Diabetes Mellitus, Type 1
Conditions
Brief summary
The study will investigate the efficacy, safety, tolerability and Pharmacokinetic(PK) of 3 doses of empagliflozin compared with placebo over 26 weeks in 960 patients with type 1 diabetes mellitus as adjunctive therapy to insulin
Interventions
DRUGEmpagliflozin
DRUGPlacebo
For blinding purposes
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Signed and dated written informed consent * Male or female patient receiving insulin for the treatment of documented diagnosis of type 1 diabetes mellitus (T1DM) \> 1 year * C-peptide value of \< 0.7 ng/mL * Use of Multiple Daily Injections (MDI) of insulin or insulin pump user with total daily insulin \>= 0.3 and \<= 1.5 U/kg * Glycated haemoglobin (HbA1c) \>= 7.5% and \<= 10.0% * Good understanding of T1DM * Age \>= 18 years * Body Mass Index (BMI) \>= 18.5 kg/m2 * Estimated glomerular filtration rate \>= 30 mL/min/1.73 m2 * Women of child-bearing potential must use highly effective methods of birth control * Compliance with trial medication administration between 80% and 120% during placebo run-in period Further inclusion criteria apply
Exclusion criteria
* History of type 2 diabetes mellitus, maturity onset diabetes of the young (MODY), pancreatic surgery or chronic pancreatitis * Pancreas, pancreatic islet cells or renal transplant recipient * T1DM treatment with any other antihyperglycaemic drug except subcutaneous basal and bolus insulin within last 3 months * Occurrence of severe hypoglycaemia within last 3 months and until randomisation * Occurence of diabetic ketoacidosis within 3 months prior to Visit 1 and until Visit 6 * Irregular sleep/wake cycle * Acute coronary syndrome, stroke or Transient Ischaemic Attack (TIA) within last 3 months * Severe gastroparesis * Brittle diabetes * Liver disease * Eating disorders * Treatment with anti-obesity drugs, weight-loss surgery or aggressive diet regimen * Treatment with systemic corticosteroids * Change in dose of thyroid hormones within last 6 weeks and until randomisation * Cancer or treatment for cancer in the last five years * Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells * Women who are pregnant, nursing, or who plan to become pregnant whilst in the trial * Alcohol or drug abuse * Intake of an investigational drug in another trial within last 30 days Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Full Analysis Set (FAS) (Observed Cases [OC]) | Baseline to week 26 | Change from baseline in Glycated hemoglobin (HbA1c) for full analysis set (FAS) (observed cases \[OC\]) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline. |
| Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD)) | Baseline to week 26 | Change from baseline in Glycated hemoglobin (HbA1c) for modified intention-to-treat population set (mITT) (observed case - all data \[OC-AD\]) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 5 to Week 26, Week 1 to Week 26 | Rate per patient-year of investigator-reported symptomatic hypoglycemic adverse events (AEs) with confirmed plasma glucose (PG) \<54 milligram per deciliter (mg/dL) (\<3.0 millimoles per litre (mmol/L)) and/or severe hypoglycemic AEs (i.e. all investigator-reported AEs that had confirmed PG \<54 mg/dL \[\<3.0 mmol/L\] with symptoms reported and all severe hypoglycemic events that were confirmed by adjudication) is presented for (i) From week 5 to 26 and (ii) From week 1 to 26. Least squares mean is actually an adjusted event rate. This is key secondary endpoints. |
| Change From Baseline in Body Weight at Week 26 | Baseline to week 26 | Change from baseline in body weight is presented With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline. |
| Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26 | Baseline to week 26 | Change from baseline in Total daily insulin dose (TDID) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline. |
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 | Baseline to week 26 | Change from baseline in Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline. |
Countries
Australia, Canada, Czechia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Romania, Russia, South Africa, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
A randomized, placebo-controlled, double-blind, parallel-group study compared 3 doses of empagliflozin (2.5 milligram (mg), 10 mg, and 25 mg) with placebo in patients with type 1 diabetes mellitus (T1DM) as adjunctive to optimized insulin therapy.
