Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial will compare the use of fixed dose combination of empagliflozin and linagliptin to linagliptin alone in patient with type 2 diabetes mellitus
Interventions
DRUGLinagliptin
DRUGEmpagliflozin placebo + linagliptin placebo low dose
Matching placebo empagliflozin + linagliptin
DRUGEmpagliflozin + linagliptin low dose
tablet
Matching placebo linagliptin
DRUGEmpagliflozin + linagliptin high dose
tablet
DRUGEmpa + lina highdose placebo
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of Type-2 Diabetes Mellitus (T2DM) prior to informed consent 2. Male and female patients on diet and exercise regimen for at least 12 weeks prior to informed consent who are: * 1 drug-naïve, defined as no antidiabetic drugs for at least 12 weeks prior to informed consent, or * 2 pre-treated with one oral antidiabetic drug (for sulfonylurea, with up to half of the maximum approved dose) on stable dosage for at least 12 weeks prior to informed consent (for thiazolidinedione, therapy has to be unchanged for at least 18 weeks prior to the informed consent, for linagliptin 5 mg at least 16 weeks prior to Visit 1). Individual antidiabetic drug (except linagliptin) will have to be discontinued at Visit 1. 3. HbA1c at Visit 1 * 1 HbA1c =8.0% and =10.5% for patients who are drug-naïve, or * 2 HbA1c =7.5% and =10.5% for patients with one oral antidiabetic drug (except linagliptin), or * 3 HbA1c =7.5% and =10.0% for patients with linagliptin 5 mg 4. HbA1c =7.5% and =10.0% at Visit 4 for randomisation into the double-blind treatment period. Patient who are pre-treated with linagliptin 5 mg for 16 weeks or more prior to Visit 1 and meet the criteria of HbA1c can directly move on to the run-in (Visit 4). 5. Age =20 years at informed consent 6. BMI =40.0 kg/m2 at Visit 1 (screening) 7. Signed and dated written informed consent by date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation
Exclusion criteria
1. Uncontrolled hyperglycemia with a glucose level \>270 mg/dL (\>15.0 mmol/L) after an overnight fast during the open-label stabilisation period (from Visit 2 to Visit 4) and run-in period (from Visit 4 to Visit 5) , confirmed by a second measurement (not on the same day and done either at the central or at local laboratory). 2. Acute coronary syndrome (ST-elevation myocardial infarction \[STEMI\], non-STEMI, and unstable angina pectoris), stroke or transient ischemic attack within 12 weeks prior to informed consent 3. Indication of liver disease, defined by serum levels of either alanine aminotransferase (ALT Serum glutamic pyruvate transaminase \[SGPT\]), aspartate aminotransferase (AST, Serum glutamic oxaloacetic transaminase \[SGOT\]), or alkaline phosphatase (ALP) above 3 x upper limit of normal (ULN) as determined during screening, open-label stabilisation period and/or run-in period 4. Impaired renal function, defined as estimated glomerular filtration rate (eGFR) \<45 mL/min/1.73 m2 (MDRD formula) as determined during screening, open-label stabilisation period and/or run-in period 5. Known hereditary galactose intolerance 6. Known contraindications to linagliptin and empagliflozin according to the Japanese label 7. Any previous (within 2 years prior to informed consent) or planned bariatric surgery (or any other weight loss surgery) or other gastrointestinal surgery that induce chronic malabsorption 8. Medical history of cancer (except for resected non-invasive basal cell or squamous carcinoma) and/or treatment for cancer within the last 5 years 9. Known blood dyscrasias or any disorders causing haemolysis or unstable red blood cell (RBC) count (e.g. malaria, babesiosis, haemolytic anaemia). 10. Treatment with insulin, Glucagon-like peptide-1 agonists, within 12 weeks prior to informed consent 11. Treatment with anti-obesity drugs within 12 weeks prior to informed consent or any other treatment at the time of screening (i.e., surgery, aggressive diet regimen, etc.) leading to unstable body weight 12. Current treatment with systemic steroids (other than inhaled or topical steroids) at informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except T2DM 13. Pre-menopausal women (last menstruation =1 year prior to informed consent) who: * 1 are nursing or pregnant or * 2 are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the trial and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, intra uterine devices/systems, oral contraceptives, complete sexual abstinence, double barrier method and vasectomised partner 14. Known or suspected allergy or hypersensitivity to trial products or related products (e.g., Dipeptidyl-peptidase-4 inhibitors or Sodium-glucose co-transporter-2 inhibitors) 15. Alcohol or drug abuse within the 12 weeks prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to trial procedures or trial drug intake, by the judgment of the investigator 16. Intake of an investigational drug in another trial within 30 days prior to Visit 1 or participation in the follow-up period of