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Effect of Targeting Inflammation with Salsalate

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Effect of Targeting Inflammation with Salsalate TINSAL-CVD Protocol v 2.7 Targeting INflammation using SAlsalate or Lifestyle intervention in CardioVascular Disease Protocol Funded by National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI) P50-HL-083813 Distributed by TINSAL-CVD Study Group Beth Israel Deaconess Hospital Joslin Diabetes Center The Jean Mayer USDA Human Nutrition Center on Aging at Tufts University Boston, MA Version 2.7 February 12,2013 CONFIDENTIAL Downloaded From: https://jamanetwork.com/ on 09/25/2021 Protocol Amendment: Version 2.7 Modifications of the protocol for performance of the end of study MDCTA for study subjects with heart rate above 65bpm upon arrival at BIDMC’s Department of Radiology. These changes are a revision of the then current protocol used by the radiology department which were approved in version 2.3. Previously, the dosing criteria was based solely on the heart rate and did not take the blood pressure into consideration. The new criteria for metoprolol dosing are: Version 2.7: For patients who did NOT take their β-blocker, give them their usual daily dose 1 hour before scan. For all patients regardless of heart rate: SBP < 100 - no metoprolol SBP 100 – 105 - should receive a maximum 25mg of metoprolol SBP 106 - 110 - should receive a maximum of 50mg of metoprolol For patients with SBP > 110 and who do not normally take a β-blocker: For heart rates > 81 - maximum 100mg metoprolol For heart rates 76-80 - maximum 75mg metoprolol For heart rates 71-75 - maximum 50mg metoprolol For heart rates 65-70 - maximum 25mg metoprolol If necessary, IV Metoprolol can be given in 5 mg doses every 5 minutes to 20 mg total. For patients who took their β-blocker more than 1 hour prior to initial vitals being taken: For heart rates > 81 – give a maximum additional 75mg metoprolol For heart rates 65-80 - give a maximum additional 50mg metoprolol Version 2.3 For subjects with a heart rate greater than this, the beta-blocker Metoprolol (50 mg) will be administered by mouth to reduce the rate to less than 65 beats per minute one hour before the MDCTA. If the subject’s heart rate remains greater than 65 beats per minute at 1 hour after 50 mg of metoprolol is given by mouth, additional metoprolol will be given per the current radiology protocol until the heart rate goes down to 65 beats per minute. Protocol Amendment: Version 2.6 Modification of the protocol for performance of end of study MDCTA for study subjects with creatinine up to 1.9 mg/dL. The clinical radiology protocol for the Beth Israel Deaconess Medical Center will be utilized. • For Cr level of 1.3 to 1.6 mg/dL: oral hydration (1 liter of water by mouth) pre and post administration of Optiray 320 or 350. • For Cr level of 1.7 to 1.9 mg/dL: oral hydration (1 liter of water by mouth) pre and post administration of 100cc of Visipaque. Page ii Downloaded From: https://jamanetwork.com/ on 09/25/2021 Section 2.2.2, page 49 and Section 2.3.3, page 52 Two weeks before end of treatment visit, subjects will have blood drawn to check BUN, Cr and eCrCLCG. If eCrCLCG is <55 ml/min or serum Cr > 1.3 mg/dL, subjects will drink additional water for 3 days and have blood work repeated. If eCrCLCG continues to be <55 ml/min or serum Cr > 1.3 mg/dL, subjects will not undergo the final MDCTA but will finish all other aspects of the study, we will use the Beth Israel Deaconess Hospital clinical radiology protocol for hydration: Cr level 1.3 to 1.6 mg/dL: oral hydration (1 liter of water by mouth) pre and post administration of Optiray 320 or 350, and for Cr level of 1.7 to 1.9 mg/dL: oral hydration pre and post administration of 100cc of Visipaque. At the end of the visit at month 30, subjects will be dismissed from the study and returned to the care of their primary and cardiac care physicians. Version 2.4 Two weeks before end of treatment visit, subjects will have blood drawn to check BUN, Cr and eCrCLCG. If eCrCLCG is <55, subjects will drink additional water for 3 days and have blood work repeated. If eCrCLCG continues to be <55, subjects will not undergo the final MDCTA but will finish all other aspects of the study. Section 5.2.4, page 66 and Section 6.2.1.4, page 73 For those few subjects who may have a Cr >1.3 mg/dL or CrCl < 55 ml/min, we will use the Beth Israel Deaconess Hospital clinical radiology protocol for hydration: Cr level 1.3 to 1.6 mg/dL: oral hydration (1 liter of water by mouth) pre and post administration of Optiray 320 or 350. For Cr level of 1.7 to 1.9 mg/dL: oral hydration pre and post administration of 100cc of Visipaque. Version 2.4 Those with eCrCLCG < 55 ml/min at 30 month follow-up are excluded from MDCTA. Protocol Amendment 2.5 Section 3.6 Statistical Analysis, pg. 61 The following statement