Efficacy of Alogliptin and Pioglitazone in Subjects With Type 2 Diabetes Mellitus
Information source: Takeda
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Diabetes Mellitus
Intervention: Alogliptin (Drug); Pioglitazone (Drug); Metformin (Drug); Placebo (Drug)
Phase: Phase 3
Status: Completed
Sponsored by: Takeda Official(s) and/or principal investigator(s): VP Biological Sciences, Study Director, Affiliation: Takeda
Summary
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.
Clinical Details
Official title: A Multicenter, Randomized, Double-Blind Study to Determine the Efficacy and Safety of the Addition of SYR-322 25 mg Versus Dose Titration From 30 mg to 45 mg of Pioglitazone HCl (ACTOS®) in Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Control on a Combination of Metformin and 30 mg of Pioglitazone HCl Therapy
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Change From Baseline in Glycosylated Hemoglobin (HbA1c)
Secondary outcome: Change From Baseline in HbA1c Over TimePercentage of Participants With Glycosylated Hemoglobin ≤ 6.5% Percentage of Participants With Glycosylated Hemoglobin ≤ 7.0% Percentage of Participants With Glycosylated Hemoglobin ≤ 7.5% Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 0.5% Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.0% Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.5% Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 2.0% Change From Baseline in Fasting Plasma Glucose Percentage of Participants With Marked Hyperglycemia Percentage of Participants Meeting Hyperglycemic Rescue Criteria Change From Baseline in Fasting Proinsulin Change From Baseline in Fasting Insulin Change From Baseline in Proinsulin/Insulin Ratio Change From Baseline in C-peptide Change From Baseline in Calculated HOMA Insulin Resistance Change From Baseline in Calculated HOMA Beta-cell Function Change From Baseline in Body Weight Change From Baseline in Total Cholesterol Change From Baseline in High-Density Lipoprotein Cholesterol Change From Baseline in Low-Density Lipoprotein Cholesterol Change From Baseline in Triglycerides Change From Baseline in Free Fatty Acids Change From Baseline in Apolipoprotein A1 Change From Baseline in Apolipoprotein A2 Change From Baseline in Apolipoprotein B Change From Baseline in Apolipoprotein C-III Change From Baseline in Plasminogen Activator Inhibitor-1 Change From Baseline in High-sensitivity C-Reactive Protein Change From Baseline in Adiponectin Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles Change From Baseline in VLDL / Chylomicron Triglycerides Change From Baseline in VLDL Particles Change From Baseline in Mean VLDL Particle Size Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles Change From Baseline in Low Density Lipoprotein (LDL) Particles Change From Baseline in Mean LDL Particle Size Change From Baseline in High Density Lipoprotein (HDL) Particles Change From Baseline in Mean HDL Particle Size
Detailed description:
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.
Eligibility
Minimum age: 18 Years.
Maximum age: 80 Years.
Gender(s): Both.
Criteria:
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 and Contacts
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Additional Information
ACTOS® Package Insert FDA Safety Alerts and Recalls
Starting date: January 2007
Last updated: April 1, 2013
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