An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition. AE's were classified as related to the study medication, based on the investigator's judgment.

Intensity for each AE was categorized as mild, moderate and severe. Mild was defined as awareness of sign or symptom, but easily tolerated; moderate was defined as discomfort enough to cause interference with normal daily activities; severe was defined as inability to perform normal daily activities.

Participant's body weight was assessed in the beginning of the study (at Day 1) and at the end of the study (Day 28 and Day 35). The clinical staff was instructed to use calibrated scales for weight measurement. The same scale was used at the clinical site for all participants at each specified time point during the study. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 28 and Day 35) values.

Vital sign assessment of SBP and DBP was done at Day 1 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours and 24 hours post-dose), Day 2 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 8 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 15 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 22 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 27, Day 28 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours and 24 hours post-dose) and Day 35. A window of plus or minus 5 minutes was allowed during the active treatment visit vital sign assessments. Baseline was defined as the assessment done on Day 1 (pre-dose). The change from Baseline was calculated by subtracting the Baseline value (Day 1, pre-dose) from the individual post-Baseline (Day 1, Day 2, Day 8, Day 15, Day 22, Day 27, Day 28 and Day 35) values.

Vital sign assessment of HR was done at Day 1 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours and 24 hours post-dose), Day 2 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 8 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 15 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 22 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 27, Day 28 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours and 24 hours post-dose) and Day 35. A window of plus or minus 5 minutes was allowed during the active treatment visit vital sign assessments. Baseline was defined as the assessment done on Day 1 (pre-dose). The change from Baseline was calculated by subtracting the Baseline value (Day 1, pre-dose) from the individual post-Baseline (Day 1, Day 2, Day 8, Day 15, Day 22, Day 27, Day 28 and Day 35) values.

Vital sign assessment of RR was done at Day 1 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours and 24 hours post-dose), Day 2 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 8 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 15 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 22 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 27, Day 28 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours and 24 hours post-dose) and Day 35. A window of plus or minus 5 minutes was allowed during the active treatment visit vital sign assessments. Baseline was defined as the assessment done on Day 1 (pre-dose). The change from Baseline was calculated by subtracting the Baseline value (Day 1, pre-dose) from the individual post-Baseline (Day 1, Day 2, Day 8, Day 15, Day 22, Day 27, Day 28 and Day 35) values.

Vital sign assessment of temperature was done at Day 1 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours and 24 hours post-dose), Day 2 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 8 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 15 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 22 (pre-dose, 5 minutes, 30 minutes and 1 hour post-dose), Day 27, Day 28 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours and 24 hours post-dose) and Day 35. A window of plus or minus 5 minutes was allowed during the active treatment visit vital sign assessments. Baseline was defined as the assessment done on Day 1 (pre-dose). The change from Baseline was calculated by subtracting the Baseline value (Day 1, pre-dose) from the individual post-Baseline (Day 1, Day 2, Day 8, Day 15, Day 22, Day 27, Day 28 and Day 35) values.

12-lead ECG was obtained in the rested state. Participants lied in supine position with ECG leads on for at least 5 minutes prior to ECG recording. The ECG was performed at Day 1 (pre-dose and post-dose), Day 8, Day 15, Day 22, Day 28 (pre-dose and pre-dose) and Day 35, and included the assessment of PR interval, QRS interval, QT interval and QTc interval. Baseline was defined as the assessment done on Day 1 (pre-dose). The change from Baseline was calculated by subtracting the Baseline value (Day 1, pre-dose) from the individual post-Baseline (Day 1 \[post-dose\], Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Assessment for basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelet and white blood cell (WBC) count were performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Assessment for RBC count was performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Assessment for hematocrit was performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Assessment for hemoglobin was performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Assessment for mean corpuscular hemoglobin was performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Assessment for mean corpuscular hemoglobin concentration was performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Assessment for mean corpuscular volume was performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Assessment for aPTT and PT were performed on Day 1, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 28 and Day 35) values.