another trial (participation in observational studies is permitted) 17. Any other clinical condition that, in the opinion of the investigator, would jeopardize patient's safety while participating in this clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Glycosylated Haemoglobin A1c (Glycosylated Haemoglobin A1c After 24 Weeks of Double-blind Treatment From Baseline) | Baseline and 24 week | Change from baseline in Glycosylated haemoglobin A1c (HbA1c) at Week 24 was calculated as: HbA1c at Week 24 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Week 28 at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Only) | 28 Week (pre up-titration) and 52 Week | Change from Week 28 in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at Week 28. Week 28 (pre up-titration) is referred to the last observed measurement prior to the first administration of any double-blind randomized trial medication in the up-titration period. Adjusted mean (Least square mean) and its standard error (SE) is presented. This endpoint was based on 1 group of the Full analysis set with up-titration (FASUT-II) whose dose was up-titrated to Empagliflozin 25 mg/Linagliptin 5 mg fixed dose combination thus there is no comparison group. Hence, no comparison is made. A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline eGFR, prior use of antidiabetic drug, visit as fixed effect(s). The covariance used to fit the model was unstructured. |
| Change in HbA1c From Baseline at Week 52 (All Empagliflozin Versus All Placebo) | Baseline and 52 week | Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented. |
| Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus Linagliptin 5 mg + Placebo 25 mg) | Baseline and 52 week | Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented. |
| Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus All Placebo) | Baseline and 52 week | Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Empagliflozin 10 mg/Linagliptin 5 mg Patients were administered a fixed dose combination (FDC) of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with matching placebo of Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period. | 182 |
| Linagliptin 5 mg + Placebo 10 mg Patients were administered a matching placebo of FDC of 10 mg Empagliflozin and 5 mg Linagliptin tablet along with Linagliptin 5 mg orally once daily for 24 weeks of double-blind treatment period. | 93 |
| Total | 275 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| 24-week Double-blind Treatment Period | Adverse Event | 2 | 0 | 0 | 0 | 0 | 0 |
| 24-week Double-blind Treatment Period | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 |
| 24-week Double-blind Treatment Period | Other than specified above | 0 | 3 | 0 | 0 | 0 | 0 |
| 24-week Double-blind Treatment Period | Withdrawal by Subject | 2 | 4 | 0 | 0 | 0 | 0 |
| Extension Period | Adverse Event | 0 | 0 | 1 | 2 | 1 | 1 |
| Extension Period | Protocol Violation | 0 | 0 | 1 | 0 | 0 | 0 |
| Extension Period | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Empagliflozin 10 mg/Linagliptin 5 mg | Linagliptin 5 mg + Placebo 10 mg | Total |
|---|---|---|---|
| Age, Continuous | 60.0 Years STANDARD_DEVIATION 9.9 | 59.8 Years STANDARD_DEVIATION 10.8 | 59.9 Years STANDARD_DEVIATION 10.2 |
| Sex: Female, Male Female | 40 Participants | 21 Participants | 61 Participants |
| Sex: Female, Male Male | 142 Participants | 72 Participants | 214 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 62 / 182 | 46 / 93 |
| serious Total, serious adverse events | 8 / 182 | 1 / 93 |
Outcome results
Primary
Change of Glycosylated Haemoglobin A1c (Glycosylated Haemoglobin A1c After 24 Weeks of Double-blind Treatment From Baseline)
Change from baseline in Glycosylated haemoglobin A1c (HbA1c) at Week 24 was calculated as: HbA1c at Week 24 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.
Time frame: Baseline and 24 week
Population: The primary analysis was performed on the FAS (observed case \[OC\]) with treatment assignment as randomised.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 10 mg/Linagliptin 5 mg | Change of Glycosylated Haemoglobin A1c (Glycosylated Haemoglobin A1c After 24 Weeks of Double-blind Treatment From Baseline) | -0.93 Percentage (%) | Standard Error 0.06 |
| Linagliptin 5 mg + Placebo 10 mg | Change of Glycosylated Haemoglobin A1c (Glycosylated Haemoglobin A1c After 24 Weeks of Double-blind Treatment From Baseline) | 0.21 Percentage (%) | Standard Error 0.09 |
Comparison: A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline estimated glomerular filtration rate (eGFR) (Modification of Diet in Renal Disease \[MDRD\] formula), prior use of antidiabetic drug, treatment, visit, visit by Treatment interaction as fixed effect(s). The covariance used to fit the model was unstructured.p-value: <0.000195% CI: [-1.36, -0.91]Mixed Models Analysis
Secondary
Change in HbA1c From Baseline at Week 52 (All Empagliflozin Versus All Placebo)
Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.
