Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARMELINA)

• ClinicalTrials.gov Identifier: NCT01897532
• Recruitment Status: Completed
• First Posted: July 12, 2013
• Results First Posted: January 25, 2019
• Last Update Posted: April 4, 2019
• Sponsor: Boehringer Ingelheim
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Boehringer Ingelheim

Tracking Information

• First Submitted Date: July 9, 2013
• First Posted Date: July 12, 2013
• Results First Submitted Date: December 21, 2018
• Results First Posted Date: January 25, 2019
• Last Update Posted Date: April 4, 2019
• Actual Study Start Date: July 10, 2013
• Actual Primary Completion Date: January 18, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 21, 2018)

Time to the First Occurrence of Any of the Following Adjudication-confirmed Components of the Primary Composite Endpoint 3-point Major Adverse Cardiovascular (CV) Events (3-point MACE): CV Death, Non-fatal Myocardial Infarction (MI) or Non-fatal Stroke. [ Time Frame: From randomization to individual end of observation; up to 4.3 years ]

Time to event analysis of patients with first occurrence of any of the following adjudication-confirmed components of the primary composite endpoint (3-point MACE): CV death, non-fatal MI or non-fatal stroke. The percentage of observed patients with first occurrence of any of the following adjudication-confirmed components of the primary composite endpoint (3-point MACE) was reported.

• Original Primary Outcome Measures (submitted: July 9, 2013): Time to the first occurence of any of the following adjudicated components of the primary composite endpoint (4-point MACE): CV death, non-fatal MI, non fatal stroke and hospitalization for unstable angina pectoris [ Time Frame: 48 months ]

Current Secondary Outcome Measures (submitted: December 21, 2018)

Time to the First Occurrence of Any of the Following Adjudication-confirmed Components: Renal Death, Sustained End Stage Renal Disease (ESRD), or Sustained Decrease of 40% or More in Estimated Glomerular Filtration Rate (eGFR). [ Time Frame: From randomization to individual end of observation; up to 4.3 years ]

Time to the first occurrence of any of the following adjudication-confirmed components: renal death, sustained ESRD, or sustained decrease of 40% or more in eGFR. The percentage of observed patients with first occurrence of any of the following adjudication-confirmed components: renal death, sustained ESRD, or sustained decrease of 40% or more in eGFR was reported.

Original Secondary Outcome Measures (submitted: July 9, 2013)

• Time to first occurance of any of the following adjudicated components: CV death, non fatal MI and non fatal stroke (3-point MACE) [ Time Frame: 48 months ]
• Time to first occurance of any of the following adjudicated composite renal endpoint: renal death, end stage renal disease and a sustained decrease of 50% or more in eGFR [ Time Frame: 48 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARMELINA)
• Official Title: CARMELINA: A Multicenter, International, Randomized, Parallel Group, Double-blind, Placebo-controlled, Cardiovascular Safety and Renal Microvascular Outcome Study With Linagliptin, 5 mg Once Daily in Patients With Type 2 Diabetes Mellitus at High Vascular Risk
• Brief Summary: The aim of the study is to investigate the longterm impact on cardiovascular morbidity, mortality and renal function of treatment with linagliptin in a selected population of patients with Type 2 diabetes mellitus (T2DM) and to compare outcomes against placebo, on a background of standard of care.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Diabetes Mellitus, Type 2

Intervention

• Drug: Placebo
  placebo matching tablets
• Drug: Linagliptin

Study Arms

• Experimental: Linagliptin
  Intervention: Drug: Linagliptin
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Publications *

• Verhagen C, Janssen J, Exalto LG, van den Berg E, Johansen OE, Biessels GJ. Diabetes-specific dementia risk score (DSDRS) predicts cognitive performance in patients with type 2 diabetes at high cardio-renal risk. J Diabetes Complications. 2020 Oct;34(10):107674. doi: 10.1016/j.jdiacomp.2020.107674. Epub 2020 Jul 16.
• Perkovic V, Toto R, Cooper ME, Mann JFE, Rosenstock J, McGuire DK, Kahn SE, Marx N, Alexander JH, Zinman B, Pfarr E, Schnaidt S, Meinicke T, von Eynatten M, George JT, Johansen OE, Wanner C; CARMELINA investigators. Effects of Linagliptin on Cardiovascular and Kidney Outcomes in People With Normal and Reduced Kidney Function: Secondary Analysis of the CARMELINA Randomized Trial. Diabetes Care. 2020 Aug;43(8):1803-1812. doi: 10.2337/dc20-0279. Epub 2020 May 22.
• Biessels GJ, Verhagen C, Janssen J, van den Berg E, Zinman B, Rosenstock J, George JT, Passera A, Schnaidt S, Johansen OE; CARMELINA Investigators. Effect of Linagliptin on Cognitive Performance in Patients With Type 2 Diabetes and Cardiorenal Comorbidities: The CARMELINA Randomized Trial. Diabetes Care. 2019 Oct;42(10):1930-1938. doi: 10.2337/dc19-0783. Epub 2019 Aug 9.
• McGuire DK, Alexander JH, Johansen OE, Perkovic V, Rosenstock J, Cooper ME, Wanner C, Kahn SE, Toto RD, Zinman B, Baanstra D, Pfarr E, Schnaidt S, Meinicke T, George JT, von Eynatten M, Marx N; CARMELINA Investigators. Linagliptin Effects on Heart Failure and Related Outcomes in Individuals With Type 2 Diabetes Mellitus at High Cardiovascular and Renal Risk in CARMELINA. Circulation. 2019 Jan 15;139(3):351-361. doi: 10.1161/CIRCULATIONAHA.118.038352.
• Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, Alexander JH, Pencina M, Toto RD, Wanner C, Zinman B, Woerle HJ, Baanstra D, Pfarr E, Schnaidt S, Meinicke T, George JT, von Eynatten M, McGuire DK; CARMELINA Investigators. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial. JAMA. 2019 Jan 1;321(1):69-79. doi: 10.1001/jama.2018.18269.
• Rosenstock J, Perkovic V, Alexander JH, Cooper ME, Marx N, Pencina MJ, Toto RD, Wanner C, Zinman B, Baanstra D, Pfarr E, Mattheus M, Broedl UC, Woerle HJ, George JT, von Eynatten M, McGuire DK; CARMELINA® investigators. Rationale, 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-renal risk. Cardiovasc Diabetol. 2018 Mar 14;17(1):39. doi: 10.1186/s12933-018-0682-3.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 21, 2018): 6991
• Original Estimated Enrollment (submitted: July 9, 2013): 8300
• Actual Study Completion Date: January 18, 2018
• Actual Primary Completion Date: January 18, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

