Safety and Efficacy Study of Empagliflozin and Metformin for 24 Weeks in Treatment Naive Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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This study will investigate the efficacy and safety of two doses (high and low) of empagliflozin in combination with metformin (500 mg and 1000 mg) administered twice daily in patients with type 2 diabetes mellitus (T2DM). Study will compare four dose combinations of empagliflozin + metformin versus each individual component after 24 weeks of treatment.

Official Title
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A 24-week Phase III Randomized, Double-blind, Parallel Group Study to Evaluate the Efficacy and Safety of Twice Daily Oral Administration of Empagliflozin + Metformin Compared With the Individual Components of Empagliflozin or Metformin in Drug Naive Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2, Hyperglycemia

Intervention / Treatment
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* Drug: Metformin 500 mg bid
* Drug: Metformin 1000 mg bid
* Drug: Empagliflozin low dose qd
* Drug: Empagliflozin high dose qd
* Drug: Empagliflozin low dose bid
* Drug: Metformin 500 mg bid
* Drug: Empagliflozin high dose bid
* Drug: Empagliflozin low dose bid
* Drug: Metformin 1000 mg bid
* Drug: Metformin 500 mg bid
* Drug: Metformin 1000 mg bid
* Drug: Empagliflozin high dose bid
* Drug: Metformin 1000 mg bid
* Drug: Empagliflozin high dose bid


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of type 2 diabetes mellitus prior to informed consent Male and female patients on diet and exercise regimen who are drug-naive, defined as absence of any oral antidiabetic therapy for 12 weeks prior to randomization HbA1c >=7.5% and <= 12% (>=58.5 mmol/mol and <=107.7 mmol/mol) Body Mass Index (BMI) <= 45 kg/m2 at screening Exclusion criteria: Uncontrolled hyperglycemia with a glucose level >240 mg/dl (>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second laboratory measurement (not on the same day) Any antidiabetic drug within 12 weeks prior to randomization Impaired renal function, defined as estimated creatinine clearance rate (eCCr) <60 ml/min (Cockcroft-Gault formula) as determined during screening and/or run-in period Contraindications to metformin according to the local label

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 qd<br>Empagliflozin low dose once daily | Drug: Empagliflozin low dose qd<br>* Empagliflozin low dose once daily<br>|
| Experimental: Empagliflozin high dose qd<br>Empagliflozin high dose once daily | Drug: Empagliflozin high dose qd<br>* Empagliflozin high dose once daily<br>|
| Experimental: OL empa high dose + met 1000 mg bid<br>Open label empagliflozin high dose split twice daily + metformin 1000 mg twice daily - Patients are no longer enrolled into this arm because of change in the inclusion criteria in protocol version 2.0 all patients are now enrolled into remaining double-blind arms. Patients already enrolled in the open-label arm according to protocol version 1.0 can complete the study. | Drug: Metformin 1000 mg bid<br>* Metformin 1000 mg twice daily<br>Drug: Empagliflozin high dose bid<br>* Empagliflozin high dose split twice daily<br>|
| Experimental: Empagliflozin low dose + met 500 mg bid<br>Empagliflozin low dose split twice daily + metformin 500 mg twice daily | Drug: Metformin 500 mg bid<br>* Metformin 500 mg twice daily<br>Drug: Empagliflozin low dose bid<br>* Empagliflozin low dose split twice daily<br>|
| Experimental: Empagliflozin low dose + met 1000 mg bid<br>Empagliflozin low dose split twice daily + metformin 1000 mg twice daily | Drug: Empagliflozin low dose bid<br>* Empagliflozin low dose split twice daily<br>Drug: Metformin 1000 mg bid<br>* Metformin 1000 mg twice daily<br>|
| Experimental: Empagliflozin high dose + met 500 mg bid<br>Empagliflozin high dose split twice daily + metformin 500 mg twice daily | Drug: Metformin 500 mg bid<br>* Metformin 500 mg twice daily<br>Drug: Empagliflozin high dose bid<br>* Empagliflozin high dose split twice daily<br>|
| Experimental: Empagliflozin high dose + met 1000mg bid<br>Empagliflozin high dose split twice daily + metformin 1000 mg twice daily | Drug: Metformin 1000 mg bid<br>* Metformin 1000 mg twice daily<br>Drug: Empagliflozin high dose bid<br>* Empagliflozin high dose split twice daily<br>|
| Experimental: Metformin 500 mg bid<br>Metformin 500 mg twice daily | Drug: Metformin 500 mg bid<br>* Metformin 500 mg twice daily<br>|
| Experimental: Metformin 1000 mg bid<br>Metformin 1000 mg twice daily | Drug: Metformin 1000 mg bid<br>* Metformin 1000 mg twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24 | Change from baseline in HbA1c (%) after 24 weeks of treatment. Baseline refers to the last observation before the start of any randomised trial treatment medication. Means presented are the adjusted means | baseline and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FPG (Fasting Plasma Glucose) Change From Baseline at Week 24 | Change from baseline in FPG (mg/dL) after 24 weeks of treatment. Baseline refers to the last observation before the start of any randomised trial treatment medication. Means presented are the adjusted means. | baseline and 24 weeks | 
| Body Weight Change From Baseline at Week 24 | Change from baseline in body weight (kg) after 24 weeks of treatment. Baseline refers to the last observation before the start of any randomised trial treatment. medication. Means presented are the adjusted means. | baseline and 24 weeks |