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Rationale and Design of the CAROLINA Trial: An Active Comparator CARdiOvascular Outcome Study of the DPP-4 InhibitorLINAgliptin in Patients With Type 2 Diabetes at High Cardiovascular RiskJulio Rosenstock1, Nikolaus Marx2, Steven E. Kahn3, Bernard Zinman4, John J. Kastelein5, John Lachin6, Erich Bluhmki7, Arno Schlosser8, Dietmar Neubacher7, Sanjay Patel9, Odd Erik Johansen10, Hans-Jüergen Woerle111Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA; 2Department of Internal Medicine, University Hospital Aachen, Aachen, Germany; 3Department of Medicine, University of Washington, Seattle, WA, USA; 4Mount Sinai Hospital,University of Toronto, Toronto, Canada; 5Department of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands; 6Biostatistics Center, George Washington University, Rockville, MD, USA; 7Boehringer Ingelheim, Biberach, Germany;8Boehringer Ingelheim, Alkmaar, The Netherlands; 9Boehringer Ingelheim, Bracknell, UK; 10Boehringer Ingelheim, Asker, Norway; 11Boehringer Ingelheim, Ingelheim, Germany • Treating hyperglycemia in type 2 diabetes mellitus (T2DM) can reduce the onset and progression • CAROLINA is a head-to-head, event-driven, multicenter, randomized, double-blind, active Study Interventions
Statistical Analysis
• Clinical studies of most glucose-lowering drugs have failed to demonstrate of microvascular complications; however, the effect on macrovascular complications remains comparator study designed to compare treatment with linagliptin versus glimepiride both as • Patients will enter a 2-week, open-label, placebo run-in phase up to 4 weeks before being • The primary objective of CAROLINA is to demonstrate the non-inferiority (by means of comparing monotherapy or as add-on therapy to metformin or α-glucosidase inhibitors (NCT01243424) randomly assigned to 1 of the following treatment groups (Figure 1): the upper limit of a 2-sided 95% confidence interval with the non-inferiority margin of 1.3) of a beneficial effect on CV complications, which is the leading cause of • The successful management of T2DM complications may be limited by the anti-diabetic drugs – Masked linagliptin 5 mg plus placebo once daily, or treatment with linagliptin versus glimepiride with respect to time to first occurrence of any of the Patient Recruitment and Eligibility
currently available; limitations include: • Approximately 700 trial centers in 45 countries will participate to ensure that at least 6000 patients – Masked glimepiride 1–4 mg plus placebo once daily • Long-term efficacy of oral glucose-lowering drugs is equivocal and AEs can – Adverse events (AEs) and contraindications in certain patient populations • If non-inferiority is achieved, the secondary primary objective is to demonstrate CV superiority of • After a starting dose of 1 mg/day, glimepiride will be up-titrated to a potential maximum dose linagliptin versus glimepiride with a hypothesized risk reduction of 20% limit their use in certain at-risk patient populations – Inadequate efficacy to maintain treatment goals beyond 5 to 10 years • Patients with T2DM without optimal glycemic control and at high risk of CV events will be enrolled of 4 mg/day at 4-week intervals during the first 16 weeks of treatment (if the fasting bloodglucose values are >110 mg/dL [6.1 mmol/L]) • At an estimated annual CV event rate of 2% for the primary event definition for glimepiride, – Concerns regarding cardiovascular (CV) safety – Other inclusion criteria are body mass index ≤45 kg/m2, and age ≥40 and ≤85 years 631 events will be required to provide 91% power to yield the upper limit of the adjusted 95% • Concerns regarding the CV safety of some treatment modalities requires • Patients on previous glimepiride treatment may continue on their current dose (e.g., if the • The oral anti-diabetic drug linagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, has recently • At screening, the dose of anti-diabetic background therapy should have been stable for at least 8 weeks confidence interval for a hazard ratio <1.3 at a 1-sided α level of 0.025 assuming equal risks and further investigation in large, head-to-head, active-comparator studies glimepiride dose was ≥4 mg/day, the masked starting dose will be 4 mg/day) become available for the treatment of T2DM 80% power to demonstrate superiority at a true hazard ratio of 0.8 • The masked dose of glimepiride can be altered to prevent recurrent hypoglycemic events at any time – In clinical trials, linagliptin once daily improved glycemic control without weight gain and • All other secondary analyses will be exploratory with no correction for multiple hypotheses • Although there is a need for the development of new anti-diabetic therapies Glycemic Entry Criteria
