Participants with BMI >18.5 and <25.0kg/m²

Participants with BMI ≥25.0 and <35.0kg/m²

Participants with BMI >18.5 and <25.0kg/m². All participants received each of the 6 interventions in a randomized manner.

Lean Participants

Participants with BMI ≥25.0 and <35.0kg/m². All participants received each of the 6 interventions in a randomized manner.

Overweight/Obese Participants

Total

Sex: Female, Male

Race/Ethnicity, Customized

Region of Enrollment

Body Mass Index (BMI)

Percentage change in the incremental area under the glucose response curve (AUC) after 75g glucose for capsules and tablets containing Axulin powder relative to the water control. Incremental AUC is the AUC below the curve above the fasting level; area below fasting is ignored. Percentage change will be calculated as 100 x (A-P)/P where A and P are the mean AUC's after Axulin and water control treatments, respectively. The blinded AUC results for the 6 treatments will be subjected to repeated measures analysis of variance (ANOVA) examining for the main effects of treatment and participant-group, and treatment*group interaction. After demonstration of significant heterogeneity among the 6 coded treatments, differences between individual means will be assessed using Tukey's test to adjust for multiple comparisons. The code will be broken after this analysis has been done. The percentage changes will be considered to be significant if the difference in mean AUC is significant.

All Participants randomized to receive 250ml water.

Water Control

All Participants randomized to receive 250ml water with 8 x 250mg capsules containing Axulin powder plus 8 x 250mg placebo capsules.

2g Capsules

All Participants randomized to receive 250ml water with 16 x 250mg capsules containing Axulin powder.

4g Capsules

All Participants randomized to receive 250ml water.with 16 x 250mg placebo capsules.

Placebo Capsules

All Participants randomized to receive 250ml water with 2 x 1g tablets containing Axulin powder.

2g Tablets

All Participants randomized to receive 250ml water with 4 x 1g tablets containing Axulin powder.

4g Tablets

Percentage Change in Area Under The Curve (AUC) for Blood Glucose 0-2 Hours

Incremental area under the blood glucose response curve (AUC) is the AUC below the glucose response curve above the fasting level; area below fasting is ignored. The blinded AUC results for the 6 treatments will be subjected to repeated measures analysis of variance (ANOVA) examining for the main effects of treatment and participant-group, and treatment*group interaction. After demonstration of significant heterogeneity among the 6 coded treatments, differences between individual means will be assessed using Tukey's test to adjust for multiple comparisons. The code will be broken after this analysis has been done.

All Participants randomized to receive 250ml water.with 8 x 250mg capsules containing Axulin powder plus 8 x 250mg placebo capsules.

Blood Glucose Area Under The Curve (AUC) 0-2 Hours

Incremental area under the serum insulin response curve (AUC) is the AUC below the insulin response curve above the fasting level; area below fasting is ignored. The blinded AUC results for the 6 treatments will be subjected to repeated measures analysis of variance (ANOVA) examining for the main effects of treatment and participant-group, and treatment*group interaction. After demonstration of significant heterogeneity among the 6 coded treatments, differences between individual means will be assessed using Tukey's test to adjust for multiple comparisons. The code will be broken after this analysis has been done.

Serum Insulin Area Under The Curve (AUC) 0-2 Hours

Percentage change in the incremental area under the insulin response curve (AUC) after 75g glucose for the capsules containing Axulin powder relative to the water control. Incremental AUC is the AUC below the curve above the fasting level; area below fasting is ignored. Percentage change will be calculated as 100 x (A-P)/P where A and P are the mean AUC's after Axulin and water control treatments, respectively. The blinded AUC results for the 6 treatments will be subjected to repeated measures analysis of variance (ANOVA) examining for the main effects of treatment and participant-group, and treatment*group interaction. After demonstration of significant heterogeneity among the 6 coded treatments, differences between individual means will be assessed using Tukey's test to adjust for multiple comparisons. The code will be broken after this analysis has been done. The percentage changes will be considered to be significant if the difference in mean AUC is significant.

