Diabetes Mellitus, Type 2
Conditions
Brief summary
This is a study in Chinese adults with type 2 diabetes. The study is open to people who take insulin but still have too high blood sugar levels. Participants may additionally be taking up to 2 other medicines for their diabetes. The purpose of this study is to find out whether empagliflozin taken together with insulin helps people with type 2 diabetes to better control their blood sugar. The participants are in the study for about 7 months. During this time, they visit the study site about 8 times, 1 additional visit may be either a visit to the study site or a phone call. At the start of the study, participants are put into 3 groups by chance. Participants get either 10 mg empagliflozin tablets, or 25 mg empagliflozin tablets, or placebo tablets once a day. Placebo tablets look like empagliflozin tablets but do not contain any medicine. The doctors regularly take blood samples from the participants. The changes in blood sugar levels are compared between the groups. The doctors also check the general health of the participants.
Interventions
DRUGEmpagliflozin
Empagliflozin
DRUGPlacebo
Placebo
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years and ≤75 years old at Visit 1; * Chinese patient with diagnosis of Type 2 diabetes prior to Visit 1; * A stable treatment with premixed Insulin (≥ 20IU/day) or basal insulin (≥ 16 IU/day) for at least 12 weeks prior to enrolment with or without up to two OADs * With maximum insulin dose of ≤ 1 unit/kg/day. Acceptable basal insulins should have duration of action up to 24 h such as insulin Degludec, insulin glargin, insulin detemir or NPH (neutral protamine hagedorn) insulin; Acceptable pre-mixed insulins could be once or twice daily posology only. The total insulin dose should not be changed by more than 20% of the baseline value within the 12 weeks prior to randomisation (Visit 3). Both human insulin & insulin analogue are acceptable; * If the patient is taking OADs, regimen has to be unchanged for at least 12 weeks prior to randomization (Visit 3); * If the patient is taking metformin, stable dose (at least 1500 mg daily or maximum tolerated dose) must be maintained for at least 12 weeks without dose adjustments prior to randomization (Visit 3); * HbA1c ≥7.5% and ≤11.0% at Visit 1; * Fasting C-peptide: \>0.5 ng/mL (\>166pmol/L) at Visit 1； * 18.5 kg/m2 ≤ BMI ≤ 45 kg/m2 at Visit 1; * Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial; * Male or female patients. Women of childbearing potential (WOCBP) must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information.
Exclusion criteria
* Diagnosis of Type 1 diabetes; * Patients receiving MDI insulin or insulin pump treatment; * eGFR \<45ml/min/1.73m2 calculated based on MDRD formula; * Uncontrolled hyperglycemia \[glucose level \>13. 9 mmol/l after an overnight fast during placebo run-in\]; * Severe hypoglycemia episode (event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions) within 6 months prior to Visit 1; * History of diabetic ketoacidosis or hyperosmolar non-ketotic coma. Myocardial infarction, stroke or transient ischaemic attack within 3 months prior to Visit 1; * Bariatric surgery; * Further criteria apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) at Week 24 | At baseline (Week 0) and at Week 24 | A restricted maximum likelihood (REML) based mixed model repeated measures (MMRM) approach was applied including treatment, background therapy, and visit as fixed classification effects, baseline HbA1c and baseline estimated glomerular filtration rate (eGFR) as the linear covariates, treatment by visit interaction, and baseline HbA1c by visit interaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour Post-prandial Glucose (PPG) at Week 24 | At baseline (Week 0) and at Week 24 | The Analysis of covariance (ANCOVA) model included treatment and background therapy as classification effects, baseline PPG and baseline Estimated glomerular filtration rate (eGFR) as the linear covariates. |
