Diabetes Mellitus, Type 2
Conditions
Brief summary
Evaluate linagliptin in terms of glycemic control as defined by HbA1c after 24 weeks of treatment and in terms of renal efficacy as defined by changes in albuminuria (UACR) after 24 weeks of treatment.
Interventions
DRUGPlacebo
DRUGLinagliptin 5mg
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of type 2 diabetes mellitus * Glycosylated Hemoglobin (HbA1c) between 6.5 and 10% (inclusive) * Current therapy with ACEi or ARB at stable dose for 10 weeks * Urinary albumin-to-creatinine ratio (UACR): 30-3000 mg/g creatinine documented in the previous 12 months or detected at Screening. * Estimated Glomerular Filtration Rate (eGFR) greater than 30 ml/min. * Age between 18 and 80 years.
Exclusion criteria
* Dual or triple blockade of the Renin Angiotensin System (RAS) * Uncontrolled hyperglycaemia * Mean arterial blood pressure \> 110 mmHg * Known hypersensitivity or allergy to the investigational product, or their excipients (including matching placebos). * Treatment with a glitazone within 6 months prior to informed consent. * Treatment with a DiPeptidyl-Peptidase 4 (DPP-4) inhibitor, a Glucagon Like Peptide-1 (GLP-1) agonist, a Sodium/Glucose coTransporter 2 (SGLT2) inhibitor, a dopamine-agonist, a bile-acid sequestrant a short acting (prandial) insulin or premixed insulin within 10 weeks prior to informed consent. * Treatment with anti-obesity drugs 10 weeks prior to informed consent. * Alcohol or drug abuse within 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake in the opinion of the investigator. * Current treatment with systemic steroids (glucocorticoids) at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent. * Participation in another trial with an investigational drug within 2 months prior to informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment | Baseline and 24 weeks | Change from baseline in Glycated haemoglobin (HbA1c) \[%\] after 24 weeks of treatment with double- blind trial medication. The term baseline refers to the last observation before the start of any randomised trial treatment. The number of participants analysed displays the number of participants with available data at the timepoint of interest. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Time Weighted Average of Percentage Change From Baseline in UACR During the Course of 24 Weeks of Treatment | Baseline and 24 weeks | The time weighted average of percentage change from baseline in UACR (mg/g creatinine) during the course of 24 weeks of treatment. The term baseline for UACR refers to the geometric mean of UACR values measured at Visits 2 and 3. The number of participants analysed displays the number of participants with available data at the timepoint of interest. The Least Squares Means are adjusted geometric means. |
| The Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 24 Weeks of Treatment | Baseline and 24 weeks | The change from baseline in estimated glomerular filtration rate (eGFR) as assessed by chronic kidney disease epidemiology collaboration (CKD-EPI) equation (cystatin C) after 24 weeks of treatment. The term baseline refers to the last observation before the start of any randomised trial treatment. The number of participants analysed displays the number of participants with available data at the timepoint of interest. This outcome measure is a secondary safety endpoint. |
Countries
Canada, Denmark, Finland, France, Germany, Japan, Philippines, South Korea, Spain, Taiwan, United States, Vietnam
Participant flow
Recruitment details
360 patients were randomised and treated (Placebo: 178 patients, Linagliptin: 182 patients.)
Pre-assignment details
Randomized, double-blind, placebo controlled, parallel group study to evaluate glycemic and renal efficacy of once daily administration of Linagliptin 5 milligram (mg) for 24 weeks in type 2 diabetes patients, with micro- or macroalbuminuria on top of current treatment with Angiotensin Converting Enzyme inhibitor or Angiotensin Receptor Blocker
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients received 1 matching placebo tablet to Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period. | 178 |
| Linagliptin 5 mg Patients received 1 tablet of Linagliptin 5 mg, administered orally, once every day for 24 weeks during the double blind treatment period. | 182 |
| Total | 360 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 4 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Other Reason | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Linagliptin 5 mg | Total |
|---|---|---|---|
| Age, Continuous | 60.1 Years STANDARD_DEVIATION 9.3 | 61.0 Years STANDARD_DEVIATION 10 | 60.6 Years STANDARD_DEVIATION 9.6 |
| Gender Female | 65 Participants | 66 Participants | 131 Participants |
| Gender Male | 113 Participants | 116 Participants | 229 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 178 | 39 / 182 |
| serious Total, serious adverse events | 8 / 178 | 17 / 182 |
Outcome results
Primary
HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment
Change from baseline in Glycated haemoglobin (HbA1c) \[%\] after 24 weeks of treatment with double- blind trial medication. The term baseline refers to the last observation before the start of any randomised trial treatment. The number of participants analysed displays the number of participants with available data at the timepoint of interest.