Percentage Change in Area Under The Curve (AUC) for Serum Insulin 0-2 Hours

Insulinogenic Index is an index of the ability of a change in blood glucose to stimulate an increase in serum insulin. It is a unitless measure with higher numbers indicating improved beta cell function. It is calculated by dividing the change in serum insulin between 0 and 30 minutes by the change in blood glucose between 0 and 30 minutes.

Insulinogenic Index

Matsuda Insulin Sensitivity Index is an index of whole body insulin sensitivity derived from glucose and insulin responses after a 75g Oral Glucose Tolerance Test (OGTT). It is calculated by 10000 divided by the square root of (FG*FI*MG*MI) where FG is fasting glucose, FI is fasting insulin, MG is the mean AUC for blood glucose at 0, 30, 60, 90 and 120 minutes and MI is the mean AUC for serum insulin at 0, 30, 60, 90 and 120 minutes.

Matsuda Insulin Sensitivity Index

Insulin Secretion-Sensitivity Index-2 (ISSI-2) is an index of β-cell function with insulin secretion adjusted for whole body insulin sensitivity. It is calculated by the total area under the curve for serum insulin divided by the area under the curve for blood glucose, and that result times the Matsuda insulin sensitivity index (defined above).

ISSI-2 Index of Beta-cell Function

Percentage change in blood glucose area under the curve (AUC) in lean participants compared to overweight participants.

Lean Participants randomized to receive 250ml water.

Water Control, Lean Participants

Overweight Participants randomized to receive 250ml water.

Water Control, Overweight Participants

Lean Participants randomized to receive 250ml water.with 8 x 250mg capsules containing Axulin powder plus 8 x 250mg placebo capsules.

2g Capsules, Lean Participants

Overweight Participants randomized to receive 250ml water.with 8 x 250mg capsules containing Axulin powder plus 8 x 250mg placebo capsules.

2g Capsules, Overweight Participants

Lean Participants randomized to receive 250ml water with 16 x 250mg capsules containing Axulin powder.

4g Capsules, Lean Participants

Overweight Participants randomized to receive 250ml water with 16 x 250mg capsules containing Axulin powder.

4g Capsules, Overweight Participants

Lean Participants randomized to receive 250ml water with 2 x 1g tablets containing Axulin powder.

2g Tablets, Lean Participants

Overweight Participants randomized to receive 250ml water with 2 x 1g tablets containing Axulin powder.

2g Tablets, Overweight Participants

Lean Participants randomized to receive 250ml water with 4 x 1g tablets containing Axulin powder.

4g Tablets, Lean Participants

Overweight Participants randomized to receive 250ml water with 4 x 1g tablets containing Axulin powder.

4g Tablets, Overweight Participants

Lean Participants randomized to receive 250ml water.with 16 x 250mg placebo capsules.

Placebo Capsules, Lean Participants

Overweight Participants randomized to receive 250ml water.with 16 x 250mg placebo capsules.

Placebo Capsules, Overweight Participants

Effect of Axulin in Lean vs. Overweight Participants

Percentage change in blood glucose area under the curve (AUC) elicited by capsules compared to the same dose of tablets.

Effect of Capsules vs. Tablets

Change from baseline (CFB) in blood glucose will be computed at 90 minutes. The CFB results for the water control and the placebo capsule treatments will be subjected to a paired t-test examining whether the mean difference between the two sets of observations is equal to zero.

Blood Glucose Change From Baseline in the Water Control Compared to the Placebo Capsules at 90 Minutes for All Participants

Incremental area under the blood glucose response curve (AUC) will be computed using the values recorded at 60 minutes and beyond. The blinded AUC results for the Axulin capsule treatments and the water control will be subjected to repeated measures analysis of variance (ANOVA) examining for the main effects of treatment and participant-group, and treatment*group interaction. After demonstration of significant heterogeneity among the 3 coded treatments, differences between individual means will be assessed using Tukey's test to adjust for multiple comparisons.

