Diabetes Mellitus, Type 1
Conditions
Brief summary
Comparison of 2 doses of empagliflozin vs placebo in patients already using either an insulin regimen of multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). Randomisation to 3 treatments arms (equal assignment) following a screening period, an optimisation period and a run-in period. 52 week double-blind treatment period, and 3 week follow-up period.
Interventions
DRUGEmpagliflozin
DRUGPlacebo
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
* Male or female patient receiving insulin for the treatment of documented diagnosis of Type 1 Diabetes Mellitus (T1DM) for at least 1 year at the time of Visit 1 * Fasting C-peptide value of \< 0.7 ng/mL (0.23 nmol/L) at Visit 2 measured by the central laboratory * Use of, and be willing, based on the Investigator's judgement, to continue throughout the duration of the trial, either: * Multiple Daily Injections (MDI) of insulin consisting of at least one basal insulin injection and at least three daily bolus injections OR * Continuous Subcutaneous Insulin Infusion (CSII) of any insulin type, with at least 5 months experience of using CSII prior to Visit 1 * HbA1c \>/= 7.5% and \</= 10.0% at Visit 5 measured by the central laboratory * Age \>/= 18 years at Visit 1 Additional inclusion criteria may apply
Exclusion criteria
* History of Type 2 Diabetes Mellitus (T2DM), 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 (e.g. metformin, alpha-glucosidase inhibitors, Glucagon-like-peptide 1 (GLP-1) analogues, Sodium-Glucose Co-Transporter (SGLT-2) inhibitors, pramlintide, inhaled insulin, pre-mixed insulins etc.) except subcutaneous basal and bolus insulin within 3 months prior to Visit 1 * Occurrence of severe hypoglycaemia involving coma/unconsciousness and/or seizure that required hospitalisation or hypoglycaemia-related treatment by an emergency physician or paramedic within 3 months prior to Visit 1 and until randomisation * Occurence of Diabetic Ketoacidosis (DKA) within 3 months prior to Visit 1 and until randomisation Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 26 | Baseline to week 26 | Change from baseline in glycated haemoglobin (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 randomised trial medication. Least squares mean is adjusted mean change from baseline. Restricted maximum likelihood estimation based on mixed-effect model for repeated measures (MMRM) analysis was used to obtain adjusted means for the treatment effects. |
| Change From Baseline in Glycated Haemoglobin (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 haemoglobin (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 randomised trial medication. Least squares mean is adjusted mean change from baseline. Restricted maximum likelihood estimation based on mixed-effect model for repeated measures (MMRM) analysis was used to obtain adjusted means for the treatment effects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Percentage of Time Spent in Target Glucose Range From Weeks 23 to 26 | Week 23 to 26 | Change from baseline in the percentage of time spent in target glucose range of \>70 to ≤180 mg/dL (\>3.9 to ≤10.0 mmol/L) as determined by continuous glucose monitoring (CGM) is presented in week 23 to 26. Least squares mean is actually an adjusted event rate. |
| Change From Baseline in Interstitial Glucose Variability Based on the Interquartile Range (IQR) as Determined by CGM in Weeks 23 to 26 | Week 23 to 26 | Change from baseline in interstitial glucose variability based on the IQR as determined by CGM is presented for week 23 to 26. Least squares mean is actually an adjusted event rate. |
| Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycaemia Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 5 to Week 26, Week 1 to Week 26 | This is a key secondary endpoint. Rate per patient-year of investigator-reported symptomatic hypoglycaemia adverse events (AEs) with confirmed plasma glucose (PG) \<54 milligram per deciliter (mg/dL) (\<3.0 millimoles per litre (mmol/L)) and/or severe hypoglycaemia AEs (i.e. all investigator-reported AEs that had confirmed PG \<54 mg/dL \[\<3.0 mmol/L\] with symptoms reported and all severe hypoglycaemia 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. |
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 | Baseline to week 26 | Change from baseline in SBP and DBP is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised 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 TDID is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised trial medication. Least squares mean is adjusted mean change from baseline. |
| 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 randomised trial medication. Least squares mean is adjusted mean change from baseline. |
Countries
Australia, Austria, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Netherlands, Norway, Poland, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Randomised, double-blind, placebo-controlled, parallel group, 52-week trial comparing 2 oral once daily doses (10 mg and 25 mg) of empagliflozin with placebo in patients with type 1 diabetes mellitus (T1DM), each as adjunctive to optimised insulin therapy.