Pre-assignment details
6-Week T1DM therapy (insulin) optimisation period followed by a 2-Week placebo run-in period before randomization. Patients who successfully completed both of the periods were randomized into the 26-Week double-blind treatment period. All treatments were administered in addition to optimized insulin therapy.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching Empagliflozin Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks. | 242 |
| Empagliflozin 2.5 Milligram (mg) Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks. | 242 |
| Empagliflozin 10 mg Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks. | 248 |
| Empagliflozin 25 mg Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks. | 245 |
| Total | 977 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 2 | 5 |
| Overall Study | Lost to Follow-up | 5 | 3 | 3 | 1 |
| Overall Study | Not treated | 1 | 1 | 0 | 0 |
| Overall Study | Other than specified | 3 | 2 | 5 | 2 |
| Overall Study | Protocol Violation | 3 | 2 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 1 | 2 | 3 |
Baseline characteristics
| Characteristic | Placebo Matching Empagliflozin | Empagliflozin 2.5 Milligram (mg) | Empagliflozin 10 mg | Empagliflozin 25 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 42.3 Years STANDARD_DEVIATION 13.2 | 43.4 Years STANDARD_DEVIATION 14.3 | 42.3 Years STANDARD_DEVIATION 13.2 | 44.4 Years STANDARD_DEVIATION 13.6 | 43.1 Years STANDARD_DEVIATION 13.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 215 Participants | 220 Participants | 233 Participants | 224 Participants | 892 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 22 Participants | 15 Participants | 21 Participants | 85 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 7 Participants | 0 Participants | 1 Participants | 5 Participants | 13 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 2 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 3 Participants | 10 Participants | 4 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 227 Participants | 234 Participants | 234 Participants | 231 Participants | 926 Participants |
| Sex: Female, Male Female | 126 Participants | 120 Participants | 132 Participants | 121 Participants | 499 Participants |
| Sex: Female, Male Male | 116 Participants | 122 Participants | 116 Participants | 124 Participants | 478 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 / 241 | 0 / 241 | 0 / 248 | 1 / 245 |
| other Total, other adverse events | 153 / 241 | 146 / 241 | 172 / 248 | 162 / 245 |
| serious Total, serious adverse events | 16 / 241 | 13 / 241 | 21 / 248 | 16 / 245 |
Outcome results
Primary
Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Full Analysis Set (FAS) (Observed Cases [OC])
Change from baseline in Glycated hemoglobin (HbA1c) for full analysis set (FAS) (observed cases \[OC\]) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.
Time frame: Baseline to week 26
Population: Full analysis set (FAS) (observed cases \[OC\]): Patients in the Treated Set (TS) who had a baseline and at least 1 on-treatment HbA1c measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching Empagliflozin | Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Full Analysis Set (FAS) (Observed Cases [OC]) | 0.20 Percentage (%) | Standard Error 0.05 |
| Empagliflozin 2.5 Milligram (mg) | Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Full Analysis Set (FAS) (Observed Cases [OC]) | -0.09 Percentage (%) | Standard Error 0.05 |
| Empagliflozin 10 mg | Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Full Analysis Set (FAS) (Observed Cases [OC]) | -0.25 Percentage (%) | Standard Error 0.05 |
| Empagliflozin 25 mg | Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Full Analysis Set (FAS) (Observed Cases [OC]) | -0.33 Percentage (%) | Standard Error 0.05 |
Comparison: Model includes baseline HbA1c, baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000199% CI: [-0.46, -0.11]Mixed effect Model Repeat Measurement
Comparison: Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000197.5% CI: [-0.6, -0.3]Mixed effect Model Repeat Measurement
Comparison: Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000197.5% CI: [-0.68, -0.37]Mixed effect Model Repeat Measurement
Primary
Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD))
Change from baseline in Glycated hemoglobin (HbA1c) for modified intention-to-treat population set (mITT) (observed case - all data \[OC-AD\]) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.
