Empagliflozin as Adjunctive to Insulin Therapy Over 26 Weeks in Patients With T1DM (EASE-3)

Study Overview
=================
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

Official Title
-----------------
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 26 Weeks in Patients With Type 1 Diabetes Mellitus (EASE-3)

Conditions
-----------------
Diabetes Mellitus, Type 1

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


Participation Criteria
=================
Eligibility Criteria
-----------------
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 exclusion criteria apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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> | Drug: Empagliflozin<br> <br> Drug: Placebo<br>* For blinding purposes<br>|
| Experimental: Empagliflozin high dose<br> | Drug: Empagliflozin<br> <br> Drug: Placebo<br>* For blinding purposes<br>|
| Experimental: Empagliflozin medium dose<br> | Drug: Empagliflozin<br> <br> Drug: Placebo<br>* For blinding purposes<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* For blinding purposes<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 randomized trial medication. Least squares mean is adjusted mean change from baseline. | Baseline to week 26 | 
| 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. | Baseline to week 26 | 
| 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. | Baseline to week 26 |