Assessment for international normalized ratio was performed on Day 1, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 28 and Day 35) values.

Assessment for ALT, AST, ALP, creatinine phosphokinase and LDH were performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Assessment for bicarbonate, BUN, calcium, chloride, magnesium, phosphate, potassium and sodium were performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Assessment for direct bilirubin, indirect bilirubin, serum creatinine, total bilirubin and uric acid were performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Assessment for lipid profile was performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. The parameters included high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol and triglycerides. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Assessment for albumin and total protein were performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Urinary specific gravity is a measure of the concentration of solutes in urine. It measures the ratio of urine density compared with water density and provides information on the kidney's ability to concentrate urine. The assessments were performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

Urinalysis parameter included urine pH. pH was calculated on a scale of 0 to 14, such that, the lower the number, more acidic the urine and higher the number, more alkaline the urine with 7 being neutral. The assessment was performed on Day 1, Day 8, Day 15, Day 22, Day 28 and Day 35. Baseline was defined as the assessment done on Day 1. The change from Baseline was calculated by subtracting the Baseline value (Day 1) from the individual post-Baseline (Day 8, Day 15, Day 22, Day 28 and Day 35) values.

The pre-dose blood samples were collected within one hour prior to study medication administration. The post-dose blood samples were collected within 2 minutes of the scheduled time. AUC values reported in the analysis of AUC 0-infinity of Day 28 versus Day 1 included AUC 0-infinity on Day 1 and AUC 0-τ on Day 28. Participants fasted for at least 10 hour overnight on Day 1, 2 and 29. The AUC 0-t was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. AUC0-infinity was estimated by linear trapezoidal rule and was sum of the AUC0-t and extrapolated to infinity by dividing the estimated last measurable plasma concentration by elimination rate constant lambda z. Where lambda z is the terminal phase rate constant estimated by linear regression analysis of the log10 transformed concentration-time data after each single dose. The AUC0-infinity was the sum of the estimated and extrapolated parts.

Blood samples were collected on Day 1 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hour, 3 hour, 4 hour, 8 hour and 12 hour post-dose), Day 2 (24 hour post-Day 1 dose), Day 8 (pre-dose), Day 15 (pre-dose), Day 22 (pre-dose), Day 28 (pre-dose, and 15 minutes, 30 minutes, 1 hour, 2 hour, 3 hour, 4 hour, 8 hour and 12 hour post-dose) and Day 29 (24 hour post-Day 28 dose). The pre-dose sample was collected within one hour prior to study medication administration. On Day 1, Day 2 and Day 29, participants fasted for at least 10 hour overnight. The post-dose sample was collected within 2 minutes of the scheduled time. The first occurrence of the Cmax was determined directly from the raw concentration-time data.

Blood samples were collected on Day 1 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hour, 3 hour, 4 hour, 8 hour and 12 hour post-dose), Day 2 (24 hour post-Day 1 dose), Day 8 (pre-dose), Day 15 (pre-dose), Day 22 (pre-dose), Day 28 (pre-dose, and 15 minutes, 30 minutes, 1 hour, 2 hour, 3 hour, 4 hour, 8 hour and 12 hour post-dose) and Day 29 (24 hour post-Day 28 dose). The pre-dose sample was collected within one hour prior to study medication administration. The post-dose sample was collected within 2 minutes of the scheduled time. The time at which Cmax was observed was determined directly from the raw concentration-time data.

Blood samples were collected on Day 1 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hour, 3 hour, 4 hour, 8 hour and 12 hour post-dose), Day 2 (24 hour post-Day 1 dose), Day 8 (pre-dose), Day 15 (pre-dose), Day 22 (pre-dose), Day 28 (pre-dose, and 15 minutes, 30 minutes, 1 hour, 2 hour, 3 hour, 4 hour, 8 hour and 12 hour post-dose) and Day 29 (24 hour post-Day 28 dose). The pre-dose sample was collected within one hour prior to study medication administration. The post-dose sample was collected within 2 minutes of the scheduled time. On Day 1 Day 2 and Day 29, participants fasted for at least 10 hour overnight. The t1/2 was obtained as the ratio of ln2/λz, where λz is the terminal phase rate constant estimated by linear regression analysis of the concentration-time data.