| Percentage of Participants With HbA1c<7.0% at Week 24 | At Week 24 | Percentage of participants with glycosylated haemoglobin A1c (HbA1c) \<7.0% at Week 24 is reported. |
| Change in Body Weight From Baseline to Week 24 | At baseline (Week 0) and at Week 24 | Change in body weight from baseline to Week 24 is reported. A restricted maximum likelihood (REML) based mixed model repeated measures (MMRM) approach was applied including baseline body weight, and its interaction with visit. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | At baseline (Week 0) and at Week 24 | A restricted maximum likelihood (REML) based mixed model repeated measures (MMRM) approach was applied including baseline FPG and its interaction with visit. |
| Change From Baseline in Diastolic Blood Pressure (DBP) at Week 24 | At baseline (Week 0) and at Week 24 | A restricted maximum likelihood (REML) based mixed model repeated measures (MMRM) approach was applied including baseline DBP and its interaction with visit. |
| Number of Participants With Confirmed Hypoglycaemic Events | From first administration of the initial randomised study medication to last intake of study medication + 7 days (inclusive), up to 176 days. | Confirmed hypoglycemic events refer to the hypoglycaemic events with a plasma glucose value of ≤70 milligrams per deciliter (mg/dL) or where assistance was required. |
| Number of Participants With Adjudicated Diabetic Ketoacidosis (DKA) Events | From first administration of the initial randomised study medication to last intake of study medication + 7 days (inclusive), up to 176 days. | The risk of DKA had to be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty in breathing, confusion, unusual fatigue or sleepiness. In case of a suspected DKA, the investigator was to ensure that appropriate tests were performed at the earliest opportunity according to 2017 China Type 2 diabetes mellitus (T2DM) guidelines. An independent external Clinical event committee (CEC) was established to adjudicate centrally and in a blinded fashion events suspected of DKA and certain hepatic events. DKA was investigated using both broad and narrow Boehringer Ingelheim customised MedDRA query (BIcMQs). |
| Change From Baseline in Systolic Blood Pressure (SBP) at Week 24 | At baseline (Week 0) and at Week 24 | A restricted maximum likelihood (REML) based mixed model repeated measures (MMRM) approach was applied including baseline SBP and its interaction with visit. |
Countries
China
Participant flow
Recruitment details
This study was to determine the efficacy and safety of Empagliflozin added to insulin-treated type 2 diabetes patients.
Pre-assignment details
4 patients did not meet eligibility criteria but randomized and treated in this trial. The rest of the subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo was administered orally once daily for a treatment period of 24 weeks.
Before the first dose of randomised drug, all participants went through a 2-week open label placebo run-in period, taking Placebo tablets orally once daily. | 73 |
| Empagliflozin 10 mg 1 table of 10 milligrams (mg) of Empagliflozin was administered orally once daily for a treatment period of 24 weeks.
Before the first dose of randomised drug, all participants went through a 2-week open label placebo run-in period, taking Placebo tablets orally once daily. | 73 |
| Empagliflozin 25 mg 1 table of 25 milligrams (mg) of Empagliflozin was administered orally once daily for a treatment period of 24 weeks.
