A Study to Test the Combination of Two Different Kinds of Medications for the Treatment of Diabetes

Study Overview
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Brief Summary
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Test the safety, tolerability and improvement of blood sugar control with combination therapy in individuals with Type 2 Diabetes.

Official Title
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A Proof of Concept Study to Evaluate the Coadministration of TT223 Given Daily and LY2428757 Given Once-Weekly for Four Weeks in Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: LY2428757
* Drug: TT223
* Drug: Placebo for LY2428757
* Drug: Placebo for TT223


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Have type 2 diabetes mellitus (T2DM) for at least 6 months Currently treated with diet and exercise alone or in combination with stable metformin Glycosylated hemoglobin (HbA1c) 7.0% to 10.0% Ages 18 to 70 years Women not of childbearing potential Body mass index (BMI) between 25 and 40 kilograms per meters squared (kg/m^2), and stable weight in the 3 months prior to screening. Exclusion Criteria: Use of diabetes medicine other than metformin in past 3 months Gastrointestinal disease or surgery or drugs that significantly impacts gastric filling, emptying or motility; ongoing cholelithiasis or cholecystitis. Chronic, daily proton pump inhibitors (PPIs) and histamine (H2) antagonists. Severe hypoglycemia or hyperglycemia Advanced microvascular diabetes complications Medications to promote weight loss. Breastfeeding women Cardiac autonomic neuropathy In the past 6 months have cardiac disease with functional status that is Class II-IV or a history of myocardial infarction, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, transient ischemic attack, cerebrovascular accident (stroke), or decompensated congestive heart failure. History of a supraventricular or ventricular tachycardia, pacemaker implantation, or other cardiac arrhythmia: Poorly controlled hypertension, malignant hypertension, renal artery stenosis, and/or evidence of labile blood pressure including symptomatic postural hypotension. Electrocardiograms (ECG) abnormality or medication that impairs the ability to measure QT interval (QT), or correct the QT interval (QT) for rate. QT interval Bazett corrected (QTcB) >450 milliseconds (msec) or PR interval (PR) >220 milliseconds (msec) Personal or family history of long QT interval (QT) syndrome, sudden death, or unexplained syncope Clinical signs or symptoms of liver disease, acute or chronic hepatitis, or alanine transaminase levels > 2.5 times the upper limit of the reference range Hypertriglyceridemia > 400 mg/deciliter (dL) Inadequately treated hypothyroidism or hyperthyroidism Peptic ulcer disease and/or gastrointestinal bleeding/perforation. Known pentagastrin hypersensitivity Impaired renal function Transplanted organ. Active, uncontrolled endocrine or autoimmune abnormality > 2 weeks systemic glucocorticoid therapy Ongoing courses of non-steroidal anti-inflammatory drugs (NSAIDs), except for aspirin 81-325 milligrams (mg) Diagnosed malignancy or in remission for less than 5 years. Prior acute or chronic pancreatitis or elevated serum lipase or amylase Current central nervous system stimulant Other conditions that preclude the participant from participating, following or completing the protocol. Chronic infection Personnel affiliated with the study and their immediate families. Within 30 days of the initial dose of study drug, have participated in an interventional medical, surgical, or pharmaceutical study in which a medical or surgical treatment was given. Have previously completed or withdrawn from this study after providing informed consent. Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug or device (other than the study drug/device used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2428757 plus TT223 3 milligrams (mg)<br>Weekly LY2428757 plus 3 milligrams (mg) daily TT223 | Drug: LY2428757<br>* 14 mg subcutaneous injection 1 time a week for 5 weeks<br>Drug: TT223<br>* subcutaneous injection once a day for 4 weeks<br>|