demonstrated a benign safety and tolerability profile without the need for dose adjustment in testing. All statistical tests and confidence intervals will be 2-sided with a significance level with increased efficacy, it is essential to explore long-term safety, in Insufficient glycemic control defined as:
Figure 1: Study design
Masked linagliptin 5 mg/day
Interim Assessments
HbA1c 6.5–8.5% while patient is treatment naïve or treated with: • An independent Data Monitoring Committee (DMC) will perform formal interim analyses of the • The CAROLINA trial is investigating the long-term impact on CV morbidity Screening
primary outcome and, in consultation with the Steering Committee and the Sponsor, will decide and mortality of treatment with linagliptin in a patient population α-glucosidase inhibitor monotherapy (e.g., acarbose, voglibose), or on the number and timepoints of the interim analyses without sharing the results iii) metformin plus α-glucosidase inhibitor (e.g., acarbose, voglibose), or • With preliminary evidence from short-term trials suggesting that DPP-4 inhibitors are associated Masked glimepiride 1–4 mg/day
– The DMC might recommend terminating the trial after an interim analysis HbA1c 6.5–7.5% while patient is treated with: with potential CV benefits, long-term studies are now required • The CAROLINA study population at an earlier stage of T2DM may provide Sub-Studies
• In keeping with the spirit of comparative effectiveness testing for new diabetes drugs, ideally glinide monotherapy (e.g., repaglinide, nateglinide), or • Several sub-studies are planned to explore key epidemiologic information and further examine an opportunity to test the impact of DPP-4 inhibitors and sulfonylureas on long-term CV outcome trials need to have active comparators iii) metformin plus sulfonylurea (combination maximal up to 5 years), or the potential benefits of linagliptin and glimepiride (Table 1) • The CAROLINA (CARdiOvascular Safety of LINAgliptin) trial will investigate the long-term iv) metformin plus glinide (combination maximal up to 5 years), or impact on CV morbidity and mortality of treatment with linagliptin or glimepiride, a widely used α-glucosidase inhibitor plus sulfonylurea (combination maximal up to 5 years), or Randomization at Visit 2 (Study Week 0; Baseline) vi) α-glucosidase inhibitor plus glinide (combination maximal up to 5 years) *16-week titration phase: glimepiride uptitrated from 1 mg/day to 4 mg/day at 4-week intervals Table 1: Outline of planned sub-studies
– The trial will be conducted with linagliptin versus glimepiride both administered as monotherapy or as add-on therapy to metformin or α-glucosidase inhibitors Sub-study
Primary outcome
CV Risk Entry Criteria
• In addition to important efficacy and safety parameters, the trial will include a number of sub-studies • After randomization, study visits are scheduled to occur monthly until 4 months, and then designed to advance further our understanding of DPP-4 inhibition in the management of patients High risk of CV events defined as any 1 (or more) of a), b), c), or d):
• CAROLINA, as an active control trial, is unique among CV outcomes – All patients, including those who discontinue treatment, will be followed up until the end of the study studies of DPP-4 inhibitors as it aims to demonstrate the non-inferiority of • Rescue treatments to maintain glucose levels at HbA1c ≤7.5% (58 mmol/mol) are permitted treatment with linagliptin versus glimepiride with respect to time to first throughout the study and include metformin, pioglitazone, or insulin Documented coronary artery disease (≥50% luminal diameter narrowing of left main coronary occurrence of any of the components of the primary composite CV outcome – Dosing will be according to local labeling and at the investigator’s discretion artery or in at least 2 major coronary arteries in angiogram) iii) Percutaneous coronary intervention >6 weeks • All patients should be provided healthy lifestyle advice • If non-inferiority is achieved, the secondary primary objective is to Primary Outcomes
