A Study to Determine Acute (After First Dose) and Chronic (After 28 Days) Effects of Empagliflozin (BI 10773) on Pre and Postprandial Glucose Homeostasis in Patients With Impaired Glucose Tolerance and Type 2 Diabetes Mellitus and Healthy Subjects

Study Overview
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Brief Summary
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An open-label, phase II study to assess the acute and chronic effects of empagliflozin (BI 10773)on fasting and postprandial glucose homeostasis in patients with IGT and type 2 diabetes mellitus and assess the acute effects of empagliflozin in healthy subjects.

Official Title
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An Open-label, Phase II Study to Determine Acute (After the First Dose Administration) and Chronic (After 28 Days of Treatment) Effects of the Sodium-glucose Co-transporter-2 (SGLT-2) Inhibitor Empagliflozin (BI 10773) (25 mg Once Daily) on Pre and Postprandial Glucose Homeostasis in Patients With IGT and, Type 2 Diabetes Mellitus and Healthy Subjects

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: BI 10773


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female patients diagnosed with IGT according to the current ADA guidelines as a two-hour glucose levels of 140 to 199 mg/dl (7.8 mmol/l to 11.1 mmol/l) on the 75-g oral glucose tolerance test (OGTT), with an OGTT performed at the time of the screening visit (Visit 1), or ¿ Male and female patients diagnosed with type 2 diabetes mellitus (T2DM) prior to informed consent, on diet and exercise regimen who are drug-naïve, defined as absence of any oral antihyperglycemic therapy for 12 weeks prior starting with open-label active treatment, or Male and female patients diagnosed with type 2 diabetes mellitus prior to informed consent, who are pre-treated with metformin background therapy, on a stable dose of metformin of at least 1500 mg per day, unchanged for at least 12 weeks prior starting with open-label active treatment HbA1c at Visit 1 (screening) for patients diagnosed of IGT and for healthy subjects: HbA1c < 6.5% for patients diagnosed of T2DM: HbA1c =6.5% and =10.5% Age = 18 at Visit 1 BMI = 20 and = 40 Kg/m2 at Visit 1 For patients with antihypertensive treatment, this must be stable (with no change in dosage) within 4 weeks prior starting with open-label active treatment Signed and dated written informed consent by date of Visit 1 in accordance with GCP and local legislation Inclusion criteria for healthy subjects: Males or females matching the below mentioned criteria and otherwise healthy according to the investigator¿s assessment, as based on the following criteria: a complete medical history including a physical examination, vital signs (BP, PR) and clinical laboratory tests . HbA1c at Visit 1 (screening): HbA1c < 6.5% Confirmed normal glucose tolerance (NGT) by OGTT Age = 45 and = 55 at Visit 1. BMI = 30 and = 40 Kg/m2 (Body Mass Index) at Visit 1. Signed and dated written informed consent by date of Visit 1 in accordance with GCP and local legislation. Exclusion criteria: Acute coronary syndrome (non-STEMI [ST elevation myocardial infarction], STEMI, unstable AP [angina pectoris]), stroke or Transient Ischemic Attack (TIA) within 6 months prior to informed consent. 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 starting the open-label active treatment (Visit 4) except those defined as background via inclusion criterion 1c. Indication of liver disease, defined by serum levels of either Alanine Aminotransferase (ALT [SGPT]), Aspartate Aminotransferase (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 estimated Glomerular Filtration Rate (eGFR) < 60 ml/min (moderate and severe renal impairment) as determined during screening and/or run-in phase. Medical history of insufficient bladder emptying (i.e. neurogenic bladder disorders). Patients with an Haemoglobin (Hb) < 11.5 g/dl (for males) and Hb < 10.5 g/dl (for females) at Visit 1. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption within the last 5 years. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years. For patients on metformin background therapy, the investigator must check for potential exclusion criteria according to local metformin label. Treatment with anti-obesity drugs 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 T2DM. However, the use of inhaled steroids (e.g., for asthma, Chronic Obstructive Pulmonary Disease [COPD]) is not an exclusion as these do not cause systemic steroid action. Alcohol or drug abuse (according to investigators judgment) 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. Intake of an investigational drug in another trial Participation in another trial within 30 days prior to intake of study medication in this trial. 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. 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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 10773 Arm<br>BI 10773 high dose once daily | Drug: BI 10773<br>* BI 10773 tablets once daily high dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Plasma Glucose at Day 1 | Change from baseline of Fasting Plasma glucose (FPG) 3 hours and 35 minutes before meal at day 1 | Baseline and day 1 | 
| Change From Baseline in Fasting Plasma Glucose at Day 28 | Change from baseline of Fasting Plasma glucose (FPG) 3 hours and 35 minutes before meal at day 28. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable | Baseline and day 28 | 
| Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 1 | Change from baseline in the incremental area under the curve of postprandial plasma glucose from 0 to 5 hours (PPG iAUC 5h), defined as the area under the curve of timepoints 0 to 5 hours after meal reduced by the pre-meal plasma glucose at 0 hours. | 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after meal at baseline and day 1 | 
| Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 28 | Change from baseline in the incremental area under the curve of postprandial plasma glucose from 0 to 5 hours (PPG iAUC 5h), defined as the area under the curve of timepoints 0 to 5 hours after meal reduced by the pre-meal plasma glucose at 0 hours. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable. | 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after meal at baseline and day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 1 | Change from baseline in rate of endogenous glucose production (EGP) fast after one dose | Baseline and day 1 | 
| Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 28 | Change from baseline in rate of endogenous glucose production (EGP) fast after 28 days of treatment. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable. | Baseline and day 28 | 
| Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 1 | Change from baseline in the area under the curve of endogenous glucose production (EGP) from 0 to 5 hours (EGP AUC 5h) after meal. | 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after meal at baseline and day 1 | 
| Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 28 | Change from baseline in the area under the curve of endogenous glucose production (EGP) from 0 to 5 hours (EGP AUC 5h) after meal. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable. | 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after meal at baseline and day 28 | 
| Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 1 | Change from baseline in the incremental area under the curve of endogenous glucose production from 0 to 5 hours (EGP iAUC 5h), defined as the area under the curve of timepoints 0 to 5 hours after meal reduced by the pre-meal endogenous glucose production at 0 hour. | 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after drug administration at baseline and day 1 | 
| Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 28 | Change from baseline in the incremental area under the curve of endogenous glucose production from 0 to 5 hours (EGP iAUC 5h), defined as the area under the curve of timepoints 0 to 5 hours after meal reduced by the pre-meal endogenous glucose production at 0 hour. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable. | 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after drug administration at baseline and day 28 |