Before the first dose of randomised drug, all participants went through a 2-week open label placebo run-in period, taking Placebo tablets orally once daily. | 73 |
| Total | 219 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Other than listed | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 3 |
Baseline characteristics
| Characteristic | Placebo | Empagliflozin 10 mg | Empagliflozin 25 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 60.1 Years STANDARD_DEVIATION 8 | 59.9 Years STANDARD_DEVIATION 7.7 | 60.7 Years STANDARD_DEVIATION 9.1 | 60.2 Years STANDARD_DEVIATION 8.2 |
| Background antidiabetic treatment Insulin only | 13 Participants | 14 Participants | 14 Participants | 41 Participants |
| Background antidiabetic treatment Insulin + Oral antidiabetic drug (OAD) | 60 Participants | 59 Participants | 59 Participants | 178 Participants |
| Glycosylated haemoglobin A1c (HbA1c) | 8.64 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.81 | 8.64 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.91 | 8.64 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.88 | 8.64 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.87 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 73 Participants | 73 Participants | 73 Participants | 219 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 37 Participants | 30 Participants | 33 Participants | 100 Participants |
| Sex: Female, Male Male | 36 Participants | 43 Participants | 40 Participants | 119 Participants |
| Time since diagnosis of diabetes | 14.14 Years STANDARD_DEVIATION 7.26 | 14.74 Years STANDARD_DEVIATION 7.01 | 15.05 Years STANDARD_DEVIATION 7.45 | 14.64 Years STANDARD_DEVIATION 7.22 |
| Type of insulin Basal | 32 Participants | 38 Participants | 34 Participants | 104 Participants |
| Type of insulin Pre-mixed | 41 Participants | 35 Participants | 39 Participants | 115 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 73 | 0 / 73 | 0 / 73 | 0 / 219 |
| other Total, other adverse events | 39 / 73 | 27 / 73 | 27 / 73 | 46 / 219 |
| serious Total, serious adverse events | 6 / 73 | 10 / 73 | 7 / 73 | 2 / 219 |
Outcome results
Primary
Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) at Week 24
A restricted maximum likelihood (REML) based mixed model repeated measures (MMRM) approach was applied including treatment, background therapy, and visit as fixed classification effects, baseline HbA1c and baseline estimated glomerular filtration rate (eGFR) as the linear covariates, treatment by visit interaction, and baseline HbA1c by visit interaction.
Time frame: At baseline (Week 0) and at Week 24
Population: Modified Intention-to-Treat (mITT) set: The mITT set consisted of all randomised patients who were treated with at least one dose of the study drug and had a baseline HbA1c assessment and at least one on-treatment glycosylated haemoglobin A1c (HbA1c) value. The assignment of patients to treatment groups were based on the planned randomised study drug at the time of randomisation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) at Week 24 | -0.13 Percentage of glycosylated hemoglobin | Standard Error 0.1 |
| Empagliflozin 10 mg | Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) at Week 24 | -1.12 Percentage of glycosylated hemoglobin | Standard Error 0.1 |
| Empagliflozin 25 mg | Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c) at Week 24 | -1.12 Percentage of glycosylated hemoglobin | Standard Error 0.1 |
p-value: <0.000195% CI: [-1.28, -0.71]Mixed model repeated measures
p-value: <0.000195% CI: [-1.26, -0.7]Mixed model repeated measures
Secondary
Change From Baseline in 2-hour Post-prandial Glucose (PPG) at Week 24
The Analysis of covariance (ANCOVA) model included treatment and background therapy as classification effects, baseline PPG and baseline Estimated glomerular filtration rate (eGFR) as the linear covariates.
Time frame: At baseline (Week 0) and at Week 24
Population: Modified Intention-to-Treat (mITT) set: The mITT set consisted of all randomised patients who were treated with at least one dose of the study drug and had a baseline HbA1c assessment and at least one on-treatment glycosylated haemoglobin A1c (HbA1c) value. The assignment of patients to treatment groups were based on the planned randomised study drug at the time of randomisation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 2-hour Post-prandial Glucose (PPG) at Week 24 | 3.27 Milligrams per deciliter (mg/dL) | Standard Error 7.53 |
| Empagliflozin 10 mg | Change From Baseline in 2-hour Post-prandial Glucose (PPG) at Week 24 | -53.05 Milligrams per deciliter (mg/dL) | Standard Error 8.14 |
| Empagliflozin 25 mg | Change From Baseline in 2-hour Post-prandial Glucose (PPG) at Week 24 | -57.44 Milligrams per deciliter (mg/dL) | Standard Error 7.89 |
p-value: <0.000195% CI: [-78.22, -34.41]ANCOVA
p-value: <0.000195% CI: [-82.31, -39.11]ANCOVA
Secondary
Change From Baseline in Diastolic Blood Pressure (DBP) at Week 24
A restricted maximum likelihood (REML) based mixed model repeated measures (MMRM) approach was applied including baseline DBP and its interaction with visit.