| Experimental: LY2428757 plus TT223 2mg<br>Weekly LY2428757 plus 2 mg daily TT223 | Drug: LY2428757<br>* 14 mg subcutaneous injection 1 time a week for 5 weeks<br>Drug: TT223<br>* subcutaneous injection once a day for 4 weeks<br>|
| Experimental: LY2428757 plus placebo<br>Weekly LY2428757 plus daily TT223 placebo | Drug: LY2428757<br>* 14 mg subcutaneous injection 1 time a week for 5 weeks<br>Drug: Placebo for TT223<br>* subcutaneous injection once a day for 4 weeks<br>|
| Placebo Comparator: Placebo plus Placebo<br>Weekly LY2428757 placebo plus daily TT223 placebo | Drug: Placebo for LY2428757<br>* subcutaneous injection 1 time a week for 5 weeks<br>Drug: Placebo for TT223<br>* subcutaneous injection once a day for 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at 6-Month Endpoint | Values obtained from repeated measures analysis, which included the fixed categorical effects of treatment, baseline therapy strata (metformin versus diet and exercise [D&E]), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline glycosylated hemoglobin (HbA1c). Change from baseline means the absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at 4-Week Endpoint | Values obtained from repeated measures analysis, which included the fixed categorical effects of treatment, baseline therapy strata (metformin versus diet and exercise [D&E]), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline glycosylated hemoglobin (HbA1c). Change from baseline means the absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 4 weeks | 
| Change From Baseline in Mixed-Meal Tolerance Test (MMTT) Response - Glucose Area Under the Curve (AUC) at 3-Week and 6-Month Endpoints | Standardized mixed-meal tolerance test (MMTT) used to assess changes in function of cells that make insulin (pancreatic beta cell function). Area under the plasma glucose concentration versus time curve calculated using linear-trapezoidal method. AUC for glucose represents area under curve of values when plotted over time. Larger area under the curve values represent greater average glucose value over time in response to meal. Least squares (LS) means adjusted for baseline, treatment, visit, treatment-by-visit. Change from baseline=absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 3 weeks, 6 months | 
| Change From Baseline in Mixed-Meal Tolerance Test (MMTT) Response - C-Peptide Area Under the Curve (AUC) at 3-Week and 6-Month Endpoints | The area under the C-peptide concentration versus time curve was calculated using the linear-trapezoidal method. Area under the curve (AUC) for C-peptide represents area under the curve (AUC) of C-peptide values when plotted over time. Larger area under the curve (AUC) values represent a greater average C-peptide value over time in response to a meal. Least squares (LS) means adjusted for baseline, treatment, visit, treatment-by-visit interaction. Change from baseline means the absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 3 weeks, 6 months | 
| Change From Baseline in Mixed Meal Tolerance Test (MMTT) Response - Ratio of Insulin Area Under the Curve (AUC)/Glucose Area Under the Curve (AUC) at 3-Week and 6-Month Endpoints | Mixed meal tolerance test (MMTT) to assess changes in function of cells making insulin. AUCinsulin/AUCglucose ratio: index of insulin secretion. Larger values reflect greater secretion adjusted for glucose in response to meal. Area under insulin concentration versus time curve and area under plasma glucose concentration versus time curve calculated using linear-trapezoidal method. AUC for insulin and glucose represents AUC of values plotted over time. LS means adjusted for baseline, treatment, visit, treatment-by-visit. Change from baseline=absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 3 weeks, 6 months | 
