Empagliflozin as Adjunctive to InSulin thErapy Over 52 Weeks in Patients With Type 1 Diabetes Mellitus (EASE-2)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase III, Randomised, Double Blind, Placebo-controlled, Parallel Group, Efficacy, Safety and Tolerability Trial of Once Daily, Oral Doses of Empagliflozin as Adjunctive to inSulin thErapy Over 52 Weeks in Patients With Type 1 Diabetes Mellitus (EASE-2)

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Empagliflozin
* Drug: Empagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin low dose<br>Empagliflozin tablets once daily | Drug: Empagliflozin<br> <br> |
| Experimental: Empagliflozin high dose<br>Empagliflozin tablets once daily | Drug: Empagliflozin<br> <br> |
| Placebo Comparator: Placebo<br>Placebo tablets matching empagliflozin once daily | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to week 26 | 
| 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. | Baseline to week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 5 to Week 26, Week 1 to Week 26 | 
| 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. | Baseline to week 26 | 
| 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. | Week 23 to 26 | 
| 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. | Week 23 to 26 | 
| 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. | Baseline to week 26 | 
| 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. | Baseline to week 26 |