The primary objective is to demonstrate non-inferiority (by means of comparing the upper limit of a two-sided 95% confidence interval with the non-inferiority margin of 1.3) of treatment with linagliptin in comparison to placebo (as add-on therapy…
ID
Source
Brief title
Condition
- Diabetic complications
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint in this trial is time to the first occurence of any of the
following by adjudication confirmed components of the primary composite
endpoint (3-point MACE): CV death, non-fatal MI or non fatal stroke.
Secondary outcome
Time to first occurance of any of the following by adjudication confirmed
components: Composite renal endpoint (renal death,
sustained end stage renal disease [ESRD], sustained decrease of 40% or more in
eGFR
Background summary
The DPP-4 inhibitor compound linagliptin was discovered by Boehringer Ingelheim
Pharma GmbH & Co. KG, Germany. Linagliptin is a potent inhibitor of DPP-4
activity and prolongs the half-life of GLP-1. Its efficacy and safety are
well-known through extensive data collection. The aim of the present study is
to investigate the long*term impact on CV morbidity and mortality of treatment
with linagliptin in a selected population of patients with T2DM and compare
outcomes against placebo, on a background of standard of care. To date, this
has not been tested in long-term trials of linagliptin.
Study objective
The primary objective is to demonstrate non-inferiority (by means of comparing
the upper limit of a two-sided 95% confidence interval with the non-inferiority
margin of 1.3) of treatment with linagliptin in comparison to placebo (as
add-on therapy on top of standard of care) with respect to time to first
occurrence of any of the adjudicated components of the primary composite
endpoint (i.e. cardiovascular (CV) death
[including fatal stroke, fatal MI and sudden death], non-fatal stroke,
non-fatal myocardial infarction (MI) (excluding silent MI) and hospitalisation
for unstable angina pectoris) in patients with type 2 diabetes mellitus (T2DM).
If non-inferiority has been demonstrated, then the primary composite endpoint
will be tested for superiority and the other objective, to assess the impact of
treatment with respect to the composite renal endpoint (i.e. renal death,
sustained end-stage renal disease (ESRD), sustained loss in estimated global
filtration rate (eGFR) * 50% from baseline), will be investigated separately
with a test on superiority.
Study design
This randomized, double-blind, placebo controlled, parallel group study
compares treatment with linagliptin (5 mg once daily) to treatment with placebo
(matching tablets once daily) as add-on therapy to standard of care.
Intervention
Treatment with linagliptin (5 mg once daily) or placebo treatment (matching
tablets once daily) as add-on
therapy to standard antidiabetic treatment.
Study burden and risks
Potential general benefits for study participants in this trial irrespective of
investigational drug received are 1) improvements in glycaemic control, 2)
improvements of other CV risk factors and 3) general medical benefit from
careful and close monitoring by medical
personnel and home blood glucose monitoring during the study. General risks
associated with participating are related to trial specific procedures such as
blood sampling that can be associated with bruising and pain. The amount of
blood taken during the whole course of the trial is not believed to be
associated with any discomfort for the patients.
Linagliptin from its clinical phase III testing has shown a safety profile
similar to placebo. It carries a low risk for inducing hypoglycaemia and is
generally weight neutral. Safety will be ensured by monitoring the patients for
AEs both clinically and by laboratory testing. If any
investigator should have a clinical concern, the safety of the patients will be
of paramount importance. Given the large safety margin derived from the
toxicology studies, the wide therapeutic window of linagliptin (120-fold
recommended clinical dose), the high tolerability
observed in previous trials in subjects with T2DM, and the monitoring
throughout the trial the sponsor is of the opinion that the risks for the
participating patients are minimal and justified.
Binger Strae 173
Ingelheim am Rhein 55216
DE
Binger Strae 173
Ingelheim am Rhein 55216
DE
Listed location countries
Age
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 GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors if * 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).
6) Body Mass Index (BMI) < of gelijk aan 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 CV events
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 ALT (SGPT), AST (SGOT), or alkaline phosphatase (AP) =>; 3 x upper limit of normal (ULN) as determined at Visit 1.
4) eGFR <15 ml/min 1.73 m2 (severe renal impairment or ESRD, 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 laparascopic) 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-004148-23-NL |
| ClinicalTrials.gov | NCT01897532 |
| CCMO | NL44998.068.13 |