Pre-assignment details
6-week T1DM therapy (insulin) optimisation period followed by a 2-week placebo run-in period before randomisation. Patients who successfully completed both of the periods were randomised into the 52-week double-blind treatment period. All treatments were administered in addition to optimised insulin therapy.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching Empagliflozin Patients administered placebo matching empagliflozin film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks | 243 |
| Empagliflozin 10 mg Patients administered empagliflozin 10 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks. | 243 |
| Empagliflozin 25 mg Patients administered empagliflozin 25 mg film-coated tablet orally once daily as adjunctive to optimised insulin therapy for 52 weeks. | 244 |
| Total | 730 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 6 | 3 |
| Overall Study | Lost to Follow-up | 7 | 4 | 0 |
| Overall Study | Other than specified | 4 | 4 | 5 |
| Overall Study | Protocol Violation | 10 | 3 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 3 | 5 |
Baseline characteristics
| Characteristic | Placebo Matching Empagliflozin | Empagliflozin 10 mg | Empagliflozin 25 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 44.2 Years STANDARD_DEVIATION 13.6 | 45.7 Years STANDARD_DEVIATION 12.5 | 45.3 Years STANDARD_DEVIATION 14 | 45.0 Years STANDARD_DEVIATION 13.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 4 Participants | 6 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 236 Participants | 239 Participants | 238 Participants | 713 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 6 Participants | 10 Participants | 23 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 6 Participants | 4 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 227 Participants | 230 Participants | 230 Participants | 687 Participants |
| Sex: Female, Male Female | 133 Participants | 125 Participants | 131 Participants | 389 Participants |
| Sex: Female, Male Male | 110 Participants | 118 Participants | 113 Participants | 341 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 243 | 0 / 243 | 0 / 244 |
| other Total, other adverse events | 197 / 243 | 197 / 243 | 195 / 244 |
| serious Total, serious adverse events | 28 / 243 | 43 / 243 | 26 / 244 |
Outcome results
Primary
Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 26
Change from baseline in glycated haemoglobin (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 randomised trial medication. Least squares mean is adjusted mean change from baseline. Restricted maximum likelihood estimation based on mixed-effect model for repeated measures (MMRM) analysis was used to obtain adjusted means for the treatment effects.
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; the FAS was the basis for the primary efficacy analysis
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching Empagliflozin | Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 26 | 0.09 Percentage (%) | Standard Error 0.04 |
| Empagliflozin 10 mg | Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 26 | -0.44 Percentage (%) | Standard Error 0.04 |
| Empagliflozin 25 mg | Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 26 | -0.44 Percentage (%) | Standard Error 0.04 |
Comparison: Model Mixed effect Model Repeated Measures (MMRM) included the fixed categorical effects of treatment, pre-existing insulin therapy, visit , and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline HbA1c, baseline estimated glomerular filtration rate (eGFR), and baseline HbA1c-by- visit interaction. Patient was included as random effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000197.5% CI: [-0.66, -0.41]Mixed effect Model Repeated Measures
Comparison: Model MMRM included the fixed categorical effects of treatment, pre-existing insulin therapy, visit, and treatment-by- visit interaction, as well as the continuous, fixed covariates of baseline HbA1c, baseline eGFR, and baseline HbA1c-by- visit interaction. Patient was included as random effect. An unstructured covariance structure was used to model the within-patient measurements.p-value: <0.000197.5% CI: [-0.66, -0.41]MMRM
Primary
Change From Baseline in Glycated Haemoglobin (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 haemoglobin (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 randomised trial medication. Least squares mean is adjusted mean change from baseline. Restricted maximum likelihood estimation based on mixed-effect model for repeated measures (MMRM) analysis was used to obtain adjusted means for the treatment effects.
