| Outcome Measures: |
Primary: Mean Change From Baseline in Plasma HbA1c (Glycosylated Hemoglobin / Hemoglobin A1c), Blood was drawn after an overnight fast to measure plasma HbA1c levels. End of Study is defined as the last Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed., Baseline, Day 28, Day 84, Day 126, End of Study (168 [+/- 5] days after dosing)|Mean Change From Baseline in Plasma Glucose Area Under the Curve (AUC) 0 - 4 Hours Following Oral Glucose Tolerance Test (OGTT ), Mean Change in Glucose level stimulated by OGTT. Blood samples were taken at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes. Glucose levels over 4 hrs were shown as Area Under the Curve, (AUC). Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed., Baseline, Day 28, Day 84 | Secondary: Mean Change From Baseline in Plasma C-peptide AUC ( Area Under the Curve) 0-4 Hours, Following Oral Glucose Tolerance Test (OGTT), Blood samples were drawn after an overnight fast and standard OGTT at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min. C-peptide levels over 4 hrs were shown as Area Under the Curve, (AUC). Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed., Baseline, Day 28, Day 84|Mean Change From Baseline in Plasma Insulin AUC ( Area Under the Curve) 0-4 Hours, Following Oral Glucose Tolerance Test ( OGTT ), Blood samples were drawn after an overnight fast and OGTT at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min. Insulin levels over 4 hrs were shown as Area Under the Curve, (AUC). Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed., Baseline, Day 28, Day 84|Mean Change From Baseline in Plasma Proinsulin AUC ( Area Under the Curve) 0-4 Hours, Following Oral Glucose Tolerance Test ( OGTT ), Blood samples were drawn after an overnight fast and OGTT at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min. Insulin levels over 4 hrs were shown as Area Under the Curve, (AUC). Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed., Baseline, Day 28, Day 84|Mean Change From Baseline in Plasma Glucagon AUC ( Area Under the Curve) 0-4 Hours, Following Oral Glucose Tolerance Test, Blood samples were drawn after an overnight fast and OGTT at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min. Glucagon levels over 4 hrs were shown as Area Under the Curve, (AUC). Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed., Baseline, Day 28, Day 84|Mean Change From Baseline in Peak Plasma Insulin/Proinsulin Level, Following Oral Glucose Tolerance Test (OGTT), Blood samples were drawn after an overnight fast and OGTT at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min. Insulin and proinsulin levels were measured. The insulin/proinsulin level was calculated by dividing the insulin level by the proinsulin level. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed., Baseline, Day 28, Day 84|Mean Insulin Secretion Rate ( ISR ) Relative to Glucose, 0 - 4 Hours, Blood samples were taken at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes. Mean ISR relative to glucose over 0-4 hours was calculated as follows: Mean ISR relative to glucose = mean ISR / (glucose AUC/time interval). The mean ISR was computed as an AUC (area under the curve) using the linear trapezoidal rule divided by the corresponding time interval. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed., Day 28, Day 84|Mean Insulin Secretion Rate ( ISR ), 0 - 4 Hours, Blood samples were taken at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes. The mean ISR over 0 - 4 hours was computed as an AUC (area under the curve) using the linear trapezoidal rule divided by the corresponding time interval. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed., Day 28, Day 84|Insulin Sensitivity Index ( ISI ) at Day 28, Day 48, Insulin sensitivity index (ISI) = 10000 / \[fasting insulin (μIU/mL) x fasting glucose (mg/dL) x mean 2 hour insulin(μIU/mL) x mean 2 hour glucose (mg/dL)\]1/2 where mean 2 hour insulin (or glucose) was defined as the insulin (or glucose)AUC(0-2 hr) divided by the time period (2 hr). In normal subjects the mean score ± SE is 0.366 ± 0.029. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed on log transformed data., Day 28, Day 84|Insulinogenic Index, 0 - 30 Minutes, Insulinogenic index (0-30 min) * \[Change in insulin (0-30 min) (μIU/mL)\] / \[Change in glucose (0-30 min) (mg/dL)\] * \[insulin (μIU/mL) at 30 min - insulin (μIU/mL) at 0 min\] / \[glucose (mg/dL) at 30 min - glucose (mg/dL) at 0 min), where insulin (or glucose) at 0 min was defined as the arithmetic mean of the -15, -10 and 0 min pre-glucose load values. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed on log transformed data.., Day 28, Day 84|Mean Change From Baseline in Peak Plasma Glucose Following Oral Glucose Tolerance Test ( OGTT ), Mean Change in Peak Glucose level stimulated by OGTT. Blood samples were taken at sample times: -20, -10, -1 and 10, 20, 30, 60, 90, 120, 180, and 240 minutes. Change from baseline assessed at Day 28 and 84. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed., Baseline, Day 28, Day 84|Mean Change From Baseline in Peak Plasma Fructosamine Level, Blood was drawn to measure change in plasma Fructosamine Level, from baseline to Day 14, 28, 56, 84, 126 and End of Study ( defined as the final available post-randomization assessment up to the last regularly scheduled visit at Day 168 \[+/- 5\]). Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed., Baseline, Day 14, Day 28, Day 56, Day 84, Day 126, End of Study (168 [+/- 5] days after dosing)|Insulin Resistance as Measured by the Homeostatic Model Assessment (HOMA-IR), Insulin Resistance is measured via the Homeostatic Model Assessment (HOMA-IR) using a computer to model insulin sensitivity. Insulin Sensitivity (HOMA-%S), where 100% is normal, is the reciprocal of insulin resistance (100/S%). HOMA IR = \[fasting insulin (μU/mL)\] x \[fasting plasma glucose (mmol/L)\] / 22.5 where fasting insulin (or glucose) was defined as the arithmetic mean of the -15, -10 and 0 min pre-glucose load values. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed on log transformed data., Baseline, Day 28, Day 84|β-cell Function as Measured by the Homeostatic Model Assessment (HOMA-β ), β cell function is measured by the Homeostatic Model Assessment(HOMA-β) using a computer to model β cell function and insulin sensitivity . β cell function is related to Insulin Sensitivity (HOMA-%S) and is the reciprocal of insulin resistance (100/S%). HOMA β = \[20 x fasting insulin (μU/mL)\] / \[fasting plasma glucose (mmol/L) - 3.5\] where fasting insulin (or glucose) was defined as the arithmetic mean of the -15, -10 and 0 min pre-glucose load values. Analysis of covariance with treatment as a fixed effect and baseline as the covariate was performed on log transformed data., Baseline, Day 28, Day 84|Number of Participants Reporting Death, Serious Adverse Events (SAEs), Adverse Events (AE) Above 5% Frequency, An adverse event is any unwanted event, whether related to study drug or not occurring during the study period. A Serious Adverse Event (SAE) is an event resulting in death, requiring or prolonging hospitalization, a congenital anomaly or other important medical event. AEs and SAEs were recorded at each visit., Baseline to End of Study (56[+/-2] and 168 [+/- 5] days after dosing for Cohort 1 and Cohorts 2-4, respectively)
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| Locations: |
Arkansas Research Medical Testing, Little Rock, Arkansas, 72202, United States|Allied Research International - Cetero Research Miami, Miami, Florida, 33169, United States|Elite Research Institute Miami, Miami, Florida, 33169, United States|International Research Center Towson, MD, Maryland, 21286, United States|Covance Clinical Research Unit Inc, Portland, Oregon, 97239, United States|Charles River Clinical Services, NW Tacoma, Washington, 98418, United States|Novartis Investigator Site, Berlin, Germany|Novartis Investigator Site, Kiel, Germany|Novartis Investigator Site, Moenchengladbach, Germany|Novartis Investigator Site, Munich, Germany|Novartis Investigative Site, Neuss, Germany|Novartis Investigative Site, Moscow, Russian Federation|Novartis Investigative Site, St. Petersberg, Russian Federation
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