Time frame: Baseline to week 26
Population: Modified intention-to-treat set (mITT) (observed case - all data \[OC-AD\]): Patients in the TS who had a baseline and at least 1 post-baseline HbA1c measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching Empagliflozin | Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD)) | 0.21 Percentage (%) | Standard Error 0.05 |
| Empagliflozin 2.5 Milligram (mg) | Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD)) | -0.06 Percentage (%) | Standard Error 0.05 |
| Empagliflozin 10 mg | Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD)) | -0.23 Percentage (%) | Standard Error 0.05 |
| Empagliflozin 25 mg | Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD)) | -0.30 Percentage (%) | Standard Error 0.05 |
Comparison: Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.95% CI: [-0.4, -0.14]Mixed effect Model Repeat Measurement
Comparison: Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000197.5% CI: [-0.59, -0.28]Mixed effect Model Repeat Measurement
Comparison: Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000197.5% CI: [-0.66, -0.35]Mixed effect Model Repeat Measurement
Secondary
Change From Baseline in Body Weight at Week 26
Change from baseline in body weight is presented With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.
Time frame: Baseline to week 26
Population: FAS (OC)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching Empagliflozin | Change From Baseline in Body Weight at Week 26 | 0.21 Kilogram (kg) | Standard Error 0.2 |
| Empagliflozin 2.5 Milligram (mg) | Change From Baseline in Body Weight at Week 26 | -1.55 Kilogram (kg) | Standard Error 0.2 |
| Empagliflozin 10 mg | Change From Baseline in Body Weight at Week 26 | -2.83 Kilogram (kg) | Standard Error 0.2 |
| Empagliflozin 25 mg | Change From Baseline in Body Weight at Week 26 | -3.22 Kilogram (kg) | Standard Error 0.2 |
Comparison: Model includes baseline weight, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline weight by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.95% CI: [-2.32, -1.2]Mixed effect Model Repeat Measurement
Comparison: Model includes baseline weight, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline weight by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000199.75% CI: [-3.91, -2.18]Mixed effect Model Repeat Measurement
Comparison: Model includes baseline weight, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline weight by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000199.75% CI: [-4.3, -2.57]Mixed effect Model Repeat Measurement
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26
Change from baseline in Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.
Time frame: Baseline to week 26
Population: FAS observed cases excluding data after change in use of anti-hypertensives (OC-H)
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Matching Empagliflozin | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 | SBP | 0.4 Millimeters of mercury (mmHg) | Standard Error 0.7 |
| Placebo Matching Empagliflozin | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 | DBP | 0.0 Millimeters of mercury (mmHg) | Standard Error 0.4 |
| Empagliflozin 2.5 Milligram (mg) | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 | DBP | -0.4 Millimeters of mercury (mmHg) | Standard Error 0.4 |
| Empagliflozin 2.5 Milligram (mg) | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 | SBP | -1.7 Millimeters of mercury (mmHg) | Standard Error 0.7 |
| Empagliflozin 10 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 | SBP | -3.5 Millimeters of mercury (mmHg) | Standard Error 0.7 |
| Empagliflozin 10 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 | DBP | -1.8 Millimeters of mercury (mmHg) | Standard Error 0.4 |
| Empagliflozin 25 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 | SBP | -3.4 Millimeters of mercury (mmHg) | Standard Error 0.7 |
| Empagliflozin 25 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 | DBP | -1.5 Millimeters of mercury (mmHg) | Standard Error 0.4 |
Comparison: For SBP, the model includes baseline SBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, treatment by visit interaction, baseline SBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.95% CI: [-3.9, -0.2]Mixed effect Model Repeat MeasurementMix
Comparison: For SBP, the model includes baseline SBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, , treatment by visit interaction, baseline SBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000199.75% CI: [-6.8, -1.1]Mixed effect Model Repeat Measurement
Comparison: For SBP, the model includes baseline SBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, treatment by visit interaction, baseline SBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000199.75% CI: [-6.6, -0.9]Mixed effect Model Repeat Measurement
Comparison: For DBP, the model includes baseline DBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, treatment by visit interaction, baseline DBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.95% CI: [-1.5, 0.9]Mixed effect Model Repeat Measurement
Comparison: For DBP, the model includes baseline DBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, ß, treatment by visit interaction, baseline DBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: 0.004799.75% CI: [-3.6, 0.1]Mixed effect Model Repeat Measurement
Comparison: For DBP, the model includes baseline DBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, ß, treatment by visit interaction, baseline DBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: 0.020299.75% CI: [-3.3, 0.4]Mixed effect Model Repeat Measurement
Secondary
Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26
Change from baseline in Total daily insulin dose (TDID) is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.
