TnI/GAPDH | Posted | Mean | Standard Error | Arbitrary units-Cleaved TnI/GAPDH | Before surgery and 10 minutes reperfusion after surgery |
|
|
|
| Secondary | Venous Plasma Concentration of C-reactive Protein | Measurement of inflammation marker C-reactive protein in plasma | Posted | Mean | Standard Error | ng/ml | Before surgery and up to 72 h reperfusion after surgery |
|
|
|
| Secondary | Venous Plasma Concentration of IL-6 | Measurement of inflammation marker interleukin-6 in plasma | Posted | Mean | Standard Error | pg/ml | Before surgery and up to 72 h reperfusion after surgery |
|
|
|
| 0 |
| 22 |
| 0 |
| 22 |
| 0 |
| 22 |
| EG001 | 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). 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. | 0 | 20 | 0 | 20 | 0 | 20 |
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| D013568 | Pathological Conditions, Signs and Symptoms |
| D006844 |
| Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| 10 min reperfusion |
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| 20 min reperfusion |
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| 3 h reperfusion |
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| 6 h reperfusion |
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| 24 h reperfusion |
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| 72 h reperfusion |
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| 10 min reperfusion |
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| 20 min reperfusion |
|
| 3 h reperfusion |
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| 6 h reperfusion |
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| 24 h reperfusion |
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| 72 h reperfusion |
|
| 10 min reperfusion |
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| 20 min reperfusion |
|
| 3 h reperfusion |
|
| 6 h reperfusion |
|
| 24 h reperfusion |
|
| 72 h reperfusion |
|
| 10 min reperfusion |
|
| 20 min reperfusion |
|
| 3 h reperfusion |
|
| 6 h reperfusion |
|
| 24 h reperfusion |
|
| 72 h reperfusion |
|