Blood samples were collected on Day 1 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hour, 3 hour, 4 hour, 8 hour and 12 hour post-dose), Day 2 (24 hour post-Day 1 dose), Day 8 (pre-dose), Day 15 (pre-dose), Day 22 (pre-dose), Day 28 (pre-dose, and 15 minutes, 30 minutes, 1 hour, 2 hour, 3 hour, 4 hour, 8 hour and 12 hour post-dose) and Day 29 (24 hour post-Day 28 dose). The pre-dose sample was collected within one hour prior to study medication administration. The post-dose sample was collected within 2 minutes of the scheduled time. On Day 1 Day 2 and Day 29, participants fasted for at least 10 hour overnight.

Blood samples were collected on Day 1 (pre-dose, 15 minutes, 30 minutes, 1 hour, 2 hour, 3 hour, 4 hour, 8 hour and 12 hour post-dose), Day 2 (24 hour post-Day 1 dose), Day 8 (pre-dose), Day 15 (pre-dose), Day 22 (pre-dose), Day 28 (pre-dose, and 15 minutes, 30 minutes, 1 hour, 2 hour, 3 hour, 4 hour, 8 hour and 12 hour post-dose) and Day 29 (24 hour post-Day 28 dose). The pre-dose sample was collected within one hour prior to study medication administration. The post-dose sample was collected within 2 minutes of the scheduled time. On Day 1 Day 2 and Day 29, participants fasted for at least 10 hour overnight.

AUC 0-2h, glucose was obtained pre-dose (Day -1), at the end of the dosing period (Day 28), and at end-of-study (Day 42). Blood samples were obtained prior to administration of 75 g of oral glucose which was administered as standard glucose beverage after an overnight fast, within 15 minutes. A peripheral blood sample was drawn from a peripheral arm vein prior to the participant consuming the beverage. Additional blood samples were drawn at 30, 60, 90, and 120 minutes after the participant had consumed the glucose beverage for the measurement of glucose, insulin and C-peptide concentrations. Blood glucose concentrations were determined with a glucose analyzer. On Day 28, on which the participant received also investigational product, the OGTT had to be performed prior to consumption of standard meal and administration of investigational product.

AUC 0-2h, insulin was obtained pre-dose (Day -1), at the end of the dosing period (Day 28), and at end-of-study (Day 42). Blood samples were obtained prior to administration of 75 g of oral glucose which was administered as standard glucose beverage after an overnight fast, within 15 minutes. A peripheral blood sample was drawn from a peripheral arm vein prior to the participant consuming the beverage. Additional blood samples were drawn at 30, 60, 90, and 120 minutes after the participant had consumed the glucose beverage for the measurement of glucose, insulin and C-peptide concentrations. Blood glucose concentrations were determined with a glucose analyzer. On Day 28, on which the participant received also investigational product, the OGTT had to be performed prior to consumption of standard meal and administration of investigational product.unit of measurement was microunits×hours per milliliter

Stumvoll Index: ISIest was obtained pre-dose (Day -1), at the end of the dosing period (Day 28), and at end-of-study (Day 42). Blood samples were obtained prior to administration of 75 g of oral glucose which was administered as standard glucose beverage after an overnight fast, within 15 minutes. ISI is based on insulin and glucose levels in a fasting state during OGTT and is calculated as: ISI (Matsuda) = 10000/√ G0 X I0 X Gmean X Imean where G0 - fasting plasma glucose (mg/dL) I0 - fasting plasma insulin (milliinternational units (miU)/L) Gmean - mean plasma glucose during OGTT (mg/dL) Imean - mean plasma insulin during OGTT (mIU/L). Unit of measure was (Deciliter × liter)(mg × milliinternational units)

ISI is based on insulin and glucose levels in a fasting state during an oral glucose tolerance test (OGTT) and is calculated as: ISI (Matsuda) = 10000/√ G0 X I0 X Gmean X Imean where G0 - fasting plasma glucose (mg/dL) I0 - fasting plasma insulin (mIU/L) Gmean - mean plasma glucose during OGTT (mg/dL) Imean - mean plasma insulin during OGTT (mIU/L). ISIcomposite was obtained pre-dose (Day -1), at the end of the dosing period (Day 28), and at end-of-study (Day 42).