Time frame: Baseline and 24 weeks
Population: Full Analysis Set (FAS) - including all randomised patients who were treated with at least one dose of study drug, had a baseline HbA1c and a baseline Urinary albumin creatinine ratio (UACR), and at least one on treatment HbA1c or UACR assessment. Observed Case (OC): Values after the use of rescue medication were set to missing.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment | -0.03 Percentage of HbA1c | Standard Error 0.06 |
| Linagliptin 5 mg | HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment | -0.63 Percentage of HbA1c | Standard Error 0.06 |
Comparison: Superiority of Linagliptin 5 mg vs. placebo: change in HbA1c is analysed using mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c, baseline log10 (UACR), baseline HbA1c by visit and baseline log10 (UACR) by visit as linear covariates and treatment, visit, visit by treatment interaction as fixed effects.p-value: <0.000195% CI: [-0.78, -0.43]Mixed Models Analysis
Secondary
The Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 24 Weeks of Treatment
The change from baseline in estimated glomerular filtration rate (eGFR) as assessed by chronic kidney disease epidemiology collaboration (CKD-EPI) equation (cystatin C) after 24 weeks of treatment. The term baseline refers to the last observation before the start of any randomised trial treatment. The number of participants analysed displays the number of participants with available data at the timepoint of interest. This outcome measure is a secondary safety endpoint.
Time frame: Baseline and 24 weeks
Population: Treated Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 24 Weeks of Treatment | -2.35 milliliter/minute/1.73 square metre | Standard Error 1.92 |
| Linagliptin 5 mg | The Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 24 Weeks of Treatment | -4.98 milliliter/minute/1.73 square metre | Standard Error 1.89 |
Comparison: Change in eGFR is analysed using mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c, baseline log10 (UACR), baseline eGFR, baseline HbA1c by visit, baseline log10 (UACR) by visit and baseline eGFR by visit as linear covariates and treatment, visit, visit by treatment interaction as fixed effects.p-value: 0.330695% CI: [-7.95, 2.68]Mixed Models Analysis
Secondary
The Time Weighted Average of Percentage Change From Baseline in UACR During the Course of 24 Weeks of Treatment
The time weighted average of percentage change from baseline in UACR (mg/g creatinine) during the course of 24 weeks of treatment. The term baseline for UACR refers to the geometric mean of UACR values measured at Visits 2 and 3. The number of participants analysed displays the number of participants with available data at the timepoint of interest. The Least Squares Means are adjusted geometric means.
Time frame: Baseline and 24 weeks
Population: Full Analysis Set (FAS) - including all randomised patients who were treated with at least one dose of study drug, had a baseline HbA1c and a baseline Urinary albumin creatinine ratio (UACR), and at least one on treatment HbA1c or UACR assessment. Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Time Weighted Average of Percentage Change From Baseline in UACR During the Course of 24 Weeks of Treatment | 0.9487 mg/g creatinine | 95% Confidence Interval 0.06 |
| Linagliptin 5 mg | The Time Weighted Average of Percentage Change From Baseline in UACR During the Course of 24 Weeks of Treatment | 0.8902 mg/g creatinine | 95% Confidence Interval 0.06 |
Comparison: Superiority of Linagliptin 5 mg vs. placebo: change in UACR is analysed using analysis of covariance model. Model includes baseline HbA1c and baseline log10 (UACR) as linear covariates and treatment as fixed effect.p-value: 0.195495% CI: [0.85, 1.03]ANCOVA