60-Minute Blood Glucose Area Under the Curve (AUC)

Change from baseline (CFB) in blood glucose will be computed at 90 and 120 minutes. The CFB results for the capsule treatments and the water control will be subjected to a paired t-test examining whether the mean difference between the two sets of observations is equal to zero.

Blood Glucose Change From Baseline at 90 and 120 Minutes in All Participants

Change from baseline (CFB) in blood glucose will be computed at 90 and 120 minutes for the Lean Participants. The CFB results for the capsule treatments and the water control will be subjected to a paired t-test examining whether the mean difference between the two sets of observations is equal to zero.

Blood Glucose Change From Baseline at 90 and 120 Minutes in Lean Participants

Change from baseline (CFB) in blood glucose will be computed at 90 and 120 minutes for the Obese/Overweight Participants. The CFB results for the capsule treatments and the water control will be subjected to a paired t-test examining whether the mean difference between the two sets of observations is equal to zero.

Blood Glucose Change From Baseline at 90 and 120 Minutes in Overweight Participants

Change from baseline (CFB) in insulin will be computed at 90 minutes. The CFB results for the capsule treatments and the water control will be subjected to a paired t-test examining whether the mean difference between the two sets of observations is equal to zero.

Insulin Change From Baseline at 90 Minutes in All Participants

Overall Study

Project Manager

Participants randomized to receive 250ml water.

Water Control, Overweight/Obese Participants

Participants randomized to receive 250ml water.with 16 x 250mg placebo capsules.

Placebo Capsules, Overweight/Obese Participants

Participants randomized to receive 250ml water.with 8 x 250mg capsules containing Axulin powder plus 8 x 250mg placebo capsules.

2g Capsules, Overweight/Obese Participants

Participants randomized to receive 250ml water with 16 x 250mg capsules containing Axulin powder.

4g Capsules, Overweight/Obese Participants

Participants randomized to receive 250ml water with 2 x 1g tablets containing Axulin powder.

2g Tablets, Overweight/Obese Participants

Participants randomized to receive 250ml water with 4 x 1g tablets containing Axulin powder.

4g Tablets, Overweight/Obese Participants

Insulin Resistance, Diabetes

250ml water with 16 x 250mg placebo capsules

Placebo capsules

250ml water with 8 x 250mg capsules containing Axulin powder plus 8 x 250mg placebo capsules

2g capsules

250ml water with 16 x 250mg capsules containing Axulin powder

4g capsules

250ml water with 2 x 1g tablets containing Axulin powder

2g tablets

250ml water with 4 x 1g tablets containing Axulin powder

4g tablets

Glycemic Index Laboratories, Inc.

Acute Effect of HP-211 (Axulin) on Blood Glucose and Serum Insulin Responses in Healthy Lean and Overweight Humans

Housey Healthcare ULC

Glycemic Index Laboratories, Inc

Each participant in 2 participant groups will undergo each of 6 treatments

Capsule treatments will be fully blinded. Tablet treatments will be open label.

Gemcitabine at a dose of 1000 mg/m2 (iv, 30 minutes) will be given weekly, for 3 weeks, followed by one week without gemcitabine. Erlotinib will be administered at a daily dose of 100 mg at least one hour before or 2 hours after the ingestion of food. Metformin will be administered at a dose of 500 mg twice daily. If well tolerated the dose will be increased to 1000 mg twice daily in the second week.

Gemcitabine at a dose of 1000 mg/m2 (iv, 30 minutes) will be given weekly, for 3 weeks, followed by one week without gemcitabine. Erlotinib will be administered at a daily dose of 100 mg at least one hour before or 2 hours after the ingestion of food. PLacebo will be administered at a dose of 500 mg twice daily. If well tolerated the dose will be increased to 1000 mg twice daily in the second week.

