Efficacy of Alogliptin and Pioglitazone in Subjects With Type 2 Diabetes Mellitus

Takeda803 enrolled

Overview

The purpose of the study is to compare the effect of adding alogliptin, once daily (QD), to the ongoing treatment regimen of pioglitazone HCl and metformin in patients with inadequate glycemic control.

Despite the introduction of new classes of medications for glycemic control, just over half of adults with type 2 diabetes mellitus (T2DM) achieve a glycosylated hemoglobin level less than 7.0%, the American Diabetes Association recommended glycosylated hemoglobin goal. The rising incidence of type 2 diabetes mellitus along with limitations of the currently available treatments suggest the need for new therapies for glycemic control along with the increased requirement for combination therapy in type 2 diabetes mellitus. Thiazolidinediones increase glucose utilization, decrease gluconeogenesis, and increase glucose disposal through an incompletely understood mechanism but one associated with binding of the drug to nuclear receptors known as peroxisome proliferator-activated receptors-gamma. Peroxisome proliferator-activated receptors-gamma are found in tissues important for insulin action, such as adipose tissue, skeletal muscle, and the liver. The greatest concentration of peroxisome proliferator-activated receptors-gamma receptors is in adipose tissue. Thiazolidinediones reduce insulin resistance by enhancing insulin sensitivity in muscle cells, adipose tissue, and hepatic cells (inhibiting hepatic gluconeogenesis) with no direct impact on insulin secretion. Thus, thiazolidinediones improve glycemic control and result in reduced levels of circulating insulin. Pioglitazone HCl (ACTOS®) is a thiazolidinedione developed by Takeda Chemical Industries, Ltd. (Osaka, Japan). Pioglitazone depends on the presence of insulin for its mechanism of action. Worldwide clinical investigation has shown that, as an adjunct to diet and exercise, pioglitazone improves glycemic control when used as monotherapy, and in combination with commonly used antidiabetic medications (ie, sulfonylureas, metformin, or insulin). SYR-322 (alogliptin) is a selective, orally available inhibitor of dipeptidyl peptidase IV currently in development by Takeda Global Research \& Development Center, Inc. as a treatment for type 2 diabetes mellitus. Dipeptidyl peptidase IV is the primary enzyme involved in the in vivo degradation of at least 2 peptide hormones released in response to nutrient ingestion, namely glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. Both peptides exert important effects on islet β-cells to stimulate glucose-dependent insulin secretion and regulate β-cell proliferation and cytoprotection. Glucagon-like peptide-1 also inhibits gastric emptying, glucagon secretion, and food intake. The glucose-lowering actions of glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, are preserved in patients with type 2 diabetes. Given the complementary mechanisms of action of alogliptin (stimulation of insulin secretion) and pioglitazone (enhancement of insulin sensitivity) and the absence of overlapping safety risks, the introduction of this combination therapy in patients with T2DM could potentially show enhanced glycemic control and allow patients to reach and maintain their HbA1c goal more effectively. This study is designed to determine if the addition of alogliptin to a combination of pioglitazone with metformin can be effective at achieving glycemic control without increasing safety risks versus the titration of pioglitazone to 45 mg with metformin in patients with type 2 diabetes mellitus who are experiencing inadequate glycemic control on a current regimen of metformin.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

803

Conditions

Diabetes Mellitus

Interventions

AlogliptinDRUG

Alogliptin tablets.

PioglitazoneDRUG

Pioglitazone tablets.

MetforminDRUG

Metformin HCl tablets (immediate-release, commercially available formulation) ≥1500 mg or maximum tolerated dose.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Has a historical diagnosis of type 2 diabetes mellitus. * Meets one of the following: * Has been inadequately controlled (HbA1c between 7% and 10%, inclusive) on a stable dose of greater than or equal to 1500 mg (or maximum tolerated dose) of metformin and 30 mg of pioglitazone * Has been inadequately controlled (as defined by an HbA1c ≥7.5%) on a combination therapy including metformin and another oral antidiabetic agent (ie, sulfonylureas, rosiglitazone maleate, or pioglitazone 15 mg, etc). Subjects on a combination therapy that included a DPP-4 inhibitor were excluded. * No treatment with antidiabetic agents other than metformin and pioglitazone. * Body mass index greater than or equal to 23 kg/m\^2 and less than or equal to 45 kg/m\^2. * Fasting plasma C-peptide concentration greater than or equal to 0.8 ng/mL. * Systolic blood pressure less than 160 mmHg and diastolic pressure less than 100 mmHg. * Hemoglobin greater than or equal to 12 g/dL for males and greater than or equal to 10 g/dL for females. * Alanine aminotransferase less than or equal to 2.5 x upper limit of normal. * Serum creatinine less than 1.5 mg/dL for males and less than 1.4 mg/dL for females. * Thyroid-stimulating hormone level less than or equal to the upper limit of normal range and the patient is clinically euthyroid. * Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study. * Able and willing to monitor their own blood glucose concentrations with a home glucose monitor. * No major illness or debility that in the investigator's opinion prohibits the patient from completing the study. Exclusion Criteria: * Urine albumin/creatinine ratio of greater than 1000 μg/mg. * History of cancer, other than squamous cell or basal cell carcinoma of the skin, that has not been in full remission for at least 5 years prior to Screening. * History of bladder cancer. * History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening. * Patients with unexplained microscopic hematuria of greater than +1, confirmed by repeat testing. * History of treated diabetic gastroparesis. * History of gastric bypass surgery. * New York Heart Association Class I-IV heart failure regardless of therapy. * History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within the 6 months prior to Screening. * History of any hemoglobinopathy that may affect determination of glycosylated hemoglobin. * History of infection with hepatitis B, hepatitis C, or human immunodeficiency virus. * History of a psychiatric disorder that will affect the patient's ability to participate in the study. * History of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors. * History of alcohol abuse or substance abuse within the 2 years prior to Screening. * Receipt of any investigational drug within the 30 days prior to Screening or a history of receipt of an investigational antidiabetic drug within the 3 months prior to Screening. * Prior treatment in an investigational study of alogliptin. * Hypersensitive to pioglitazone HCl, metformin, alogliptin or other excipients. * The patient has donated more than 400 mL of blood within the 90 days prior to Screening and Pre-Screening, if applicable.

