Diabetes Mellitus, Type 2
Conditions
Brief summary
Two independent study parts (i.e. Part A and Part B) are included in this trial. Part A will evaluate empagliflozin 10 mg + linagliptin and Part B will evaluate empagliflozin 25 mg + linagliptin. All analyses will be carried out separately for these study parts. The objective of Part A is to investigate the efficacy, safety and tolerability of the fixed dose combination (FDC) of empagliflozin 10 mg / linagliptin 5 mg compared with empagliflozin 10 mg plus FDC matching placebo administered orally once daily for 24 weeks in Japanese patients with T2DM (Type 2 Diabetes Mellitus) who have insufficient glycaemic control after 16 weeks of treatment with empagliflozin 10 mg alone once daily. The study is designed to show superiority of the FDC of empagliflozin 10 mg / linagliptin 5 mg over empagliflozin 10 mg plus FDC matching placebo after 24 weeks of treatment. The objective of Part B is to investigate the efficacy, safety and tolerability of the FDC of empagliflozin 25 mg / linagliptin 5 mg compared with empagliflozin 25 mg plus FDC matching placebo administered orally once daily for 24 weeks in Japanese patients with T2DM who have insufficient glycaemic control after 16 weeks of treatment with empagliflozin 25 mg alone once daily. The study is designed to show superiority of the FDC of empagliflozin 25 mg / linagliptin 5 mg over empagliflozin 25 mg plus FDC matching placebo after 24 weeks of treatment. The 24 week treatment period will be followed by a 28 week extension treatment period to evaluate further efficacy and safety up to 52 weeks.
Interventions
DRUGempagliflozin 10 mg + linagliptin 5 mg
empagliflozin low dose + linagliptin once daily
DRUGempagliflozin 10 mg
empagliflozin low dose once daily
DRUGempagliflozin 25 mg + linagliptin 5 mg
empagliflozin high dose + linagliptin once daily
DRUGempagliflozin 25 mg
empagliflozin high dose once daily
DRUGPlacebo
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
* Diagnosis of type 2 diabetes prior to informed consent * Male and female patients on diet and exercise regimen for at least 12 weeks prior to informed consent who are: * drug-naïve, defined as no antidiabetic drugs for at least 12 weeks prior to informed consent or, * 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 the informed consent (for thiazolidinedione, therapy has to be unchanged for at least 18 weeks prior to the informed consent). Individual antidiabetic drug will have to be discontinued at Visit 1. * haemoglobin A1c (HbA1c) at Visit 1 (screening) * for patients without antidiabetic therapy : HbA1c \>=8.0 to =\<10.5% * for patients with one oral antidiabetic drug : HbA1c \>=7.5 to =\<10.5% * HbA1c \>=7.5 to =\<10.0% at Visit 4 for randomisation into the double blind treatment period
Exclusion criteria
* Uncontrolled hyperglycaemia with a glucose level \>270 mg/dL (\>15.0 mmol/L) during the open label stabilisation period and placebo run in period * Impaired renal function, defined as estimated glomerular filtration rate (eGFR) \<45 mL/min/1.73m2 (modification of diet in renal disease (MDRD) formula) * Acute coronary syndrome, stroke or transient ischemic attack (TIA) within 12 weeks prior to informed consent * Indication of liver disease, defined by serum levels of either alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase (ALP) above 3 x upper limit of normal (ULN)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycated Haemoglobin A1c (HbA1c) (%) From Baseline After 24 Weeks of Treatment | Baseline and 24 week | Change from baseline in HbA1c (%) after 24 weeks of treatment with double-blind trial medication. Change was calculated as: HbA1c value at 24-week - HbA1c value at baseline, for each patient. Baseline was defined as the last observation before the first intake of double-blind randomised trial medication. Statistical analysis presented is based on a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach. Full Analysis Set (Observed Cases) \[FAS (OC)\]: This analysis set consisted of all patients who were randomised and treated with at least 1 dose of trial drug during the double-blind part of the trial and who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment during the 24-week double-blind part of the trial. Observed cases analysis included only the available data that were observed while patients were on treatment, i.e., excluding the missing data. |