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 Haemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD) ) | 0.09 Percentage (%) | Standard Error 0.04 |
| Empagliflozin 10 mg | Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD) ) | -0.43 Percentage (%) | Standard Error 0.04 |
| Empagliflozin 25 mg | Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 26 for Modified Intention-to-treat Population Set (mITT) (Observed Case (OC) - All Data (AD) (OC-AD) ) | -0.42 Percentage (%) | Standard Error 0.04 |
Comparison: Model MMRM 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: [-0.65, -0.4]MMRM
Comparison: Model MMRM 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 measurementsp-value: <0.000197.5% CI: [-0.64, -0.39]MMRM
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 randomised 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 | -0.10 Kilogram (kg) | Standard Error 0.21 |
| Empagliflozin 10 mg | Change From Baseline in Body Weight at Week 26 | -2.79 Kilogram (kg) | Standard Error 0.2 |
| Empagliflozin 25 mg | Change From Baseline in Body Weight at Week 26 | -3.37 Kilogram (kg) | Standard Error 0.2 |
Comparison: Model MMRM includes baseline weight, baseline 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: [-3.57, -1.8]MMRM
Comparison: Model MMRM includes baseline weight, baseline 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: [-4.15, -2.39]MMRM
Secondary
Change From Baseline in Interstitial Glucose Variability Based on the Interquartile Range (IQR) as Determined by CGM in Weeks 23 to 26
Change from baseline in interstitial glucose variability based on the IQR as determined by CGM is presented for week 23 to 26. Least squares mean is actually an adjusted event rate.
Time frame: Week 23 to 26
Population: FAS observed cases excluding data after use of paracetamol (OC-P)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching Empagliflozin | Change From Baseline in Interstitial Glucose Variability Based on the Interquartile Range (IQR) as Determined by CGM in Weeks 23 to 26 | 1.62 milligrams (mg)/ deciliter (dL) | Standard Error 1.21 |
| Empagliflozin 10 mg | Change From Baseline in Interstitial Glucose Variability Based on the Interquartile Range (IQR) as Determined by CGM in Weeks 23 to 26 | -15.30 milligrams (mg)/ deciliter (dL) | Standard Error 1.18 |
| Empagliflozin 25 mg | Change From Baseline in Interstitial Glucose Variability Based on the Interquartile Range (IQR) as Determined by CGM in Weeks 23 to 26 | -17.41 milligrams (mg)/ deciliter (dL) | Standard Error 1.16 |
Comparison: The analysis of covariance (ANCOVA) model includes model includes baseline IQR of glucose, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects.p-value: <0.000199.75% CI: [-22.04, -11.81]ANCOVA
Comparison: The analysis of covariance (ANCOVA) model includes model includes baseline IQR of glucose, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects.p-value: <0.000199.75% CI: [-24.13, -13.95]ANCOVA
Secondary
Change From Baseline in Percentage of Time Spent in Target Glucose Range From Weeks 23 to 26
Change from baseline in the percentage of time spent in target glucose range of \>70 to ≤180 mg/dL (\>3.9 to ≤10.0 mmol/L) as determined by continuous glucose monitoring (CGM) is presented in week 23 to 26. Least squares mean is actually an adjusted event rate.