Locally Advanced Pancreatic Cancer

Metastatic Pancreatic Cancer

Gemcitabine at a dose of 1000 mg/m2 (iv, 30 minutes) will be given weekly, for 3 weeks, followed by one week without gemcitabine

gemcitabine

Erlotinib will be administered at a daily dose of 100 mg at least one hour before or 2 hours after the ingestion of food

erlotinib

Metformin will be administered at a dose of 500 mg twice daily for the first week. If tolerated well, the dose will be increased up to 1000 mg twice daily in the second week.

metformin

Placebo will be administered at a dose of 500 mg twice daily for the first week. If tolerated well, the dose will be increased up to 1000 mg twice daily in the second week.

placebo

Academic Medical Center

Metformin Combined With Chemotherapy for Pancreatic Cancer

A Phase II, Randomized, Placebo Controlled Study to Evaluate the Efficacy of the Combination of Gemcitabine, Erlotinib and Metformin in Patients With Locally Advanced and Metastatic Pancreatic Cancer

dr. J.W. Wilmink

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Patients with uncontrolled T2DM are treated with insulin detemir for 6 months. Insulin detemir is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl. This group will receive Long-acting bedtime insulin detemir (Levemir).

After baseline evaluations, insulin detemir will be given at bedtime and titrated to achieve a fasting plasma glucose between 80-100 mg/dl. After 3 months patients will be admitted to assess the metabolic effects of intervention. After this, insulin aspart (insulin detemir plus aspart) will be added before breakfast, lunch and dinner titrated to normalize the postprandial plasma glucose. After another 3 months patients are readmitted and all study procedures repeated. This group will receive Insulin detemir and pre-meal insulin aspart.

Patients with uncontrolled T2DM are treated with insulin detemir for 6 months
Long-acting bedtime insulin detemir (Levemir) : Insulin detemir is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl.

Insulin Detemir Only

After baseline evaluations (admission #1) insulin detemir will be given at bedtime and titrated to achieve a fasting plasma glucose between 80-100 mg/dl. After 3 months patients will be admitted to assess the metabolic effects of intervention. After this, insulin aspart will be added before breakfast, lunch and dinner titrated to normalize the postprandial plasma glucose. After another 3 months patients are readmitted and all study procedures repeated as during admissions #1 and #2.
Insulin detemir and pre-meal insulin aspart. : Insulin detemir at bedtime. Insulin aspart before breakfast, lunch and dinner.

Insulin Detemir Plus Aspart

Hepatic steatosis measured by proton magnetic resonance spectroscopy (1H-MRS).

Liver fat by MRS measured after 3 months of insulin.

Insulin Detemir x 3 Months (All Pts Had Liver MRS)

Hepatic Steatosis

All patients with uncontrolled T2DM are treated with insulin detemir for 6 months and after 3 months randomized to either arm. Long-acting bedtime insulin detemir (Levemir) : Insulin detemir is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl.

Insulin Detemir Only (3 and 6 Months)

Metabolic Control as Measured by the A1c

Derived from the hyperglycemic clamp (Plasma C-peptide change vs. pretreatment in first and second phase).

All patients with uncontrolled T2DM are treated with insulin detemir for 6 months and after 3 months randomized to either arm. Long-acting bedtime insulin detemir (Levemir) is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl.

Change in Insulin Secretion

Percent intramyocellular (IMCL) by magnetic resonance imaging and spectroscopy (MRS).

Patients with uncontrolled T2DM are treated with insulin detemir for 6 months. After patients were treated for 3 months with bedtime insulin detemir they were randomized to either continue with bedtime insulin detemir or add premeal rapid-acting insulin novolog.
Long-acting bedtime insulin detemir (Levemir) was given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl.

After baseline evaluations (admission #1) insulin detemir will be given at bedtime and titrated to achieve a fasting plasma glucose between 80-100 mg/dl. After 3 months patients will be admitted to assess the metabolic effects of intervention. After this, insulin aspart will be added before breakfast, lunch and dinner titrated to normalize the postprandial plasma glucose. After another 3 months patients are readmitted and all study procedures repeated as during admissions #1 and #2.
Insulin detemir was given at bedtime. Insulin aspart before breakfast, lunch and dinner.

Intramyocellular (IMCL) by Magnetic Resonance Imaging and Spectroscopy (MRS).

