Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARMELINA)
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Placebo; Linagliptin
Intervention description: placebo matching tablets
Intervention MeSH terms: Linagliptin
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 6991.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

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).