Clinical trial NCT00432276: Efficacy of Alogliptin and Pioglitazone in Subjects With Type 2 Diabetes Mellitus
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus
Keywords: Glucose Metabolism Disorder
Dysmetabolic Syndrome
Type II Diabetes
Diabetes Mellitus, Lipoatrophic
Dyslipidemia
Hyperglycemia
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2007-02-07
Enrollment: 803
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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 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.

Primary outcomes:
measure: Change From Baseline in Glycosylated Hemoglobin (HbA1c)
timeFrame: Baseline and Weeks 26 and 52.
Secondary outcomes:
measure: Change From Baseline in HbA1c Over Time
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, 34 and 42.
measure: Percentage of Participants With Glycosylated Hemoglobin ≤ 6.5%
timeFrame: Weeks 26 and 52.
measure: Percentage of Participants With Glycosylated Hemoglobin ≤ 7.0%
timeFrame: Weeks 26 and 52.
measure: Percentage of Participants With Glycosylated Hemoglobin ≤ 7.5%
timeFrame: Weeks 26 and 52.
measure: Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 0.5%
timeFrame: Weeks 26 and 52.
measure: Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.0%
timeFrame: Weeks 26 and 52.
measure: Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.5%
timeFrame: Weeks 26 and 52.
measure: Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 2.0%
timeFrame: Weeks 26 and 52.
measure: Change From Baseline in Fasting Plasma Glucose
timeFrame: Baseline and Weeks 2, 4, 8, 12, 16, 20, 26, 34, 42 and 52.
measure: Percentage of Participants With Marked Hyperglycemia
timeFrame: Baseline to Week 52
measure: Percentage of Participants Meeting Hyperglycemic Rescue Criteria
timeFrame: Baseline to Week 52
measure: Change From Baseline in Fasting Proinsulin
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.
measure: Change From Baseline in Fasting Insulin
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.
measure: Change From Baseline in Proinsulin/Insulin Ratio
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.
measure: Change From Baseline in C-peptide
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.
measure: Change From Baseline in Calculated HOMA Insulin Resistance
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Calculated HOMA Beta-cell Function
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Body Weight
timeFrame: Baseline and Weeks 4, 8, 12, 26, 42 and 52.
measure: Change From Baseline in Total Cholesterol
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.
measure: Change From Baseline in High-Density Lipoprotein Cholesterol
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.
measure: Change From Baseline in Low-Density Lipoprotein Cholesterol
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.
measure: Change From Baseline in Triglycerides
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.
measure: Change From Baseline in Free Fatty Acids
timeFrame: Baseline and Weeks 12, 26, 42, and 52.
measure: Change From Baseline in Apolipoprotein A1
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Apolipoprotein A2
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Apolipoprotein B
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Apolipoprotein C-III
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Plasminogen Activator Inhibitor-1
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in High-sensitivity C-Reactive Protein
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Adiponectin
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in VLDL / Chylomicron Triglycerides
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in VLDL Particles
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Mean VLDL Particle Size
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Low Density Lipoprotein (LDL) Particles
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Mean LDL Particle Size
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in High Density Lipoprotein (HDL) Particles
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
measure: Change From Baseline in Mean HDL Particle Size
timeFrame: Baseline and Weeks 12, 26, 42 and 52.
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Huntsville
country: United States
state: Alabama
city: Lake Havasu City
country: United States
state: Arizona
city: Little Rock
country: United States
state: Arkansas
city: Foothill Ranch
country: United States
state: California
city: Los Alamitos
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Pismo Beach
country: United States
state: California
city: San Diego
country: United States
state: California
city: Golden
country: United States
state: Colorado
city: Clearwater
country: United States
state: Florida
city: Hialeah
country: United States
state: Florida
city: Lakeland
country: United States
state: Florida
city: Marianna
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: North Miami Beach
country: United States
state: Florida
city: Pembroke Pines
country: United States
state: Florida
city: Sebastian
country: United States
state: Florida
city: South Miami
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Winter Park
country: United States
state: Florida
city: Blue Ridge
country: United States
state: Georgia
city: Conyers
country: United States
state: Georgia
city: Decatur
country: United States
state: Georgia
city: Duluth
country: United States
state: Georgia
city: Dunwoody
country: United States
state: Georgia
city: Warner Robins
country: United States
state: Georgia
city: Boise
country: United States
state: Idaho
city: Coeur D'Alene
country: United States
state: Idaho
city: Burr Ridge
country: United States
state: Illinois
city: Chicago
country: United States
state: Illinois
city: Melrose Park
country: United States
state: Illinois
city: Naperville
country: United States
state: Illinois
city: O'Fallon
country: United States
state: Illinois
city: Bloomington
country: United States
state: Indiana
city: Mishawaka
country: United States
state: Indiana
city: Overland Park
country: United States
state: Kansas
city: Marrero
country: United States
state: Louisiana
city: Elkton
country: United States
state: Maryland
city: Rockville
country: United States
state: Maryland
city: Towson
country: United States
state: Maryland
city: Marlborough
country: United States
state: Massachusetts
city: Bay City
country: United States
state: Michigan
city: St. Clair Shores
country: United States
state: Michigan
city: McCook
country: United States
state: Nebraska
city: Las Vegas
country: United States
state: Nevada
city: Blackwood
country: United States
state: New Jersey
city: Trenton
country: United States
state: New Jersey
city: West Caldwell
country: United States
state: New Jersey
city: Asheboro
country: United States
state: North Carolina
city: Charlotte
country: United States
state: North Carolina
city: Mooresville
country: United States
state: North Carolina
city: Shelby
country: United States
state: North Carolina
city: Sparta
country: United States
state: North Carolina
city: Bismarck
country: United States
state: North Dakota
city: Orrville
country: United States
state: Ohio
city: Norman
country: United States
state: Oklahoma
city: Ashland
country: United States
state: Oregon
city: Aliquippa
country: United States
state: Pennsylvania
city: Altoona
country: United States
state: Pennsylvania
city: Dawningtown
country: United States
state: Pennsylvania
city: Fleetwood
country: United States
state: Pennsylvania
city: Kingston
country: United States
state: Pennsylvania
city: Norristown
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Tipton
country: United States
state: Pennsylvania
city: Florence
country: United States
state: South Carolina
city: Taylors
country: United States
state: South Carolina
city: Williamston
country: United States
state: South Carolina
city: Watertown
country: United States
state: South Dakota
city: Kingsport
country: United States
state: Tennessee
city: Milan
country: United States
state: Tennessee
city: Nashville
country: United States
state: Tennessee
city: Arlington
country: United States
state: Texas
city: Austin
country: United States
state: Texas
city: Colleyville
country: United States
state: Texas
city: El Paso
country: United States
state: Texas
city: Garland
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Hurst
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Seguin
country: United States
state: Texas
city: Hampton
country: United States
state: Virginia
city: Norfolk
country: United States
state: Virginia
city: Richmond
country: United States
state: Virginia
city: Virginia Beach
country: United States
state: Virginia
Study officials:
affiliation: Takeda
name: VP Biological Sciences
role: STUDY_DIRECTOR
References:
citation: Bosi E, Ellis GC, Wilson CA, Fleck PR. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study. Diabetes Obes Metab. 2011 Dec;13(12):1088-96. doi: 10.1111/j.1463-1326.2011.01463.x.