Fasting plasma lipid concentration on day of admission at 3 and 6 months.

Plasma Lipid Concentration.

Change in anthropometric measure (body weight) done on day of admission at 3 and 6 months.

Change in Anthropometric Measure (Body Weight).

Defined as hypoglycemia <40 mg/dl and/or requiring medical assistance during the trial.

Number of Hypoglycemic Events

Metabolic Control as Measured by the Fasting Plasma Glucose Concentration

Metabolic Control as Measured by the Postprandial Plasma Glucose During the Day-long Plasma Glucose Profile.

Change in lipoprotein particle number was determined using NMR.

Advanced Lipid Testing

Change in anthropometric measure (body mass index [BMI]) done on day of admission at 3 and 6 months.

Change in Anthropometric Measure (Body Mass Index [BMI]).

Inflammatory Markers include: Adiponectin, MMP-9, E-selectin, sICAM, and sVCAM

Patients with uncontrolled T2DM are treated with insulin detemir for 6 months. Insulin detemir is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl. This group will receive Long-acting bedtime insulin detemir (Levemir).
Long-acting bedtime insulin detemir (Levemir): This group will receive Insulin detemir. Insulin detemir is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl.

After baseline evaluations, insulin detemir will be given at bedtime and titrated to achieve a fasting plasma glucose between 80-100 mg/dl. After 3 months patients will be admitted to assess the metabolic effects of intervention. After this, insulin aspart (insulin detemir plus aspart) will be added before breakfast, lunch and dinner titrated to normalize the postprandial plasma glucose. After another 3 months patients are readmitted and all study procedures repeated. This group will receive Insulin detemir and pre-meal insulin aspart.
Insulin detemir and pre-meal insulin aspart.: This group will receive Insulin detemir plus aspart. The group will start with Insulin detemir at bedtime. Then in three months they will Insulin aspart before breakfast, lunch and dinner.

Percent Change From Baseline in Vascular Inflammatory Markers

Initial Treatment (Months 0 - 3)

Randomized Period (Months 3 to 6)

Dr. Kenneth Cusi

Type 2 Diabetes

This group will receive Insulin detemir. Insulin detemir is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl.

Long-acting bedtime insulin detemir (Levemir)

This group will receive Insulin detemir plus aspart. The group will start with Insulin detemir at bedtime. Then in three months they will Insulin aspart before breakfast, lunch and dinner.

Insulin detemir and pre-meal insulin aspart.

The University of Texas H.S.C. at San Antonio and the San Antonio Audie L. Murphy VA Hospital

Effect of a Basal/Pre-Meal Insulin Strategy (Detemir/Aspart) on Insulin Secretion and Action in Type 2 Diabetes

Effect of a Basal/Pre-Meal Insulin Strategy (Detemir/Aspart) to Improve Insulin Secretion and Action in Subjects With Type 2 Diabetes

University of Florida

VA Office of Research and Development

Novo Nordisk A/S

Chronic Hepatitis C

Insulin Resistance

Division of Gastroenterology, University of Torino, Ospedale San Giovanni Battista

Pegylated-Interferon and Ribavirin Plus Metformin in the Treatment of Chronic HCV Infection and Insulin Resistance

An Efficacy and Safety Study Comparing Pegylated-Interferon and Ribavirin Plus Metformin to Pegylated-Interferon and Ribavirin in the Treatment of naïve Patients With Genotype 1 Chronic HCV Infection and Insulin Resistance

hyperinsulinism/tyrosine

Acute Effect of HP-211 (Axulin) on Blood Glucose and Serum Insulin Responses in Healthy Lean and Overweight Humans

Metformin Combined With Chemotherapy for Pancreatic Cancer

Effect of a Basal/Pre-Meal Insulin Strategy (Detemir/Aspart) on Insulin Secretion and Action in Type 2 Diabetes

Pegylated-Interferon and Ribavirin Plus Metformin in the Treatment of Chronic HCV Infection and Insulin Resistance

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