| Change From Baseline in Mixed-Meal Tolerance Test (MMTT) Response - Glucagon Area Under the Curve (AUC) at 3-Week and 6-Month Endpoints | Standardized mixed meal tolerance test (MMTT) to assess changes in hormones in response to meal. Area under the plasma glucagon concentration versus time curve was calculated using the linear-trapezoidal method. Area under the curve (AUC) for glucagon represents the AUC of glucagon values when are plotted over time. Larger area under the curve (AUC) values represent a greater average glucagon value over time in response to a meal. Least squares (LS) means adjusted for baseline, treatment, visit, treatment-by-visit. Change from baseline=absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 3 weeks, 6 months | 
| Change From Baseline in Mixed-Meal Tolerance Test (MMTT) Response - Glucagon-like Peptide-1 (GLP-1) Area Under the Cure (AUC) at 3-Week and 6-Month Endpoints | Standardized mixed meal tolerance test (MMTT) to assess changes in hormones in response to meal. Area under plasma glucagon-like peptide-1 (GLP-1) concentration versus time curve calculated using linear-trapezoidal method. Area under the curve (AUC) for glucagon-like peptide-1 (GLP-1) represents the AUC of GLP-1 values when plotted over time. Larger AUC values represent a greater average GLP-1 value over time in response to meal. Least squares (LS) means adjusted for baseline, treatment, visit, treatment-by-visit. Change from baseline=absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 3 weeks, 6 months | 
| Change From Baseline in Mixed-Meal Tolerance Test (MMTT) Response - Post-Prandial Glucose at 3-Week and 6-Month Endpoints | Standardized MMTT to assess changes in function of cells that make insulin (pancreatic beta cells). Glucose measured at 2-hour timepoint during MMTT reflects glucose values in response to meal. Change in postprandial glucose calculated based on difference of 2-hour postprandial glucose at endpoint compared to baseline. Larger changes from baseline represent a greater postprandial glucose compared to 2-hour timepoint prior to treatment. Least squares (LS) means adjusted for baseline, treatment, visit, treatment-by-visit. Change from baseline=absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 3 weeks, 6 months | 
| Change From Baseline in Fasting Blood Glucose (FBG) at 4-Week and 6-Month Endpoints | Values obtained from repeated measures analysis, which included the fixed categorical effects of treatment, baseline therapy strata (metformin versus diet and exercise [D&E]), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline fasting blood glucose (FBG). Fasting blood glucose (FBG) is the mixed meal tolerance test (MMTT) glucose assessment at time point 0, where available, otherwise it is the assessment taken from the chemistry panel. Change from baseline means the absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 4 weeks, 6 months | 
| Change From Baseline in Glycosylated Hemoglobin (HbA1C) Adjusted for Baseline Glycosylated Hemoglobin (HbA1c), C-Peptide Level, Homeostasis Model Assessment of Insulin Resistance (HOMA), Duration of Diabetes, and Body Mass Index (BMI) at 6-Month Endpoint | HbA1c adjusted: baseline HbA1c (<8%,≥8%); C-peptide level (normal, elevated); HOMA (<baseline median,≥baseline median); duration diabetes (<3,3-10,>10 years); BMI (<30,≥30). BMI estimates body fat based on weight/height squared. HOMA: index of function of cells that make insulin/insulin resistance. Indices derived from fasting glucose and insulin concentrations. LS means adjusted for treatment, baseline therapy, visit, treatment-by-visit, subgroup, subgroup-by-treatment, subgroup-by-visit, subgroup-by-treatment-by-visit. Change from baseline=absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 6 months | 
| Change From Baseline in MMTT Response (Postprandial Glucose, Glucose AUC, Insulin/c-Peptide Secretory Response, HOMA, GLP-1, Glucagon) Adjusted for Baseline HbA1c, C-Peptide Level, HOMA, Duration of Diabetes, Weight at Week 0, 3, Month 3.5, 6 Endpoints | Subgroup analyses for mixed meal tolerance test (MMTT) response (adjusted for baseline glycosylated hemoglobin (HbA1c), C-peptide level, Homeostasis Model Assessment of Insulin Resistance (HOMA), duration of diabetes, weight) not performed due to lack of statistically significant findings in subgroup analysis for HbA1c analyses. HOMA was not done for mixed meal tolerance test (MMTT) because it is not calculated from the mixed meal tolerance test (MMTT). It is reported separately as a secondary outcome measure. Change from baseline=absolute change from baseline (endpoint-baseline). | Baseline (Week -1), Week 0, 3 weeks, 3.5 months, 6 months | 