Locations (86)

Outcomes

Primary Outcomes

Change From Baseline in Glycosylated Hemoglobin (HbA1c)

The change from Baseline to Week 26 and Week 52 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound).

Time frame: Baseline and Weeks 26 and 52.

Secondary Outcomes

Change From Baseline in HbA1c Over Time

The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) during the study. Least Squares Means were from an Analysis of Covariance (ANCOVA) model with treatment, study schedule, and geographic region as class variables, and baseline metformin dose and baseline HbA1c as covariates.

Time frame: Baseline and Weeks 4, 8, 12, 16, 20, 34 and 42.

Percentage of Participants With Glycosylated Hemoglobin ≤ 6.5%

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with HbA1c less than or equal to 6.5%.

Time frame: Weeks 26 and 52.

Percentage of Participants With Glycosylated Hemoglobin ≤ 7.0%

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with HbA1c less than or equal to 7%.

Time frame: Weeks 26 and 52.

Percentage of Participants With Glycosylated Hemoglobin ≤ 7.5%

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with HbA1c less than or equal to 7.5%.

Time frame: Weeks 26 and 52.

Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 0.5%

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 0.5%.

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Matching placebo tablets.

Unnamed facility

Birmingham, Alabama, United States

Unnamed facility

Huntsville, Alabama, United States

Unnamed facility

Lake Havasu City, Arizona, United States

Unnamed facility

Little Rock, Arkansas, United States

Unnamed facility

Foothill Ranch, California, United States

Unnamed facility

Los Alamitos, California, United States

Unnamed facility

Los Angeles, California, United States

Unnamed facility

Pismo Beach, California, United States

Unnamed facility

San Diego, California, United States

Unnamed facility

Golden, Colorado, United States

...and 76 more locations

Time frame: Weeks 26 and 52.

Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.0%

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1.0%.

Time frame: Weeks 26 and 52.

Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.5%

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1.5%.

Time frame: Weeks 26 and 52.

Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 2.0%

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 2.0%.

Time frame: Weeks 26 and 52.

Change From Baseline in Fasting Plasma Glucose

The change from Baseline in fasting plasma glucose (FPG) was assessed at Weeks 2, 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least Squares Means were from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline FPG as covariates.

Time frame: Baseline and Weeks 2, 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Percentage of Participants With Marked Hyperglycemia

Marked Hyperglycemia is defined as fasting plasma glucose greater than or equal to 200 mg/dL (11.10 mmol/L).

Time frame: Baseline to Week 52

Percentage of Participants Meeting Hyperglycemic Rescue Criteria

Rescue was defined as meeting 1 of the following criteria, confirmed by a 2nd sample drawn within 7 days after the first sample and analyzed by the central laboratory: 1. After more than 2 weeks of treatment but prior to the Week 4 Visit: A single fasting plasma glucose (FPG) ≥275 mg/dL; 2. From the Week 4 Visit but prior to the Week 8 Visit: A single FPG ≥250 mg/dL; 3. From the Week 8 Visit but prior to the Week 12 Visit: A single FPG ≥225 mg/dL; 4. From the Week 12 Visit through the End-of-Treatment Visit: HbA1c ≥8.5% AND ≤0.5% reduction in HbA1c as compared with the baseline HbA1c.

Time frame: Baseline to Week 52

Change From Baseline in Fasting Proinsulin

Proinsulin is a precursor to insulin, and was measured as an indicator of pancreatic function. The change from Baseline in fasting proinsulin was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least Squares Means were from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline fasting proinsulin as covariates.