Time frame: Week 23 to 26
Population: FAS observed cases excluding data after use of paracetamol (OC-P)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching Empagliflozin | Change From Baseline in Percentage of Time Spent in Target Glucose Range From Weeks 23 to 26 | -1.13 Percentage of time | Standard Error 0.72 |
| Empagliflozin 10 mg | Change From Baseline in Percentage of Time Spent in Target Glucose Range From Weeks 23 to 26 | 10.73 Percentage of time | Standard Error 0.71 |
| Empagliflozin 25 mg | Change From Baseline in Percentage of Time Spent in Target Glucose Range From Weeks 23 to 26 | 11.74 Percentage of time | Standard Error 0.7 |
Comparison: The analysis of covariance (ANCOVA) model includes baseline time in the target range, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects.p-value: <0.000199.75% CI: [8.78, 14.93]ANCOVA
p-value: <0.000199.75% CI: [9.81, 15.93]ANCOVA
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26
Change from baseline in SBP and DBP is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised 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 | -0.8 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 | -0.3 Millimeters of mercury (mmHg) | Standard Error 0.5 |
| Empagliflozin 10 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 | SBP | -2.9 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 | -1.6 Millimeters of mercury (mmHg) | Standard Error 0.5 |
| Empagliflozin 25 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 26 | SBP | -4.5 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 | -2.6 Millimeters of mercury (mmHg) | Standard Error 0.5 |
Comparison: For SBP, the model MMRM includes baseline SBP seated, baseline estimated 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: 0.039799.75% CI: [-5.2, 1]MMRM
Comparison: For SBP, the model includes baseline SBP seated, baseline estimated 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: 0.000399.75% CI: [-6.8, -0.6]MMRM
Comparison: For DBP, the model MMRM includes baseline DBP seated, baseline 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.p-value: 0.045799.75% CI: [-2.7, 0]MMRM
Comparison: For DBP, the model MMRM includes baseline DBP seated, baseline estimated 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.p-value: 0.000699.75% CI: [-4.3, -0.3]MMRM
Secondary
Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26
Change from baseline in TDID is presented. With regards to efficacy and safety endpoints, the term 'baseline' referred to the last observed measurement prior to administration of any randomised 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 | -0.010 Unit/kilogram (U/kg) | Standard Error 0.007 |
| Empagliflozin 10 mg | Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26 | -0.102 Unit/kilogram (U/kg) | Standard Error 0.007 |
| Empagliflozin 25 mg | Change From Baseline in Total Daily Insulin Dose (TDID) at Week 26 | -0.100 Unit/kilogram (U/kg) | Standard Error 0.007 |
Comparison: Model MMRM includes baseline total daily insulin dose, baseline estimated 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: [-0.121, -0.063]MMRM
Comparison: Model MMRM includes baseline total daily insulin dose, baseline estimated 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: [-0.119, -0.062]MMRM
Secondary
Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycaemia Adverse Events (AEs) With Confirmed Plasma Glucose (PG)
This is a key secondary endpoint. Rate per patient-year of investigator-reported symptomatic hypoglycaemia adverse events (AEs) with confirmed plasma glucose (PG) \<54 milligram per deciliter (mg/dL) (\<3.0 millimoles per litre (mmol/L)) and/or severe hypoglycaemia AEs (i.e. all investigator-reported AEs that had confirmed PG \<54 mg/dL \[\<3.0 mmol/L\] with symptoms reported and all severe hypoglycaemia 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.
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 Hypoglycaemia Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 5 to 26 | 8.92 Event per patient year |
| Placebo Matching Empagliflozin | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycaemia Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 1 to 26 | 9.13 Event per patient year |
| Empagliflozin 10 mg | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycaemia Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 5 to 26 | 6.64 Event per patient year |
| Empagliflozin 10 mg | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycaemia Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 1 to 26 | 7.07 Event per patient year |
| Empagliflozin 25 mg | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycaemia Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 5 to 26 | 6.48 Event per patient year |
| Empagliflozin 25 mg | Rate Per Patient-year of Investigator-reported Symptomatic Hypoglycaemia Adverse Events (AEs) With Confirmed Plasma Glucose (PG) | Week 1 to 26 | 7.15 Event per patient year |
Comparison: For week 5 to 26, negative binomial model includes baseline rate of hypoglycaemia, baseline HbA1c, and baseline 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: 0.062397.75% CI: [0.518, 1.069]Negative binomial model
Comparison: For week 5 to 26, negative binomial model includes baseline rate of hypoglycaemia, baseline HbA1c, and baseline eGFR as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk \[days\]) was used as offsetp-value: 0.04897.75% CI: [0.502, 1.501]Negative binomial model
Comparison: For week 1 to 26, negative binomial model includes baseline rate of hypoglycaemia, baseline HbA1c, and baseline 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: 0.097295% CI: [0.572, 1.048]Negative binomial model
Comparison: For week 1 to 26, negative binomial model includes baseline rate of hypoglycaemia, baseline HbA1c, and baseline 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: 0.11897.75% CI: [0.575, 1.064]MMRM