Efficacy and Safety Study With Empagliflozin (BI 10773) vs. Placebo as add-on to Metformin or Metformin Plus Sulfonylurea Over 24 Weeks in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The objective of the current study is to investigate the efficacy, safety and tolerability of two doses of BI 10773 compared to placebo given for 24 weeks as add-on therapy to metformin or metformin plus sulfonylurea in patients with Typ 2 Diabetes Mellitus with insufficient glycaemic control.

Official Title
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A Phase III Randomised, Double-blind, Placebo-controlled, Parallel Group, Efficacy and Safety Study of BI 10773 (10 mg, 25 mg) Administered Orally, Once Daily Over 24 Weeks in Patients With Type 2 Diabetes Mellitus With Insufficient Glycaemic Control Despite Treatment With Metformin Alone or Metformin in Combination With a Sulfonylurea

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Placebo identical to BI 10773 high dose
* Drug: Placebo identical to BI 10773 low dose
* Drug: BI 10773
* Drug: BI 10773
* Drug: Placebo identical to BI 10773 low dose
* Drug: BI 10773
* Drug: Placebo identical to BI 10773 high dose


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 a diet and exercise regimen who are pre-treated with immediate release metformin or immediate release metformin plus sulfonylurea (see below for minimum doses). The treatment regimen has to be unchanged for 12 weeks prior to randomisation. Minimum dose for metformin: > or = 1500 mg/day or maximum tolerated dose or maximum dose according to local label Minimum dose for sulfonylurea: > or = half of the maximal recommended dose or maximum tolerated dose or maximum dose according to local label HbA1c of > or = 7.0% and < or = 11% at Visit 1 (screening) in order to be eligible for randomised treatment HbA1c of > 11% at Visit 1 (screening) in order to be eligible for the open-label treatment arm (25 mg BI 10773) Age> or = 18 Body Mass Index (BM)I < or = 45 kg/m2 (Body Mass Index) at Visit 1 (Screening) Signed and dated written informed consent by date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation Exclusion criteria: Uncontrolled hyperglycaemia with a glucose level > 240 mg/dl (>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day) Any other antidiabetic drug within 12 weeks prior to randomisation except those mentioned in inclusion criterion 2 Myocardial infarction, stroke or transient ischemic attack (TIA) within 3 months prior to informed consent Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during screening and/or run-in phase Impaired renal function, defined as eGFR<30 ml/min (severe renal impairment) as determined during screening and/or run-in phase Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years Contraindications to metformin and/or sulfonylurea according to the local label for those patients that enter the study with the respective background therapy Blood dyscrasias or any disorders causing haemolysis or unstable Red Blood Cell (e.g. malaria, babesiosis, haemolytic anaemia) Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except Typ 2 Diabetes Pre-menopausal women (last menstruation ¿ 1 year prior to informed consent) who: are nursing or pregnant or are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence (if acceptable by local authorities), double barrier method and vasectomised partner Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake Participation in another trial with an investigational drug within 30 days prior to informed consent Any other clinical condition that would jeopardize patients safety while participating in this clinical trial

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: BI 10773 Arm 2<br>BI 10773 once daily high dose | Drug: BI 10773<br>* BI 10773 tablets once daily high dose<br>Drug: Placebo identical to BI 10773 low dose<br>* Placebo tablets matching BI 10773 low dose<br>|
| Placebo Comparator: Placebo<br>Placebo matching BI 10773 | Drug: Placebo identical to BI 10773 low dose<br>* Placebo tablets matching BI 10773 low dose<br>Drug: Placebo identical to BI 10773 high dose<br>* Placebo tablets matching BI 10773 high dose<br>|
| Experimental: BI 10773 open-label<br>BI 10773 once daily high dose open label | Drug: BI 10773<br>* BI 10773 tablets once daily high dose open label<br>|
| Experimental: BI 10773 Arm 1<br>BI 10773 once daily low dose | Drug: Placebo identical to BI 10773 high dose<br>* Placebo tablets matching BI 10773 high dose<br>Drug: BI 10773<br>* BI 10773 tablets once daily low dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c Change From Baseline | Change from baseline in HbA1c after 24 weeks. For open-label groups the descriptive mean is provided, for randomised groups adjusted means are provided. The means are adjusted separately for metformin alone and metformin plus sulphonylurea background medication. | Baseline and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Weight Change From Baseline | Body weight change from baseline after 24 weeks. For open-label groups the descriptive mean is provided, for randomised groups adjusted means are provided. The means are adjusted separately for metformin alone and metformin plus sulphonylurea background medication. | Baseline and 24 weeks | 
| Mean Daily Plasma Glucose (MDG) Change From Baseline | Change from baseline in mean daily glucose (MDG) using the 8-point blood glucose profile, after 24 weeks of treatment. For open-label groups the descriptive mean is provided, for randomised groups adjusted means are provided. The means are adjusted separately for metformin alone and metformin plus sulphonylurea background medication. | Baseline and 24 weeks |