A Phase 2 interventional study of Periostat and Placebo Oral Tablet in Coronary Artery Bypass Grafting, Cardiopulmonary Bypass and Reperfusion Injury, sponsored by University of Alberta. Completed at 1 site in Canada. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2017-12-15.
Sponsored by University of Alberta · Phase 2, Interventional, and Prevention
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.
271 studies on the registry are indexed under Reperfusion Injury; 42 are open to participants now.
This study's enrollment of 56 is close to the median of 61 across 215 interventional studies indexed under Reperfusion Injury.
Browse Reperfusion Injury studies →University of Alberta is the lead sponsor of 800 studies on the registry; 168 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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
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.
Also known as: Doxycycline
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.
Also known as: Placebo
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.
Time frame: Before surgery up to 24h of reperfusion
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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: Before surgery and 10 minutes reperfusion after surgery
Venous Plasma Concentration of C-reactive Protein
Measurement of inflammation marker C-reactive protein in plasma
Time frame: Before surgery and up to 72 h reperfusion after surgery
Venous Plasma Concentration of IL-6
Measurement of inflammation marker interleukin-6 in plasma
Time frame: Before surgery and up to 72 h reperfusion after surgery
| Milestone | Placebo Oral Tablet | Periostat |
|---|---|---|
| Started | 28 | 28 |
| Completed | 22 | 20 |
| Not completed | 6 | 8 |
| Withdrew: Death | 1 | 0 |
| Withdrew: Additional surgery scheduled | 0 | 2 |
| Withdrew: Surgery schedule change | 4 | 4 |
| Withdrew: Other | 1 | 2 |
| Milestone | Placebo Oral Tablet | Periostat |
|---|---|---|
| Started | 22 | 20 |
| Completed | 22 | 20 |
| Not completed | 0 | 0 |
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.
| g*m/m2 | Placebo Oral Tablet | Periostat |
|---|---|---|
| Before surgery | 42 ± 2.6 | 43 ± 2.5 |
| Post surgery | 29 ± 1.7 | 28 ± 1.7 |
| 1h reperfusion | 30 ± 1.8 | 29 ± 1.9 |
| 3h reperfusion | 31 ± 1.9 | 29 ± 2 |
| 6h reperfusion | 28 ± 1.4 | 25 ± 1.4 |
| 12h reperfusion | 30 ± 1.6 | 30 ± 1.7 |
| 24h reperfusion | 32 ± 1.8 | 33 ± 1.9 |
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
| Arbitrary units | Placebo Oral Tablet | Periostat |
|---|---|---|
| Before surgery | .75 ± .25 | 1.56 ± .26 |
| 10 min reperfusion | .44 ± .28 | 1.63 ± .29 |
Biochemical activity of MMP-2 activity in right atrial biopsies, measured at 10 minutes of reperfusion after surgery.
| Arbitrary units | Placebo Oral Tablet | Periostat |
|---|---|---|
| Before surgery | .36 ± .04 | .24 ± .04 |
| 10 min reperfusion | .42 ± .04 | .25 ± .04 |
Biochemical activity of MMP-9 activity in venous plasma, measured before surgery and up to 72h of reperfusion after surgery.
| Arbitrary units | Placebo Oral Tablet | Periostat |
|---|---|---|
| Before anesthesia | .07 ± .04 | .11 ± .04 |
| After anesthesia | .06 ± .04 | .12 ± .04 |
| 10 min reperfusion | 1.22 ± .08 | 1.37 ± .08 |
| 20 min reperfusion | 1.14 ± .09 | 1.3 ± .09 |
| 3 h reperfusion | .52 ± .08 | .53 ± .08 |
| 6 h reperfusion | .21 ± .04 | .22 ± .04 |
| 24 h reperfusion | .05 ± .03 | .09 ± .01 |
| 72 h reperfusion | .03 ± .01 | .03 ± .01 |
Biochemical activity of MMP-2 activity in venous plasma, measured before surgery and up to 72h of reperfusion after surgery.
