A 16 Weeks Study on Efficacy and Safety of Two Doses of Empagliflozin (BI 10773) (Once Daily Versus Twice Daily) in Patients With Type 2 Diabetes Mellitus and Preexisting Metformin Therapy

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to investigate the efficacy and safety of two doses (high and low) of empagliflozin as add-on therapy to metformin in patients with type 2 diabetes mellitus (T2DM) and insufficient glycaemic control. Both doses may be given once daily or split to a twice daily dosage. This results in 4 different dosage regimens of empagliflozin (high dose once daily or split vs. low dose once daily or split). This is done to evaluate whether a twice daily dose regimen of empagliflozin results in a loss of efficacy relative to once daily dosing when given on top of metformin background therapy.

Official Title
-----------------
A Randomised, Double Blind, Placebo Controlled, Parallel Group Efficacy and Safety Study of Oral Administration of Empagliflozin Twice Daily Versus Once Daily in Two Different Daily Doses Over 16 Weeks as add-on Therapy to a Twice Daily Dosing Regimen of Metformin in Patients With Type 2 Diabetes Mellitus and Insufficient Glycaemic Control

Conditions
-----------------
Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: empagliflozin (low dose qd)
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: Empagliflozin (high dose qd)
* Drug: empagliflozin (high dose bid)
* Drug: Placebo
* Drug: empagliflozin (low dose bid)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: confirmed diagnosis of T2DM Glycated hemoglobin (HbA1c) >=7.0 and <=10/0% at Visit 1 Metformin therapy (at least 1500 mg/day, BID) age>=18 at Visit 1 body mass index <=45 kg/m2 Exclusion criteria: estimated creatinine clearance rate (eCCr) <60 ml/min (Cockcroft-Gault formula) screening and/or run-in a confirmed glucose level >240 mg/dl (>13.3 mmol/L) after an overnight fast during placebo run-in

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 (high dose qd)<br>Patients receive Empagliflozin high dose once daily | Drug: Placebo<br>* Patients receive placebo matching empagliflozin (low dose qd)<br>Drug: Placebo<br>* Patients receive placebo matching Empagliflozin (high dose bid)<br>Drug: Placebo<br>* Patients receive placebo matching empagliflozin (low dose bid)<br>Drug: Empagliflozin (high dose qd)<br>* Patients receive Empagliflozin high dose once daily<br>|
| Experimental: empagliflozin (high dose bid)<br>Patients receive Empagliflozin high dose split twice daily | Drug: Placebo<br>* Patients receive placebo matching Empagliflozin (high dose qd)<br>Drug: Placebo<br>* Patients receive placebo matching empagliflozin (low dose qd)<br>Drug: Placebo<br>* Patients receive placebo matching empagliflozin (low dose bid)<br>Drug: empagliflozin (high dose bid)<br>* Patients receive Empagliflozin high dose split twice daily<br>|
| Experimental: empagliflozin (low dose qd)<br>Patients receive Empagliflozin low dose once daily | Drug: empagliflozin (low dose qd)<br>* Patients receive Empagliflozin low dose once daily<br>Drug: Placebo<br>* Patients receive placebo matching empagliflozin (low dose bid)<br>Drug: Placebo<br>* Patients receive placebo matching Empagliflozin (high dose bid)<br>Drug: Placebo<br>* Patients receive placebo matching Empagliflozin (high dose qd)<br>|
| Experimental: empagliflozin (low dose bid)<br>Patients receive Empagliflozin low dose split twice daily | Drug: Placebo<br>* Patients receive placebo matching Empagliflozin (high dose qd)<br>Drug: Placebo<br>* Patients receive placebo matching empagliflozin (low dose qd)<br>Drug: Placebo<br>* Patients receive placebo matching Empagliflozin (high dose bid)<br>Drug: empagliflozin (low dose bid)<br>* Patients receive Empagliflozin low dose split twice daily<br>|
| Placebo Comparator: Placebo<br>Patients receive placebo matching Empagliflozin | Drug: Placebo<br>* Patients receive placebo matching empagliflozin (low dose bid)<br>Drug: Placebo<br>* Patients receive placebo matching Empagliflozin (high dose qd)<br>Drug: Placebo<br>* Patients receive placebo matching Empagliflozin (high dose bid)<br>Drug: Placebo<br>* Patients receive placebo matching empagliflozin (low dose qd)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 16 | Change from baseline in HbA1c (%) after 16 weeks of treatment. The term 'baseline' refers to the last observation prior to the first intake of any randomised study medication. Means provided are the adjusted means. | Baseline and 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Plasma Glucose (FPG) Change From Baseline at Week 16 | Change from baseline in FPG (mg/dL) after 16 weeks of treatment. The term 'baseline' refers to the last observation prior to the first intake of any randomised study medication. Means provided are the adjusted means. | Baseline and 16 weeks |