Time frame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Change From Baseline in Fasting Insulin

The change from Baseline in fasting insulin was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least Squares Means were from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline fasting insulin as covariates.

Time frame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Change From Baseline in Proinsulin/Insulin Ratio

The ratio of proinsulin to insulin was calculated as proinsulin (pmol/L) / insulin (μIU/mL) at weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52 relative to the Baseline value. Least squares means were from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline fasting proinsulin/insulin ratio as covariates.

Time frame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Change From Baseline in C-peptide

C-peptide is a byproduct created when the hormone insulin is produced and is measured by a blood test. Change from Baseline was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline fasting C-peptide as covariates.

Time frame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Change From Baseline in Calculated HOMA Insulin Resistance

The Homeostasis Model Assessment of insulin resistance (HOMA IR) measures insulin resistance based on fasting glucose and insulin measurements: HOMA IR = fasting plasma insulin (µIU/mL) \* fasting plasma glucose (mmol/L) / 22.5 A higher number indicates a greater degree of insulin resistance. The change from Baseline in HOMA IR was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline HOMA insulin resistance as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Calculated HOMA Beta-cell Function

The Homeostasis Model Assessment (HOMA) estimates steady state beta cell function (%B) as a percentage of a normal reference population. HOMA %B = 20 \* insulin (µIU/mL) / fasting plasma glucose (mmol/L) - 3.5 The change from Baseline in the homeostasis model assessment of beta cell function was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline HOMA beta cell function as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Body Weight

Change from Baseline in body weight was assessed at Weeks 4, 8, 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline body weight as covariates.

Time frame: Baseline and Weeks 4, 8, 12, 26, 42 and 52.

Change From Baseline in Total Cholesterol

Change from Baseline in total cholesterol was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline total cholesterol as covariates.

Time frame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Change From Baseline in High-Density Lipoprotein Cholesterol

Change from Baseline in high-density lipoprotein cholesterol (HDL-C) was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline HDL cholesterol as covariates.

Time frame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Change From Baseline in Low-Density Lipoprotein Cholesterol

Change from Baseline in low-density lipoprotein cholesterol (LDL-C) was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline LDL cholesterol as covariates.

Time frame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Change From Baseline in Triglycerides

Change from Baseline in triglycerides was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline triglycerides as covariates.

Time frame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Change From Baseline in Free Fatty Acids

Change from Baseline in free fatty acids was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline free fatty acids as covariates.

Time frame: Baseline and Weeks 12, 26, 42, and 52.

Change From Baseline in Apolipoprotein A1

Change from Baseline in Apolipoprotein A1 was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein A1 as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Apolipoprotein A2

Change from Baseline in Apolipoprotein A2 was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein A2 as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Apolipoprotein B

Change from Baseline in Apolipoprotein B was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein B as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Apolipoprotein C-III

Change from Baseline in Apolipoprotein C-III was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein C-III as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Plasminogen Activator Inhibitor-1

Change from Baseline in plasminogen activator inhibitor-1 (PAI-1) was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline PAI-1 as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in High-sensitivity C-Reactive Protein

Change from Baseline in high-sensitivity C-Reactive Protein (hsCRP) was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline hsCRP as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Adiponectin

Change from Baseline in adiponectin was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline adiponectin as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides

Nuclear Magnetic Resonance (NMR) lipid fractionation was used to assess the change from Baseline in total triglyceride levels at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline NMR triglycerides as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles

The change from Baseline in levels of total VLDL/chylomicron particles and large VLDL/chylomicron particles was assessed by NMR lipid fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline VLDL/chylomicron particles as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in VLDL / Chylomicron Triglycerides

The change from Baseline in levels of VLDL/chylomicron triglycerides was assessed by NMR lipid fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline VLDL/chylomicron triglycerides as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in VLDL Particles

The change from Baseline in levels of medium VLDL particles and small VLDL particles was assessed by NMR fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline VLDL particles as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Mean VLDL Particle Size

Change from Baseline in mean VLDL particle size was assessed by NMR lipid fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline mean VLDL particle size as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles

The change from Baseline in levels of IDL particles was assessed by NMR lipid fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline IDL particles as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Low Density Lipoprotein (LDL) Particles

The change from Baseline in levels of total, large, medium-small, total small and very small LDL particles was assessed by NMR fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline LDL particles as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Mean LDL Particle Size

Change from Baseline in mean LDL particle size was assessed by NMR lipid fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline mean LDL particle size as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in High Density Lipoprotein (HDL) Particles

The change from Baseline in levels of total, large, medium and small HDL particles was assessed by NMR fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline HDL particles as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.

Change From Baseline in Mean HDL Particle Size

Change from Baseline in mean HDL particle size was assessed by NMR lipid fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline mean HDL particle size as covariates.

Time frame: Baseline and Weeks 12, 26, 42 and 52.