Countries
Japan
Participant flow
Pre-assignment details
880 subjects started the open label period
Participants by arm
| Arm | Count |
|---|---|
| Empagliflozin 10 mg OL Patients were administered empagliflozin 10 milligram (mg) tablets, orally with water, once daily for 16-weeks of open-label stabilisation period. | 435 |
| Empagliflozin 25 mg OL Patients were administered empagliflozin 25 mg tablets, orally with water, once daily for 16-weeks of open-label stabilisation period. | 433 |
| Total | 868 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Double-blind Treatment Period | Adverse Event | 0 | 0 | 2 | 6 | 4 | 5 |
| Double-blind Treatment Period | Other than specified above | 0 | 0 | 0 | 0 | 1 | 0 |
| Double-blind Treatment Period | Protocol Violation | 0 | 0 | 0 | 0 | 1 | 1 |
| Double-blind Treatment Period | Withdrawal by Subject | 0 | 0 | 0 | 2 | 0 | 2 |
| Open-label Treatment Period | Adverse Event | 14 | 7 | 0 | 0 | 0 | 0 |
| Open-label Treatment Period | Lost to Follow-up | 0 | 3 | 0 | 0 | 0 | 0 |
| Open-label Treatment Period | Other than specified above | 204 | 189 | 0 | 0 | 0 | 0 |
| Open-label Treatment Period | Protocol Violation | 2 | 2 | 0 | 0 | 0 | 0 |
| Open-label Treatment Period | Withdrawal by Subject | 4 | 7 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Empagliflozin 10 mg OL | Empagliflozin 25 mg OL | Total |
|---|---|---|---|
| Age, Continuous | 56.8 Years STANDARD_DEVIATION 10.2 | 57.5 Years STANDARD_DEVIATION 10 | 57.2 Years STANDARD_DEVIATION 10.1 |
| Sex: Female, Male Female | 111 Participants | 124 Participants | 235 Participants |
| Sex: Female, Male Male | 324 Participants | 309 Participants | 633 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 54 / 116 | 24 / 107 | 51 / 116 | 36 / 108 | 131 / 440 | 120 / 439 |
| serious Total, serious adverse events | 6 / 116 | 1 / 107 | 8 / 116 | 4 / 108 | 11 / 440 | 9 / 439 |
Outcome results
Primary
Change in Glycated Haemoglobin A1c (HbA1c) (%) From Baseline After 24 Weeks of Treatment
Change from baseline in HbA1c (%) after 24 weeks of treatment with double-blind trial medication. Change was calculated as: HbA1c value at 24-week - HbA1c value at baseline, for each patient. Baseline was defined as the last observation before the first intake of double-blind randomised trial medication. Statistical analysis presented is based on a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach. Full Analysis Set (Observed Cases) \[FAS (OC)\]: This analysis set consisted of all patients who were randomised and treated with at least 1 dose of trial drug during the double-blind part of the trial and who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment during the 24-week double-blind part of the trial. Observed cases analysis included only the available data that were observed while patients were on treatment, i.e., excluding the missing data.
Time frame: Baseline and 24 week
Population: FAS (OC)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 10 mg + Linagliptin 5 mg | Change in Glycated Haemoglobin A1c (HbA1c) (%) From Baseline After 24 Weeks of Treatment | -0.94 Percentage (%) | Standard Error 0.05 |
| Empagliflozin 10 mg + Placebo | Change in Glycated Haemoglobin A1c (HbA1c) (%) From Baseline After 24 Weeks of Treatment | -0.12 Percentage (%) | Standard Error 0.06 |
| Empagliflozin 25 mg + Linagliptin 5 mg | Change in Glycated Haemoglobin A1c (HbA1c) (%) From Baseline After 24 Weeks of Treatment | -0.91 Percentage (%) | Standard Error 0.05 |
| Empagliflozin 25 mg + Placebo | Change in Glycated Haemoglobin A1c (HbA1c) (%) From Baseline After 24 Weeks of Treatment | -0.33 Percentage (%) | Standard Error 0.05 |
p-value: <0.000195% CI: [-0.97, -0.67]REML based MMRM
p-value: <0.000195% CI: [-0.73, -0.45]REML based MMRM