| Change From Baseline in Fasting Blood Glucose (FBG) Adjusted for Baseline HbA1c, C-Peptide Level, Homeostasis Model Assessment of Insulin Resistance, Duration of Diabetes, and Weight at 3-Week, 4-Week, 2-Month, 3.5-Month, 5-Month, and 6-Month Endpoints | The subgroup analyses for fasting blood glucose (FBG) (adjusted for baseline glycosylated hemoglobin [HbA1c]), C-peptide level, homeostasis model assessment of insulin resistance (HOMA), duration of diabetes, and weight) were not performed due to the lack of statistically significant findings in the subgroup analysis for the glycosylated hemoglobin (HbA1c) analyses. Change from baseline means the absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 3 weeks, 4 weeks, 2 months, 3.5 months, 5 months, 6 months | 
| Mean Change From Baseline in Weight at Week 0, Week 4, and 6-Month Endpoints | Values obtained from repeated measures analysis, which included the fixed categorical effects of treatment, baseline therapy strata (metformin versus diet and exercise [D&E]), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline weight. Change from baseline means the absolute change from baseline (endpoint-baseline). | Baseline (Week -1), Week 0, 4 weeks, 6 months | 
| Number of Participants With Antibodies to LY2428757 | Participants who were positive for antibodies to LY2428757. | Baseline (Week -1) through 6 months | 
| Number of Participants With Antibodies to TT223 | Participants who were positive for antibodies for TT223. | Baseline (Week -1) through 6 months | 
| Pharmacokinetics (PKs) of TT223, First Dose - Time of Maximum Observed Drug Concentration (Tmax) | Time of maximum observed drug concentration (Tmax) is the time at which the maximum observed concentration (Cmax) occurs. | 0 (pre-dose), 0.33, 0.5, 1, 2, 3, 4, 6 hours | 
| Pharmacokinetics (PKs) of TT223, First Dose - Maximum Observed Drug Concentration (Cmax) | Maximum observed drug concentration (Cmax) is the maximum observed concentration of drug. | 0 (pre-dose), 0.33, 0.5, 1, 2, 3, 4, 6 hours | 
| Pharmacokinetics (PKs) of TT223, First Dose - Half-Life (t1/2) Associated With the Terminal Rate Constant (λz) in Non-Compartmental Analysis | Half-life is the time it takes for the concentration of drug in plasma to decline by 50%. | 0 (pre-dose), 0.33, 0.5, 1, 2, 3, 4, 6 hours | 
| Pharmacokinetics (PKs) of TT223, First Dose - Area Under the Curve (AUC)(0-infinity) | Area under the curve (AUC)(0-infinity) = area under concentration versus time from zero to infinity. Area under the curve (AUC) is a measure of the total exposure to a drug. | 0 (pre-dose), 0.33, 0.5, 1, 2, 3, 4, 6 hours | 
| Pharmacokinetics (PKs) of TT223, First Dose - Apparent Total Body Clearance of Drug Calculated After Extra-Vascular Administration (CL/F) | Apparent total body clearance of drug calculated after extra-Vascular administration (CL/F) is the apparent volume of the body fluid cleared of the drug per unit of time, adjusted for how much drug goes into the body fluid. | 0 (pre-dose), 0.33, 0.5, 1, 2, 3, 4, 6 hours | 
| Pharmacokinetics (PKs) of TT223, First Dose - Apparent Volume of Distribution During the Terminal Phase After Extra-Vascular Administration (Vz/F), Apparent Volume of Distribution at Steady-State After Extra-Vascular Administration (Vss/F) | volume of distribution during the terminal phase after extra-vascular administration (Vz/F): Apparent volume that contains drug after absorption is complete and drug is no longer being given. Apparent volume of distribution at steady-State after extra-vascular administration (Vss/F): Apparent volume that contains drug when drug is being given continuously. | 0 (pre-dose), 0.33, 0.5, 1, 2, 3, 4, 6 hours | 
| Pharmacokinetics (PKs) of TT223, 3-Week Time Point - Maximum Observed Drug Concentration (Cmax) | Maximum observed drug concentration (Cmax) is the maximum observed concentration of drug. | 0 (pre-dose), 0.33, 0.5, 1, 2, 3, 4, 6 hours | 