HIRI was obtained pre-dose (Day -1), at the end of the dosing period (Day 28), and at end-of-study (Day 42). Blood samples were obtained prior to administration of 75 g of oral glucose which was administered as standard glucose beverage after an overnight fast, within 15 minutes. A peripheral blood sample was drawn from a peripheral arm vein prior to the participant consuming the beverage. Additional blood samples were drawn at 30, 60, 90, and 120 minutes after the participant had consumed the glucose beverage for the measurement of glucose, insulin and C-peptide concentrations. Blood glucose concentrations were determined with a glucose analyzer. On Day 28, on which the participant received also investigational product, the OGTT had to be performed prior to consumption of standard meal and administration of investigational product. Unit of measure was millimole × hour per liter)×(milliunits × hour per liter \[mmol\*h/L)\*(mU\*h/L\]

MISI was obtained pre-dose (Day -1), at the end of the dosing period (Day 28), and at end-of-study (Day 42). Blood samples were obtained prior to administration of 75 g of oral glucose which was administered as standard glucose beverage after an overnight fast, within 15 minutes. A peripheral blood sample was drawn from a peripheral arm vein prior to the participant consuming the beverage. Additional blood samples were drawn at 30, 60, 90, and 120 minutes after the participant had consumed the glucose beverage for the measurement of glucose, insulin and C-peptide concentrations. Blood glucose concentrations were determined with a glucose analyzer. On Day 28, on which the participant received also investigational product, the OGTT had to be performed prior to consumption of standard meal and administration of investigational product. Unit of measure was milligram per deciliter per minute per milliunits per liter (mg/dL/min/mU/L).

Measurement of insulin sensitivity consisting of the insulin resistance index obtained during OGTT was not collected.

HOMA-IR was obtained pre-dose (Day -1), at the end of the dosing period (Day 28), and at end-of-study (Day 42). Blood samples were obtained prior to administration of 75 g of oral glucose which was administered as standard glucose beverage after an overnight fast, within 15 minutes. A peripheral blood sample was drawn from a peripheral arm vein prior to the participant consuming the beverage. Additional blood samples were drawn at 30, 60, 90, and 120 minutes after the participant had consumed the glucose beverage for the measurement of glucose, insulin and C-peptide concentrations. Blood glucose concentrations were determined with a glucose analyzer. On Day 28, on which the participant received also investigational product, the OGTT had to be performed prior to consumption of standard meal and administration of investigational product.

HOMA-%B was obtained pre-dose (Day -1), at the end of the dosing period (Day 28), and at end-of-study (Day 42). Blood samples were obtained prior to administration of 75 g of oral glucose which was administered as standard glucose beverage after an overnight fast, within 15 minutes. A peripheral blood sample was drawn from a peripheral arm vein prior to the participant consuming the beverage. Additional blood samples were drawn at 30, 60, 90, and 120 minutes after the participant had consumed the glucose beverage for the measurement of glucose, insulin and C-peptide concentrations. Blood glucose concentrations were determined with a glucose analyzer. On Day 28, on which the participant received also investigational product, the OGTT had to be performed prior to consumption of standard meal and administration of investigational product.