| Arbitrary units | Placebo Oral Tablet | Periostat |
|---|---|---|
| Before anesthesia | .99 ± .05 | 1.06 ± .05 |
| After anesthesia | .93 ± .04 | .96 ± .04 |
| 10 min reperfusion | 1.01 ± .06 | 1.05 ± .06 |
| 20 min reperfusion | .87 ± .04 | 1 ± .04 |
| 3 h reperfusion | .99 ± .05 | 1.06 ± .05 |
| 6 h reperfusion | .92 ± .07 | 1.07 ± .07 |
| 24 h reperfusion | .78 ± .05 | .9 ± .05 |
| 72 h reperfusion | .78 ± .04 | .9 ± .04 |
Measurement of levels of TnI (troponin-I), a marker of cardiac cell damage
| pg/ml | Placebo Oral Tablet | Periostat |
|---|---|---|
| Before surgery | 1.23 ± .33 | 1.07 ± .34 |
| Post surgery | 1.39 ± .46 | 1.78 ± .47 |
Measurement of the ratios of cleaved TnI (troponin-I) versus GAPDH in biopsies collected from right atria. Measure is the ratio TnI/GAPDH
| Arbitrary units-Cleaved TnI/GAPDH | Placebo Oral Tablet | Periostat |
|---|---|---|
| Before surgery | 1.1318 ± .3852 | 2.3454 ± .3978 |
| Post surgery | 1.5195 ± .3745 | 2.1893 ± .3868 |
Measurement of inflammation marker C-reactive protein in plasma
| ng/ml | Placebo Oral Tablet | Periostat |
|---|---|---|
| Before anesthesia | 5.7 ± 2 | 10 ± 2 |
| After anesthesia | 5.7 ± 1.8 | 9.9 ± 2 |
| 10 min reperfusion | 4 ± 1.3 | 7.5 ± 1.5 |
| 20 min reperfusion | 4 ± 1.5 | 7.2 ± 1.3 |
| 3 h reperfusion | 5.2 ± 1.7 | 9.4 ± 1.8 |
| 6 h reperfusion | 12.9 ± 2 | 16.3 ± 2.1 |
| 24 h reperfusion | 51 ± 1.9 | 48.8 ± 1.9 |
| 72 h reperfusion | 51.1 ± 1.2 | 51.2 ± 1.2 |
Measurement of inflammation marker interleukin-6 in plasma
| pg/ml | Placebo Oral Tablet | Periostat |
|---|---|---|
| Before anesthesia | 5.7 ± 2 | 1.9 ± 2 |
| After anesthesia | 5.6 ± 1.9 | 2.8 ± 1.9 |
| 10 min reperfusion | 15.4 ± 2.7 | 7.3 ± 2.7 |
| 20 min reperfusion | 24.4 ± 3.3 | 15.1 ± 3.4 |
| 3 h reperfusion | 72.9 ± 6.6 | 76.1 ± 6.7 |
| 6 h reperfusion | 75.6 ± 5.9 | 83.4 ± 6 |
| 24 h reperfusion | 66.4 ± 6.4 | 71.8 ± 6.5 |
| 72 h reperfusion | 39 ± 5.7 | 28.1 ± 5.8 |
Collected over 72 hours. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo Oral Tablet | 0/22 (0%) | 0/22 (0%) | 0/22 (0%) |
| Periostat | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) |
| Age, Continuous(years) | Placebo Oral Tablet | Periostat | Total |
|---|---|---|---|
| Mean | 64.6 ± 1.5 | 63.1 ± 2 | 63.9 ± 1.2 |
| Sex: Female, Male(Participants) | Placebo Oral Tablet | Periostat | Total |
|---|---|---|---|
| Female | 6 | 3 | 9 |
| Male | 16 | 17 | 33 |
| Region of Enrollment(Participants) | Placebo Oral Tablet | Periostat | Total |
|---|---|---|---|
| Canada | 22 | 20 | 42 |
Plan to share: Undecided
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