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

Study Overview
=================
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.

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

Conditions
-----------------
Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: Linagliptin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Documented diagnosis of T2DM before visit 1(screening). 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. 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. HbA1c of => 6.5% and <= 10.0% at Visit 1 (screening) Age => 18 years at Visit 1(screening). For Japan only: Age => 20 years at Visit 1 Body Mass Index (BMI) <= 45 kg/m2 at Visit 1 (screening) 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 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: Type 1 diabetes mellitus. 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. 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. 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. Any previous (or planned within next 12 months) bariatric surgery (open or laparoscopic) or intervention (gastric sleeve). Pre-planned coronary artery re-vascularisation (PCI, CABG) or any previous PCI and/or CABG <= 2 months prior informed consent. Known hypersensitivity or allergy to the investigational products or its excipients. Any previous or current alcohol or drug abuse that would interfere with trial participation in the opinion of the investigator. Participation in another trial with an investigational drug ongoing or within 2 months prior to visit 1 (screening). 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. 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. Acute coronary syndrome (ACS), diagnosed <= 2 months prior to visit 1 (screening). Stroke or Transient Ischemic Attack (TIA) <= 3 months prior to visit 1 (screening).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Linagliptin<br> | Drug: Linagliptin<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* placebo matching tablets<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 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. | From randomization to individual end of observation; up to 4.3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 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. | From randomization to individual end of observation; up to 4.3 years |