QUICKI was obtained pre-dose (Day -1), at the end of the dosing period (Day 28), and at end-of-study (Day 42). Blood samples were obtained prior to administration of 75 g of oral glucose which was administered as standard glucose beverage after an overnight fast, within 15 minutes. A peripheral blood sample was drawn from a peripheral arm vein prior to the participant consuming the beverage. Additional blood samples were drawn at 30, 60, 90, and 120 minutes after the participant had consumed the glucose beverage for the measurement of glucose, insulin and C-peptide concentrations. Blood glucose concentrations were determined with a glucose analyzer. On Day 28, on which the participant received also investigational product, the OGTT had to be performed prior to consumption of standard meal and administration of investigational product.

A HEGC was carried out at Day 0, 29 and 43. HEGC was performed in participants who developed coagulation abnormalities during the study. Prior to the start of the HEGC procedure, participants were instructed to refrain from alcohol and caffeine for at least 48 hours before each inpatient visit and from exercise at least 24 hours before each inpatient visit. In the evening of the day prior to the HEGC procedure, the participants received a standard dinner at approximately 19:00 hours. Afterwards, the participants remained fasting until the end of the HEGC procedure at approximately 16:00 hours the next day. The HEGC procedure consisted of three phases: Blood glucose adjustment, Insulin infusion step 1, Insulin infusion step 2. The last 60 min of the two insulin infusion steps were defined as "steady state period 1" (SS1) and "steady state period 2" (SS2). unit of measure was Milliliter per minute permeters squared per micro units (mL/min/m2/mcU/mL).

M1 and M2 was carried out at Day 0, 29 and 43. HEGC was performed in participants who developed coagulation abnormalities during the study. Prior to the start of the HEGC procedure, participants were instructed to refrain from alcohol and caffeine for at least 48 hours before each inpatient visit and from exercise at least 24 hours before each inpatient visit. In the evening of the day prior to the HEGC procedure, the participants received a standard dinner at approximately 19:00 hours. Afterwards, the participants remained fasting until the end of the HEGC procedure at approximately 16:00 hours the next day. The HEGC procedure consisted of three phases: Blood glucose adjustment, Insulin infusion step 1, Insulin infusion step 2. The last 60 min of the two insulin infusion steps were defined as "steady state period 1" (SS1) and "steady state period 2" (SS2). Unit of measure was milligrams per minute per kilograms (mg/min/kg).

M/I1 and M/I2 was carried out at Day 0, 29 and 43. HEGC was performed in participants who developed coagulation abnormalities during the study. Prior to the start of the HEGC procedure, participants were instructed to refrain from alcohol and caffeine for at least 48 hours before each inpatient visit and from exercise at least 24 hours before each inpatient visit. In the evening of the day prior to the HEGC procedure, the participants received a standard dinner at approximately 19:00 hours. Afterwards, the participants remained fasting until the end of the HEGC procedure at approximately 16:00 hours the next day. The HEGC procedure consisted of three phases: Blood glucose adjustment, Insulin infusion step 1, Insulin infusion step 2. The last 60 min of the two insulin infusion steps were defined as "steady state period 1" (SS1) and "steady state period 2" (SS2). milligrams per minute per kilograms per microunits per milliliter (mg/min/kg/μU/mL).

MCR1, MCR2 was carried out at Day 0, 29 and 43. HEGC was performed in participants who developed coagulation abnormalities during the study. Prior to the start of the HEGC procedure, participants were instructed to refrain from alcohol and caffeine for at least 48 hours before each inpatient visit and from exercise at least 24 hours before each inpatient visit. In the evening of the day prior to the HEGC procedure, the participants received a standard dinner at approximately 19:00 hours. Afterwards, the participants remained fasting until the end of the HEGC procedure at approximately 16:00 hours the next day. The HEGC procedure consisted of three phases: Blood glucose adjustment, Insulin infusion step 1, Insulin infusion step 2. The last 60 min of the two insulin infusion steps were defined as "steady state period 1" (SS1) and "steady state period 2" (SS2). Unit of measure was kilograms per milliliters per kilo calories (kg/mL/kcal)

M1ree and M2ree was carried out at Day 0, 29 and 43. HEGC was performed in participants who developed coagulation abnormalities during the study. Prior to the start of the HEGC procedure, participants were instructed to refrain from alcohol and caffeine for at least 48 hours before each inpatient visit and from exercise at least 24 hours before each inpatient visit. In the evening of the day prior to the HEGC procedure, the participants received a standard dinner at approximately 19:00 hours. Afterwards, the participants remained fasting until the end of the HEGC procedure at approximately 16:00 hours the next day. The HEGC procedure consisted of three phases: Blood glucose adjustment, Insulin infusion step 1, Insulin infusion step 2. The last 60 min of the two insulin infusion steps were defined as "steady state period 1" (SS1) and "steady state period 2" (SS2).