has been added regarding the analysis of data for early termination subjects. We will assess the effects of missing data in the final dataset using a sensitivity analysis, imputing missing values using various optimistic and pessimistic assumptions (no change, mean/median change in the active treatment arm, mean/median change in the standard care arm, etc.) to assess the magnitude of any biased losses. Data from early assessment of the primary outcome in those participants who drop out of the trial will be used to determine the validity of these assumptions. We will also perform multiple imputation analysis using standard algorithms. Because missing data may represent informative censoring, we will also perform a formal survival analysis of both the intervention and placebo groups to determine if there has been any biased loss to follow-up. Section 4.1 Inclusion Criteria, pg. 62 The two study stratum will have different verbiage for major inclusion criteria. Page iii Downloaded From: https://jamanetwork.com/ on 09/25/2021 Version 2.5 –Lifestyle will revert to inclusion criteria from version 2.3 Eligibility will be based upon the presence of established coronary artery disease including previous myocardial infarction (≥6 months ago), previous coronary bypass surgery (> 12 months ago), stable angina, significant non-calcified plaque (as determined by Dr. Clouse) in at least one coronary artery or abnormal exercise tolerance test or an area of reversible ischemia on nuclear imaging study or pharmacologic stress, with subsequent revascularization, or angioplasty, or abnormal exercise treadmill stress test with or without nuclear imaging or echocardiography with the following exclusions: Version 2.4-Salsalate will maintain the inclusion criteria from version 2.4 Eligibility will be based upon the presence of established coronary artery disease including previous myocardial infarction (≥6 months ago), previous coronary bypass surgery (> 12 months ago), or angioplasty, stable angina, or evidence of coronary artery disease on prior imaging studies including, plaque in at least one coronary artery, or abnormal exercise tolerance test, or an area of reversible ischemia on nuclear imaging study or pharmacologic stress, with subsequent revascularization or determined not to require intervention by care providing cardiologist, or abnormal exercise treadmill stress test with or without nuclear imaging or echocardiography with the following exclusions: Note: the difference in these criteria includes the phrase “or determined not to require intervention by care providing cardiologis” We note that some patients may have known coronary artery disease associated with electrical or perfusion abnormalities on stress test and/or nuclear imaging that are medically treated and deemed medically stable and not requiring revascularization procedures at the current time. We will include these patients in the salsalate stratum of the study. The lifestyle statum employs unsupervised exercise and will exclude patients with any evidence of reversible ischemia. Section 4.2 Exclusion Criteria, pg. 63 Criterion #8 Persons with allergies to contrast dye was deleted because is is the same as criterion #10 Section 4.2 Exclusion Criteria, pg. 64 The following criterion was moved from the general exclusion criteria to the Salsalate only exclusion criteria. History of significant chronic rheumatologic or other chronic inflammatory disease (including foot ulcers). Section 6.2.4.1 Expected Risks, pg. 73 The following procedure has been added for monitoring renal function in Salsalate patients per the recommendation of the data safety monitoring board. In addition to the increased frequency of assessing unirnary microalbumin, and in accordance with the recommendations of the data safety monitoring board for this study, any participant who had a baseline MCR <150 mcg/mg cr, who develops a microalbumin to creatinine ratio (MCR) Page iv Downloaded From: https://jamanetwork.com/ on 09/25/2021 of 300mcg/mg cr or greater will have the laboratory assessment repeated with an unscheduled visit and for sustained elevation be evaluated by a nephrologist. For participants who entered the study with a baseline MCR > 150 mcg/mg cr we will recommend a nephrology consultation for a sustained doubling of the MCR rather than using a set cutoff value. Additionally, for participants with a large change, as defined above, discontinuation of the study drug will be strongly considered. All attempts will be made to keep the subject in the trial and evaluate the renal function after study drug discontinuation. Protocol Amendment: Version 2.4 Section 2.1 page 44 The inclusion criteria for normal renal function has been edited to include participants with a serum creatinine <1.3 if CrCl is < 60 ml/min/1.73m2 and there is no history of renal disease.
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