Time frame: At baseline (Week 0) and at Week 24
Population: Modified Intention-to-Treat (mITT) set: The mITT set consisted of all randomised patients who were treated with at least one dose of the study drug and had a baseline HbA1c assessment and at least one on-treatment glycosylated haemoglobin A1c (HbA1c) value. The assignment of patients to treatment groups were based on the planned randomised study drug at the time of randomisation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Diastolic Blood Pressure (DBP) at Week 24 | -1.59 Millimetre of mercury (mmHg) | Standard Error 0.78 |
| Empagliflozin 10 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at Week 24 | -3.37 Millimetre of mercury (mmHg) | Standard Error 0.84 |
| Empagliflozin 25 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at Week 24 | -0.94 Millimetre of mercury (mmHg) | Standard Error 0.83 |
p-value: 0.122295% CI: [-4.05, 0.48]Mixed model repeated measures
p-value: 0.568795% CI: [-1.59, 2.89]Mixed model repeated measures
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
A restricted maximum likelihood (REML) based mixed model repeated measures (MMRM) approach was applied including baseline FPG and its interaction with visit.
Time frame: At baseline (Week 0) and at Week 24
Population: Modified Intention-to-Treat (mITT) set: The mITT set consisted of all randomised patients who were treated with at least one dose of the study drug and had a baseline HbA1c assessment and at least one on-treatment glycosylated haemoglobin A1c (HbA1c) value. The assignment of patients to treatment groups were based on the planned randomised study drug at the time of randomisation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -5.56 Milligrams per deciliter (mg/dL) | Standard Error 3.67 |
| Empagliflozin 10 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -25.61 Milligrams per deciliter (mg/dL) | Standard Error 3.97 |
| Empagliflozin 25 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -29.69 Milligrams per deciliter (mg/dL) | Standard Error 3.9 |
p-value: 0.000395% CI: [-30.73, -9.38]Mixed model repeated measures
p-value: <0.000195% CI: [-34.72, -13.54]Mixed model repeated measures
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) at Week 24
A restricted maximum likelihood (REML) based mixed model repeated measures (MMRM) approach was applied including baseline SBP and its interaction with visit.
Time frame: At baseline (Week 0) and at Week 24
Population: Modified Intention-to-Treat (mITT) set: The mITT set consisted of all randomised patients who were treated with at least one dose of the study drug and had a baseline HbA1c assessment and at least one on-treatment glycosylated haemoglobin A1c (HbA1c) value. The assignment of patients to treatment groups were based on the planned randomised study drug at the time of randomisation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) at Week 24 | -1.95 Millimetre of mercury (mmHg) | Standard Error 1.38 |
| Empagliflozin 10 mg | Change From Baseline in Systolic Blood Pressure (SBP) at Week 24 | -5.56 Millimetre of mercury (mmHg) | Standard Error 1.49 |
| Empagliflozin 25 mg | Change From Baseline in Systolic Blood Pressure (SBP) at Week 24 | -2.96 Millimetre of mercury (mmHg) | Standard Error 1.46 |
p-value: 0.077495% CI: [-7.61, 0.4]Mixed model repeated measures
p-value: 0.61695% CI: [-4.98, 2.96]Mixed model repeated measures
Secondary
Change in Body Weight From Baseline to Week 24
Change in body weight from baseline to Week 24 is reported. A restricted maximum likelihood (REML) based mixed model repeated measures (MMRM) approach was applied including baseline body weight, and its interaction with visit.
