03879nas a2200325   4500000000100000008004100001100001600042700001900058700002800077700001800105700001900123700002400142700001500166700001900181700002100200700002100221700001900242700002000261700001600281700001900297700001900316700001500335700002200350700003000372245026000402300000700662490000700669520286300676022001403539       2018                            d1 aCooper Mark1 aPerkovic Vlado1 avon Eynatten Maximilian1 aMarx Nikolaus1 aMcGuire Darren1 aWoerle Hans-Juergen1 aBroedl Uli1 aGeorge Jyothis1 aRosenstock Julio1 aWanner Christoph1 aAlexander John1 aPencina Michael1 aToto Robert1 aZinman Bernard1 aBaanstra David1 aPfarr Egon1 aMattheus Michaela1 aCARMELINA® investigators00aRationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio  a390 v173 a<p><b>BACKGROUND: </b>Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINAtrial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk.</p><p><b>METHODS: </b>CARMELINAis a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, ≥ 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINAwas designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure.</p><p><b>RESULTS: </b>Between July 2013 and August 2016, 6980 patients were randomized and took ≥ 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean ± SD age was 65.8 ± 9.1 years, HbA1c 7.9 ± 1.0%, BMI 31.3 ± 5.3 kg/m, and eGFR 55 ± 25 mL/min/1.73 m. A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 mor macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common.</p><p><b>CONCLUSIONS: </b>CARMELINAwill add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk. Trial registration ClinicalTrials.gov identifier-NCT01897532; registered July 9, 2013.</p>  a1475-2840