Time frame: Baseline and 52 week
Population: The analysis was performed on the FAS (observed case \[OC\]) with treatment assignment as randomised.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 10 mg/Linagliptin 5 mg | Change in HbA1c From Baseline at Week 52 (All Empagliflozin Versus All Placebo) | -1.16 Percentage (%) | Standard Error 0.06 |
| Linagliptin 5 mg + Placebo 10 mg | Change in HbA1c From Baseline at Week 52 (All Empagliflozin Versus All Placebo) | 0.06 Percentage (%) | Standard Error 0.1 |
Comparison: A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline estimated glomerular filtration rate (eGFR) (Modification of Diet in Renal Disease \[MDRD\] formula), prior use of antidiabetic drug, treatment, visit, visit by Treatment interaction as fixed effect(s). The covariance used to fit the model was unstructured.p-value: <0.000195% CI: [-1.45, -0.99]Mixed Models Analysis
Secondary
Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus All Placebo)
Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.
Time frame: Baseline and 52 week
Population: Full analysis set with up-titration-II consisted patients who were up-titrated to Empagliflozin 25/linagliptin 5 and were treated with at least 1 dose after dose up-titration and who were randomized to receive Linagliptin 5 + Placebo 10 or Linagliptin 5 + Placebo 25 and who had HbA1c assessment at baseline and at least once after dose up-titration.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 10 mg/Linagliptin 5 mg | Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus All Placebo) | -1.10 Percentage (%) | Standard Error 0.07 |
| Linagliptin 5 mg + Placebo 10 mg | Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus All Placebo) | -0.01 Percentage (%) | Standard Error 0.1 |
Comparison: A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline estimated glomerular filtration rate (eGFR) (Modification of Diet in Renal Disease \[MDRD\] formula), prior use of antidiabetic drug, treatment, visit, visit by Treatment interaction as fixed effect(s). The covariance used to fit the model was unstructured.p-value: <0.000195% CI: [-1.34, -0.84]Mixed Models Analysis
Secondary
Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus Linagliptin 5 mg + Placebo 25 mg)
Change from baseline in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at baseline. Baseline is referred to the last observed measurement prior to the administration of randomized trial medication. Adjusted mean (Least square mean) and its standard error (SE) is presented.
Time frame: Baseline and 52 week
Population: FASUT-I
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 10 mg/Linagliptin 5 mg | Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus Linagliptin 5 mg + Placebo 25 mg) | -1.10 Percentage (%) | Standard Error 0.07 |
| Linagliptin 5 mg + Placebo 10 mg | Change in HbA1c From Baseline at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Versus Linagliptin 5 mg + Placebo 25 mg) | 0.11 Percentage (%) | Standard Error 0.1 |
Comparison: A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline estimated glomerular filtration rate (eGFR) (Modification of Diet in Renal Disease \[MDRD\] formula), prior use of antidiabetic drug, treatment, visit, visit by Treatment interaction as fixed effect(s). The covariance used to fit the model was unstructured.p-value: <0.000195% CI: [-1.45, -0.96]Mixed Models Analysis
Secondary
Change in HbA1c From Week 28 at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Only)
Change from Week 28 in HbA1c at Week 52 was calculated as: HbA1c at Week 52 - HbA1c at Week 28. Week 28 (pre up-titration) is referred to the last observed measurement prior to the first administration of any double-blind randomized trial medication in the up-titration period. Adjusted mean (Least square mean) and its standard error (SE) is presented. This endpoint was based on 1 group of the Full analysis set with up-titration (FASUT-II) whose dose was up-titrated to Empagliflozin 25 mg/Linagliptin 5 mg fixed dose combination thus there is no comparison group. Hence, no comparison is made. A restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach was used with baseline HbA1c as linear covariate and baseline eGFR, prior use of antidiabetic drug, visit as fixed effect(s). The covariance used to fit the model was unstructured.
Time frame: 28 Week (pre up-titration) and 52 Week
Population: The full analysis set with up-titration-I (FASUT-I) consisted of all patients who were up-titrated and were treated with at least 1 dose of Empagliflozin 25 mg/linagliptin 5 mg or Linagliptin 5 mg + Placebo 25 mg after dose up-titration and who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment after dose up-titration.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 10 mg/Linagliptin 5 mg | Change in HbA1c From Week 28 at Week 52 (Empagliflozin 25 mg/Linagliptin 5 mg Only) | -0.21 Percentage (%) | Standard Error 0.03 |