Time frame: Baseline to week 26
Population: FAS (OC)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching Empagliflozin | Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26 | -0.011 Unit/kilogram (U/kg) | Standard Error 0.007 |
| Empagliflozin 2.5 Milligram (mg) | Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26 | -0.060 Unit/kilogram (U/kg) | Standard Error 0.007 |
| Empagliflozin 10 mg | Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26 | -0.080 Unit/kilogram (U/kg) | Standard Error 0.007 |
| Empagliflozin 25 mg | Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26 | -0.102 Unit/kilogram (U/kg) | Standard Error 0.007 |
Comparison: Model includes baseline total daily insulin dose, baseline estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline total daily insulin dose by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.95% CI: [-0.069, -0.03]Mixed effect Model Repeat Measurement
Comparison: Model includes baseline total daily insulin dose, baseline estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline total daily insulin dose by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000199.75% CI: [-0.101, -0.039]Mixed effect Model Repeat Measurement
Comparison: Model includes baseline total daily insulin dose, baseline estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre-existing insulin therapy, treatment, visit, visit by treatment interaction, baseline total daily insulin dose by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000199.75% CI: [-0.122, -0.06]Mixed effect Model Repeat Measurement
Secondary
Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG)
Rate per patient-year of investigator-reported symptomatic hypoglycemic adverse events (AEs) with confirmed plasma glucose (PG) \<54 milligram per deciliter (mg/dL) (\<3.0 millimoles per litre (mmol/L)) and/or severe hypoglycemic AEs (i.e. all investigator-reported AEs that had confirmed PG \<54 mg/dL \[\<3.0 mmol/L\] with symptoms reported and all severe hypoglycemic events that were confirmed by adjudication) is presented for (i) From week 5 to 26 and (ii) From week 1 to 26. Least squares mean is actually an adjusted event rate. This is key secondary endpoints.
Time frame: Week 5 to Week 26, Week 1 to Week 26
Population: FAS (OC)
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo Matching Empagliflozin | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 5 to 26 | 6.13 Events per patient year |
| Placebo Matching Empagliflozin | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 1 to 26 | 6.62 Events per patient year |
| Empagliflozin 2.5 Milligram (mg) | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 1 to 26 | 6.17 Events per patient year |
| Empagliflozin 2.5 Milligram (mg) | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 5 to 26 | 5.77 Events per patient year |
| Empagliflozin 10 mg | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 5 to 26 | 7.37 Events per patient year |
| Empagliflozin 10 mg | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 1 to 26 | 8.33 Events per patient year |
| Empagliflozin 25 mg | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 5 to 26 | 6.25 Events per patient year |
| Empagliflozin 25 mg | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycemic Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 1 to 26 | 6.96 Events per patient year |
Comparison: For Week 5 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk \[days\]) was used as offset.95% CI: [0.673, 1.314]Negative binomial model
Comparison: For Week 5 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk \[days\]) was used as offset.p-value: 0.275297.75% CI: [0.818, 1.766]Negative binomial model
Comparison: For Week 5 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk \[days\]) was used as offset.p-value: 0.907797.75% CI: [0.693, 1.501]Negative binomial model
Comparison: For Week 1 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk \[days\]) was used as offset.95% CI: [0.682, 1.274]Negative binomial model
Comparison: For Week 1 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk \[days\]) was used as offset.p-value: 0.143895% CI: [0.925, 1.713]Negative binomial model
Comparison: For Week 1 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk \[days\]) was used as offset.p-value: 0.754395% CI: [0.771, 1.433]Negative binomial model