Time frame: At baseline (Week 0) and at Week 24
Population: Modified Intention-to-Treat (mITT) set: The mITT set consisted of all randomised patients who were treated with at least one dose of the study drug and had a baseline HbA1c assessment and at least one on-treatment glycosylated haemoglobin A1c (HbA1c) value. The assignment of patients to treatment groups were based on the planned randomised study drug at the time of randomisation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Body Weight From Baseline to Week 24 | 0.01 Kilogram | Standard Error 0.23 |
| Empagliflozin 10 mg | Change in Body Weight From Baseline to Week 24 | -1.99 Kilogram | Standard Error 0.24 |
| Empagliflozin 25 mg | Change in Body Weight From Baseline to Week 24 | -1.31 Kilogram | Standard Error 0.24 |
p-value: <0.000195% CI: [-2.66, -1.34]Mixed model repeated measures
p-value: <0.000195% CI: [-1.96, -0.67]Mixed model repeated measures
Secondary
Number of Participants With Adjudicated Diabetic Ketoacidosis (DKA) Events
The risk of DKA had to be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty in breathing, confusion, unusual fatigue or sleepiness. In case of a suspected DKA, the investigator was to ensure that appropriate tests were performed at the earliest opportunity according to 2017 China Type 2 diabetes mellitus (T2DM) guidelines. An independent external Clinical event committee (CEC) was established to adjudicate centrally and in a blinded fashion events suspected of DKA and certain hepatic events. DKA was investigated using both broad and narrow Boehringer Ingelheim customised MedDRA query (BIcMQs).
Time frame: From first administration of the initial randomised study medication to last intake of study medication + 7 days (inclusive), up to 176 days.
Population: Treated set (TS): The TS consisted of all patients who were randomised and treated with at least one dose of the study drug. The assignment of patients to treatment groups were based on the actual first study drug intake in the double-blind treatment period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Adjudicated Diabetic Ketoacidosis (DKA) Events | 0 Participants |
| Empagliflozin 10 mg | Number of Participants With Adjudicated Diabetic Ketoacidosis (DKA) Events | 0 Participants |
| Empagliflozin 25 mg | Number of Participants With Adjudicated Diabetic Ketoacidosis (DKA) Events | 0 Participants |
Secondary
Number of Participants With Confirmed Hypoglycaemic Events
Confirmed hypoglycemic events refer to the hypoglycaemic events with a plasma glucose value of ≤70 milligrams per deciliter (mg/dL) or where assistance was required.
Time frame: From first administration of the initial randomised study medication to last intake of study medication + 7 days (inclusive), up to 176 days.
Population: Treated set (TS): The TS consisted of all patients who were randomised and treated with at least one dose of the study drug. The assignment of patients to treatment groups were based on the actual first study drug intake in the double-blind treatment period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Confirmed Hypoglycaemic Events | 8 Participants |
| Empagliflozin 10 mg | Number of Participants With Confirmed Hypoglycaemic Events | 13 Participants |
| Empagliflozin 25 mg | Number of Participants With Confirmed Hypoglycaemic Events | 7 Participants |
p-value: 0.242295% CI: [0.68, 4.55]Regression, Logistic
p-value: 0.766195% CI: [0.29, 2.5]Regression, Logistic
Secondary
Percentage of Participants With HbA1c<7.0% at Week 24
Percentage of participants with glycosylated haemoglobin A1c (HbA1c) \<7.0% at Week 24 is reported.
Time frame: At Week 24
Population: Modified Intention-to-Treat (mITT) set: The mITT set consisted of all randomised patients who were treated with at least one dose of the study drug and had a baseline HbA1c assessment and at least one on-treatment glycosylated haemoglobin A1c (HbA1c) value. The assignment of patients to treatment groups were based on the planned randomised study drug at the time of randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With HbA1c<7.0% at Week 24 | 8.2 Percentage of participants |
| Empagliflozin 10 mg | Percentage of Participants With HbA1c<7.0% at Week 24 | 16.7 Percentage of participants |
| Empagliflozin 25 mg | Percentage of Participants With HbA1c<7.0% at Week 24 | 30.1 Percentage of participants |
p-value: 0.137595% CI: [0.77, 6.83]Regression, Logistic
p-value: 0.000895% CI: [2.11, 17.1]Regression, Logistic