iv) Coronary artery bypass grafting >4 years or with recurrent angina following surgery • The protocol also encourages the treatment of all other CV risk factors (lipid levels, blood pressure, • The time to the first occurrence of any of the following components of the MACE composite demonstrate CV superiority of linagliptin versus glimepiride with a Ischemic or hemorrhagic stroke (>3 months) micro/macroalbuminuria, smoking) according to local or regional guidance for primary or secondary vi) Peripheral occlusive arterial disease variability and CV biomarkers (oxidation, Evidence of vascular related end-organ damage: Moderately impaired renal function (as defined by Modified Diet in Renal Disease [MDRA] formula) Assessments
• The more homogeneous early stage of the study population in the with estimated glomerular filtration rate 30–59 mL/min/1.73 m2 CAROLINA trial will provide valuable information on the maintenance of Random spot urinary albumin:creatinine ratio ≥30 µg/mg in 2 of 3 specimens in the previous 12 months – Physical examination, vital signs, laboratory markers (including lipid profile), a check for AEs Impact on insulin secretion rate assessed by long-term glycemic control following DPP-4 inhibition iii) Proliferative retinopathy defined as retinal neovascularization or previous retinal laser coagulation therapy – Hospitalization for unstable angina pectoris and concomitant therapies, 12-lead electrocardiogram (ECG) Age ≥70 years (<25% of the study population) • The CV death component includes sudden cardiac death and death due to: • At selected visits as part of sub-studies: • In addition, the impact of glimepiride treatment on CV outcomes will be At least 2 of the following CV risk factors (<25% of the study population): – Collection of biomarkers (fasting proinsulin, C-peptide, antibodies toward the pancreatic β cell, Systolic blood pressure >140 mm Hg (or on at least 1 blood pressure-lowering treatment) troponin T, inflammatory markers, endothelial function markers, and markers of oxidative stress), pharmacogenetic sampling, periods with continuous glucose monitoring, periods with • The sub-studies will also help further our knowledge regarding the – Cerebrovascular event (intracranial hemorrhage or non-hemorrhagic stroke) iv) LDL-cholesterol ≥135 mg/dL (3.5 mmol/L) (or specific current treatment for this lipid abnormality) mixed meal tolerance testing for detailed β cell function assessment, cognitive function tests, and treatment and management of T2DM, as well as the mechanism of action of a self-reporting depression questionnaire assessment of CV prophylactic properties Safety Evaluations
Secondary Outcomes
Key Exclusion Criteria
• The occurrence of and time to each of the following events: CV death (including fatal stroke and • Treatment sustainability (need for rescue treatment to maintain glycated hemoglobin (HbA1c) Use of rescue therapy and disease trajectory fatal MI), non-fatal MI, non-fatal stroke, hospitalization for unstable angina pectoris, stable angina • Any treatment with other glucose-lowering drugs (e.g., rosiglitazone, pioglitazone, GLP-1 receptor pectoris, transient ischemic attack, hospitalization for congestive heart failure, hospitalization for agonists, DPP-4 inhibitors, or any insulin) • Treatment with anti-obesity drugs 3 months prior to screening • The incidence and intensity of AEs, physical examination, vital signs, ECG, change from baseline • Uncontrolled hyperglycemia with a fasting glucose level >240 mg/dL (>13.3 mmol/L) Boehringer Ingelheim would like to thank the patients and staff participating in this study. This work was supported by Boehringer Ingelheim. Medical writing support was provided by Paul MacCallum • Active liver disease or impaired hepatic function as per specific enzyme criteria • The proportion of patients with asymptomatic, symptomatic, and severe hypoglycemic episodes of Envision Scientific Solutions during the preparation of this poster and was supported by • The change from baseline in weight and proportion of patients with ≤2% or >2% weight gain • Any previous (or planned within next 12 months) bariatric surgery or intervention Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, and • Pre-planned coronary artery re-vascularization within next 6 months • AEs of special interest (hypersensitivity reactions, skin lesions, hepatic events, renal AEs, pancreatitis) were involved at all stages of poster development.
Poster: 1103-P, 71st Scientific Sessions of the American Diabetes Association, San Diego, California, June 24–28, 2011
Author Contact Information: Dr Odd Erik Johansen, Boehringer Ingelheim, Drengsrudbekken 25, 1373 Asker, Norway. Tel: +47 91817674
Boehringer Ingelheim 2011


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