| Pharmacokinetics (PKs) of TT223, 3-Week Time Point - Time of Maximum Observed Drug Concentration (Tmax) | Time of maximum observed drug concentration (Tmax) is the time at which the maximum observed concentration (Cmax) occurs. | 0 (pre-dose), 0.33, 0.5, 1, 2, 3, 4, 6 hours | 
| Pharmacokinetics (PKs) of TT223, 3-Week Time Point - Half Life (t1/2) | Half-life (t1/2) is the time it takes for the concentration of drug in plasma to decline by 50%. | 0 (pre-dose), 0.33, 0.5, 1, 2, 3, 4, 6 hours | 
| Pharmacokinetics (PKs) of TT223, 3-Week Time Point - Area Under Concentration Versus Time From Zero to Infinity (AUC[0-infinity]) | Area under concentration versus time curve from zero to infinity (AUC[0-infinity]). Area under the curve (AUC) is a measure of the total exposure to a drug. | 0 (pre-dose), 0.33, 0.5, 1, 2, 3, 4, 6 hours | 
| Pharmacokinetics (PKs) of TT223, 3-Week Time Point - Apparent Total Body Clearance of Drug Calculated After Extra-Vascular Administration (CL/F) | Apparent total body clearance of drug calculated after extra-vascular administration (CL/F) is the apparent volume of the body fluid cleared of the drug per unit of time, adjusted for how much drug goes into the body fluid. | 0 (pre-dose), 0.33, 0.5, 1, 2, 3, 4, 6 hours | 
| Pharmacokinetics (PKs) of TT223, 3-Week Time Point - Apparent Volume of Distribution During the Terminal Phase After Extra-Vascular Administration (Vz/F), Apparent Volume of Distribution at Steady-State After Extra-Vascular Administration (Vss/F) | Apparent volume of distribution during the terminal phase after extra-vascular administration (Vz/F) is the apparent volume that contains drug after absorption is complete and drug is no longer being given. Apparent volume of distribution at steady-state after extra-vascular administration (Vss/F) is the apparent volume that contains drug when drug is being given continuously. | 0 (pre-dose), 0.33, 0.5, 1, 2, 3, 4, 6 hours | 
| Pharmacokinetics (PKs) of LY2428757, 3-Week Time Point - Maximum Observed Drug Concentration (Cmax) | Maximum observed drug concentration (Cmax) is the maximum observed concentration of drug. LY2428757 concentrations were collected at only a single timepoint; therefore, pharmacokinetic (PK) parameters could not be modeled from the data. Analysis was not done due to insufficient time points being collected. | 0 (pre-dose) | 
| Visual Analog Scale (VAS) for Nausea | The Visual Analog Scale (VAS) is a continuous measure for degree of nausea and/or gastrointestinal discomfort. Each of these scales is 100 millimeters (mm) in length with 0 meaning no nausea at all and 100 meaning extreme nausea. Participants record self-assessment of how much nausea they have had, from 0 to 100, during the time interval indicated. | 4 weeks, 6 months | 
| Change From Baseline in Waist Circumference at 6-Month Endpoint | Change from baseline means the absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 6 months | 
| 7-point Profile, Self-Monitored Blood Glucose (SMBG) Values | The 7-point average is the average of the mean value of all time points for the visit. Time points included pre-morning meal, 2 hours after morning meal, pre-midday meal, 2 hours after midday meal, pre-evening meal, 2 hours after evening meal, and bedtime. | Baseline (Week -1), 4 weeks, 6 months | 
| Change From Baseline in 7-Point Profile, Self-Monitored Blood Glucose (SMBG) at 4-Week and 6-Month Endpoints | 7-point average=average of mean value of all time points for visit (premorning meal, 2-hours postmorning meal, premidday meal, 2-hours postmidday meal, preevening meal, 2-hours postevening meal, bedtime). Values represent mean of values collected same time on 3 separate days within week prior to visit. Values from repeated measures included fixed categorical effects: treatment, baseline therapy strata, visit, treatment-by-visit, continuous fixed covariate baseline <7-point average glucose value or time point presented. Change from baseline=absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 4 weeks, 6 months | 
