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Cardiovascular and Renal Microvascular

Outcome Study With Linagliptin in
Patients With Type 2 Diabetes Mellitus
(CARMELINA)

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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

Study Details Tabular View Study Results

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Study Go to
Description

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.

Condition
or Intervention/treatment Phase
disease ! !
!

Diabetes Drug: Placebo Phase 4

Mellitus, Drug: Linagliptin
Type 2

Study Go to
Design

Study Type ! :
Interventional (Clinical Trial)

Actual Enrollment ! :
6991 participants

Allocation:
Randomized

Intervention Model:
Parallel Assignment

Masking:
Double (Participant, Investigator)

Primary Purpose:
Treatment

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

Actual Study Start Date ! :

July 10, 2013

Actual Primary Completion Date ! :

January 18, 2018

Actual Study Completion Date ! :

January 18, 2018

Resource links provided by the National Library

of Medicine

Genetics Home Reference related topics:

Type 2 diabetes

Drug Information available for: Linagliptin

U.S. FDA Resources

Arms and Go to
Interventions

Intervention/treatment
Arm !
!

Experimental: Drug: Linagliptin

Linagliptin

Placebo Comparator: Drug: Placebo

Placebo placebo matching
tablets

Outcome Go to
Measures

Primary Outcome Measures ! :

1. 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.

Secondary Outcome Measures ! :

1. 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.

Eligibility Go to
Criteria

Information from the National Library of

Medicine

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personal decision. Talk with your doctor and family
members or friends about deciding to join a study.
To learn more about this study, you or your doctor
may contact the study research staff using the
contacts provided below. For general information,
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Ages Eligible for Study:

18 Years and older (Adult, Older Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

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).

Contacts Go to
and
Locations

Information from the National Library of

Medicine

To learn more about this study, you or your doctor

may contact the study research staff using the
contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov

identifier (NCT number): NCT01897532

Show 649 Study Locations

Sponsors and Collaborators

Boehringer Ingelheim

Eli Lilly and Company

Investigators

Study Chair: Boehringer Ingelheim Boehringer Ingelh

Study Documents (Full-Text)

Documents provided by Boehringer Ingelheim:

Study Protocol [PDF] November 22, 2016

Statistical Analysis Plan [PDF] December 18, 2017

More Go to
Information

Additional Information:
Related Info

Publications automatically indexed to this study by

ClinicalTrials.gov Identifier (NCT Number):

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.

Responsible Party:
Boehringer Ingelheim

ClinicalTrials.gov Identifier:
NCT01897532 History of Changes

Other Study ID Numbers:

1218.22
2011-004148-23 ( EudraCT Number )

First Posted:
July 12, 2013 Key Record Dates

Results First Posted:

January 25, 2019

Last Update Posted:

April 4, 2019

Last Verified:
March 2019

Additional relevant MeSH terms:

Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Linagliptin
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone
Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

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