MCR1ree and MCR2ree was carried out at Day 0, 29 and 43. HEGC was performed in participants who developed coagulation abnormalities during the study. Prior to the start of the HEGC procedure, participants were instructed to refrain from alcohol and caffeine for at least 48 hours before each inpatient visit and from exercise at least 24 hours before each inpatient visit. In the evening of the day prior to the HEGC procedure, the participants received a standard dinner at approximately 19:00 hours. Afterwards, the participants remained fasting until the end of the HEGC procedure at approximately 16:00 hours the next day. The HEGC procedure consisted of three phases: Blood glucose adjustment, Insulin infusion step 1, Insulin infusion step 2. The last 60 min of the two insulin infusion steps were defined as "steady state period 1" (SS1) and "steady state period 2" (SS2).

M/I1ree and M/I2ree was carried out at Day 0, 29 and 43. HEGC was performed in participants who developed coagulation abnormalities during the study. Prior to the start of the HEGC procedure, participants were instructed to refrain from alcohol and caffeine for at least 48 hours before each inpatient visit and from exercise at least 24 hours before each inpatient visit. In the evening of the day prior to the HEGC procedure, the participants received a standard dinner at approximately 19:00 hours. Afterwards, the participants remained fasting until the end of the HEGC procedure at approximately 16:00 hours the next day. The HEGC procedure consisted of three phases: Blood glucose adjustment, Insulin infusion step 1, Insulin infusion step 2. The last 60 min of the two insulin infusion steps were defined as "steady state period 1" (SS1) and "steady state period 2" (SS2).

Mean steady state concentration Free fatty acids and glycerols was carried out at Day 0, 29 and 43. HEGC was performed in participants who developed coagulation abnormalities during the study. Prior to the start of the HEGC procedure, participants were instructed to refrain from alcohol and caffeine for at least 48 hours before each inpatient visit and from exercise at least 24 hours before each inpatient visit. In the evening of the day prior to the HEGC procedure, the participants received a standard dinner at approximately 19:00 hours. Afterwards, the participants remained fasting until the end of the HEGC procedure at approximately 16:00 hours the next day. The HEGC procedure consisted of three phases: Blood glucose adjustment, Insulin infusion step 1, Insulin infusion step 2. The last 60 min of the two insulin infusion steps were defined as "steady state period 1" (SS1) and "steady state period 2" (SS2).

Mean C-peptideSS1 and C-peptideSS2 was carried out at Day 0, 29 and 43. HEGC was performed in participants who developed coagulation abnormalities during the study. Prior to the start of the HEGC procedure, participants were instructed to refrain from alcohol and caffeine for at least 48 hours before each inpatient visit and from exercise at least 24 hours before each inpatient visit. In the evening of the day prior to the HEGC procedure, the participants received a standard dinner at approximately 19:00 hours. Afterwards, the participants remained fasting until the end of the HEGC procedure at approximately 16:00 hours the next day. The HEGC procedure consisted of three phases: Blood glucose adjustment, Insulin infusion step 1, Insulin infusion step 2. The last 60 min of the two insulin infusion steps were defined as "steady state period 1" (SS1) and "steady state period 2" (SS2).

Data for number of participants who presented one or more adverse events (serious or non serious) was reported. An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

Symptomatic, symptomatic and Severe Symptomatic hypoglycemia definitions were used to analyze and report hypoglycemic events. Symptomatic hypoglycemic episodes were collected from Day 1 to Day 28 with the assistance of participants diaries. Symptomatic hypoglycemia and severe symptomatic hypoglycemia was recorded in CRFs as AEs in all cases.