1. Documented diagnosis of T2DM before visit 1(screening).
2. Male or female patients who are drug-naïve or pre-treated with any antidiabetic background medication, excluding treatment with Glucagon-like Peptide 1 (GLP-1) receptor agonists, Dipeptidyl-peptidase 4 (DPP-4) inhibitors or Sodium Glucose Linked Transporter 2 (SGLT-2) inhibitors if => consecutive 7 days.
3. Stable antidiabetic background medication (unchanged daily dose) for at least 8 weeks prior to randomization. If insulin is part of the background therapy, the average daily insulin dose should not have changed by more than 10% within the 8 weeks prior to randomization compared with the daily insulin dose at randomization.
4. HbA1c of => 6.5% and <= 10.0% at Visit 1 (screening)
5. Age => 18 years at Visit 1(screening). For Japan only: Age => 20 years at Visit 1
6. Body Mass Index (BMI) <= 45 kg/m2 at Visit 1 (screening)
7. Signed and dated written informed consent by date of Visit 1(screening) in accordance with Good Clinical Practice (GCP) and local legislation prior to any study related procedure
8. High risk of cardiovascular (CV) events defined by: 1) albuminuria (micro or macro) and previous macrovascular disease and/or 2) impaired renal function with predefined Urine Albumin Creatinine Ratio (UACR)

Exclusion criteria:

1. Type 1 diabetes mellitus.
2. Treatment (=> 7 consecutive days) with GLP-1 receptor agonists, other DPP-4 inhibitors or SGLT-2 inhibitors prior to informed consent. Note: This also includes clinical trials where these antidiabetic drugs have been provided to the patient.
3. Active liver disease or impaired hepatic function, defined by serum levels of either Alanine Transaminase (ALT) (SGPT), Aspartate transaminase (AST) (SGOT), or alkaline phosphatase (AP) => 3 x upper limit of normal (ULN) as determined at Visit 1.
4. Estimated Glomerular filtration Rate (eGFR) <15 ml/min/1.73 m2 (severe renal impairment or End Stage Renal Disease (ESRD), Modification of Diet in Renal Disease (MDRD) formula), as determined during screening at Visit 1 and/or the need for maintenance dialysis.
5. Any previous (or planned within next 12 months) bariatric surgery (open or laparoscopic) or intervention (gastric sleeve).
6. Pre-planned coronary artery re-vascularisation (PCI, CABG) or any previous PCI and/or CABG <= 2 months prior informed consent.
7. Known hypersensitivity or allergy to the investigational products or its excipients.
8. Any previous or current alcohol or drug abuse that would interfere with trial participation in the opinion of the investigator.
9. Participation in another trial with an investigational drug ongoing or within 2 months prior to visit 1 (screening).
10. Pre-menopausal women (last menstruation = 1 year prior to informed consent) who are nursing or pregnant, are of child-bearing potential and are not practicing an acceptable method of birth control (acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence (if allowed by local authorities), double barrier method and vasectomised partner) or do not plan to continue using acceptable method of birth control throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial.
11. Patients considered unreliable by the investigator concerning the requirements for follow up during the study and/or compliance with study drug administration, have a life expectancy less than 5 years for non-CV causes, or have cancer other than non-melanoma skin cancer within last 3 years, or has any other condition than mentioned which in the opinion of the investigator, would not allow safe participation in the study.
12. Acute coronary syndrome (ACS), diagnosed <= 2 months prior to visit 1 (screening).
13. Stroke or Transient Ischemic Attack (TIA) <= 3 months prior to visit 1 (screening).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Brazil, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czechia, Germany, Hungary, Israel, Japan, Korea, Republic of, Malaysia, Mexico, Netherlands, Poland, Portugal, Romania, Russian Federation, South Africa, Spain, Taiwan, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01897532
• Other Study ID Numbers: 1218.22; 2011-004148-23 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Boehringer Ingelheim
• Study Sponsor: Boehringer Ingelheim
• Collaborators: Eli Lilly and Company

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

• PRS Account: Boehringer Ingelheim
• Verification Date: March 2019