| Change From Baseline in Lipase at Week 0, Week 4, and 6-Month Endpoints | Values obtained from repeated measures analysis, which included the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline serum lipase. Change from baseline means the absolute change from baseline (endpoint-baseline). | Baseline (Week -1), Week 0, 4 weeks, 6 months | 
| Change From Baseline in Amylase at 6-Month Endpoint | Change from baseline means the absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 6 months | 
| Percentage of Participants With 2-Fold Elevation of Lipase and/or Amylase at Any Timepoint | Values obtained from repeated measures analysis, which included the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline amylase. | Baseline (Week -1) through 6 months | 
| Percentage of Participants With Hypoglycemia | Calculation of frequency of low glucose for time period. Hypoglycemia≥1 events: severe<50mg/dL, unable to treat self/recover after treatment; documented symptomatic≤70mg/dL, adrenergic/neuroglycopenic symptoms; asymptomatic≤70mg/dL no symptoms; probable symptomatic glucose missing, adrenergic/neuroglycopenic symptoms; relative>70mg/dL, adrenergic/neuroglycopenic symptoms, nocturnal≤70mg/dL, adrenergic/neuroglycopenic symptoms between bedtime/waking. Because number participants who experienced hypoglycemia was low for every arm (1-3/arm) did not model percentage participants with hypoglycemia. | Baseline (Week -1) through 6 months | 
| Number of Participants With Hypoglycemia | The number of participants for whom low blood glucose was reported. Hypoglycemia ≥1 events including: severe hypoglycemia(glucose <50mg/dL, unable to treat self or recover after treatment); documented symptomatic (glucose ≤70mg/dL, adrenergic or neuroglycopenic symptoms); asymptomatic (glucose ≤70mg/dL no symptoms); probable symptomatic (glucose missing, adrenergic or neuroglycopenic symptoms); relative (glucose >70mg/dL, adrenergic or neuroglycopenic symptoms), nocturnal (glucose ≤70mg/dL, adrenergic or neuroglycopenic symptoms between bedtime/waking). | Baseline (Week -1) through 6 months | 
| Number of Participants With Adjudicated and Confirmed Deaths and Non-Fatal Cardiovascular (CV) Events at Any Timepoint | The protocol specified that deaths and nonfatal cardiovascular (CV) adverse events (AEs) be adjudicated by independent physician(s) with cardiology or neurology experience. The CV AEs to be adjudicated were protocol-defined as myocardial infarction (MI), hospitalization for unstable angina or for heart failure, coronary interventions (coronary artery bypass graft or percutaneous coronary intervention [PCI]) and cerebrovascular events including cerebrovascular accident (stroke) and transient ischemic attack (TIA). 3 CV events were adjudicated by an external independent adjudication committee. | Baseline (Week -1) through 6 months | 
| Change From Baseline in Fasting Insulin at 4-Week and 6-Month Endpoints | Values obtained from repeated measures analysis, which included the fixed categorical effects of treatment, baseline therapy strata (metformin versus diet and exercise [D&E]), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline Fasting Insulin. Fasting insulin is the Mixed-Meal Tolerance Test (MMTT) insulin assessment at timepoint 0, where available, otherwise it is the assessment taken from the fasting laboratory measurements obtained during the clinic visit. Change from baseline means the absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 4 weeks, 6 months | 
| Change From Baseline in Homeostatic Model Assessment (HOMA) at 3-Week and 6-Month Endpoints | Values from repeated measures include fixed categorical effects of treatment, baseline therapy strata, visit, treatment-by-visit, continuous fixed covariate of baseline HOMA derived beta-cell function (HOMA-B). HOMA=index of function of cells that make insulin. Indices derived from fasting glucose and insulin concentrations. HOMA is measurement reflecting fasting plasma glucose and insulin. Has no defined minimum/maximum value. HOMA-B values generated from table reflecting values derived from Oxford HOMA2 model calculator. Change from baseline=absolute change from baseline (endpoint-baseline). | Baseline (Week -1), 3 weeks, 6 months |