A complete physical examination, including an ophthalmological examination to rule out diabetic neuropathy, was performed at screening. A symptom-driven, directed physical examination was performed also pre dosing (Day-2), during the dosing period (Day 14 and 27) and after dosing (Day 41). Number of participants with abnormal physical findings was reported.

SBP and DBP were investigated at screening, pre-dosing (Day -2), during the dosing period (Day 1, 14 and 27) and at end of dosing follow-up period/end-of-study (Day 41 and 43). At Day 1 the vital signs were collected pre-dose (baseline values) and 3 hours post-dose. Day 0 was Baseline and change from Baseline was a value at study day subtracted by value at baseline.

Heart rate was investigated at screening, pre-dosing (Day -2), during the dosing period (Day 1, 14 and 27) and at end of dosing follow-up period/end-of-study (Day 41 and 43). At Day 1 the vital signs were collected pre-dose (baseline values) and 3 hours post-dose. Day 0 was Baseline and change from Baseline was a value at study day subtracted by value at baseline.

Respiratory rate was investigated at screening, pre-dosing (Day -2), during the dosing period (Day 1, 14 and 27) and at end of dosing follow-up period/end-of-study (Day 41 and 43). At Day 1 the vital signs were collected pre-dose (baseline values) and 3 hours post-dose. Day 0 was Baseline and change from Baseline was a value at study day subtracted by value at baseline.

A 12-lead ECG was recorded at screening, pre-dose (Day -2), at the beginning and end of the dosing period (Day 1 and 27) and at the end of the dosing follow-up period/end-of study (Day 41 and 43). Number of participants with abnormal ECG findings was reported.

Blood samples for assessment of WBC and platelet count was collected at screening, Day -1, 14, 28 and 42. Data for mean and standard deviation was presented.

Blood samples for assessment of WBC differential count and RDW was collected at screening, Day -1, 14, 28 and 42. Data for mean and standard deviation was presented.

Blood samples for assessment of Hb and MCHC was collected at screening, Day -1, 14, 28 and 42. Data for mean and standard deviation was presented.

Blood samples for assessment of hematocrit count was collected at screening, Day -1, 14, 28 and 42. Data for mean and standard deviation was presented.

Blood samples for assessment of MCV was collected at screening, Day -1, 14, 28 and 42. Data for mean and standard deviation was presented.

Blood samples for assessment of MCH was collected at screening, Day -1, 14, 28 and 42. Data for mean and standard deviation was presented.

Blood samples for assessment of RBC count was collected at screening, Day -1, 14, 28 and 42. Data for mean and standard deviation was presented.

Samples for pH assessment were collected at screening, Day -1, 14, 28 and 42. Unscheduled and control assessments were not included in the analysis. Data for mean and standard deviation was presented.

Data for urinalysis was collected at screening, Day -1, 14, 28 and 42. Data for participants with positive and negative urinalysis result was presented. Unscheduled and control assessments were not included in the analysis.

Clinical chemistry assessment for calcium, chloride, magnesium, potassium, sodium, bicarbonate, phosphate, glucose, urea ,blood urea was done at screening, Day -1, 14, 28 and 42. Data for mean and standard deviation was presented.

Clinical chemistry assessment for direct bilirubin, indirect bilirubin, total bilirubin and uric acid was done at screening, Day -1, 14, 28 and 42. Data for mean and standard deviation was presented.

Clinical chemistry assessment for ALP, ALT, AST, LDH and creatine kinase was done at screening, Day -1, 14, 28 and 42. Data for mean and standard deviation was presented.

Clinical chemistry assessment for albumin was done at screening, Day -1, 14, 28 and 42. Data for mean and standard deviation was presented.

Clinical chemistry assessment for serum creatinine was done at screening, Day -1, 14, 28 and 42. Data for mean and standard deviation was presented.