Clinical trial NCT00395512: Efficacy of Alogliptin With Pioglitazone (Actos®) in Subjects With Type 2 Diabetes Mellitus
Official title: A Multicenter, Double-Blind Study to Determine the Efficacy and Safety of SYR-322 Plus Pioglitazone HCl (Actos®), SYR-322 Alone or Pioglitazone HCl Alone in Subjects With Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus
Keywords: Glucose Metabolism Disorder
Dysmetabolic Syndrome
Type II Diabetes
Diabetes Mellitus, Lipoatrophic
Dyslipidemia
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2006-11-03
Enrollment: 655
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 this study is to evaluate the combination of alogliptin, once daily (QD), and pioglitazone in patients with type 2 diabetes mellitus who are inadequately controlled with diet and exercise alone.

Detailed description: There are approximately 19 million people in the United States who have been diagnosed with diabetes mellitus, of which 90% to 95% is type 2. The prevalence of type 2 diabetes varies among racial and ethnic populations and has been shown to correlate with age, obesity, family history, history of gestational diabetes, and physical inactivity. Over the next decade, a marked increase in the number of adults with diabetes mellitus is expected, placing an ever-increasing burden on families and the health care system.

Current pharmacologic interventions for type 2 diabetes mellitus include a diverse range of antidiabetic medications with different mechanisms of action including insulin and insulin analogues, sulfonylureas, metformin, meglitinides, thiazolidinediones, inhibitors of alpha- glucosidase, analogs of glucagon-like peptide-1, and synthetic analogues of human amylin. Despite the variety of medications, many have clinically important or potentially life-threatening side effects, restricted use in many subpopulations, concerns with long-term tolerability, and challenges related to compliance due to side effects and route of administration. All of these reasons contribute to the difficulties patients have reaching the target glycosylated hemoglobin level less than 7%.

SYR-322 (alogliptin) is a selective, orally available inhibitor of the dipeptidyl peptidase-4 enzyme. Dipeptidyl peptidase-4 enzyme is thought to be primarily responsible for the in vivo degradation of 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 beta cells to stimulate glucose-dependent insulin secretion as well as regulating beta cell proliferation and cytoprotection. Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits gastric emptying, glucagon secretion, and food intake. Glucose-dependent insulinotropic peptide has been shown to enhance insulin secretion by direct interaction with a glucose-dependent insulinotropic peptide -specific receptor on islet beta cells. The glucose-lowering actions of glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, are preserved in patients with type 2 diabetes mellitus.

Pioglitazone (ACTOS®) is a thiazolidinedione developed by Takeda Chemical Industries, Ltd. (Osaka, Japan) that is approved for the treatment of type 2 diabetes mellitus. Pioglitazone is a selective peroxisome proliferator-activated receptor-gamma agonist that decreases insulin resistance in the periphery and liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output.

As the rate of newly diagnosed cases of type 2 diabetes mellitus continues to grow, so does the need for products that will provide better glycemic control and improved safety and tolerability. Alogliptin and pioglitazone have complementary actions. Alogliptin inhibits the degradation of glucagon-like peptide-1 by inhibiting the enzyme dipeptidyl peptidase IV, thus augmenting glucose-dependent insulin secretion while pioglitazone is a peripheral and hepatic insulin sensitizer. Given the complementary mechanisms of action of alogliptin (stimulates insulin secretion) and pioglitazone (enhances insulin sensitivity), the addition of combination therapy in treatment naïve type 2 diabetes patients may potentially allow the patients to reach and maintain their glycosylated hemoglobin goal more effectively.

The aim of this study is to evaluate the effectiveness of the combination of alogliptin with pioglitazone in patients who are inadequately controlled on diet and exercise alone. Study participation is anticipated to be approximately 8.5 months.

Eligibility criteria: Inclusion Criteria

* Historical diagnosis of type 2 diabetes.
* Failed treatment with diet and exercise for at least 2 months prior to Screening.
* Is experiencing inadequate glycemic control as defined as glycosylated hemoglobin concentration between 7.5-11%, inclusive.
* Has received any antidiabetic therapy for less than 7 days within 3 months prior to Screening.
* Has a body mass index greater than or equal to 23 kg/m2 and less than or equal to45 kg/m2.
* Fasting C-peptide greater than or equal to 0.8 ng per mL.
* Regular use of other, non-excluded medications is allowed if participant is on a stable dose for at least 4 weeks prior to Screening.
* 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.
* Must be willing and able to monitor their blood concentrations with a home glucose monitor.

Exclusion Criteria

* Systolic blood pressure greater than or equal to 160 mmHg and diastolic blood pressure greater than or equal to 100 mmHg.
* Hemoglobin less than or equal to 12 g per dL for males and less than or equal to 10 g per dL for females.
* Alanine aminotransferase greater than or equal to 2.5times the upper limit of normal.
* Serum creatinine greater than 2.0 mg per dL.
* Thyroid stimulating hormone level greater than the upper limit of normal range.
* Major illness or debility that in the investigator's opinion prohibits the subject from completing the study.
* Urine albumin to creatinine ratio of greater than 1000 ug per mg at Screening. If elevated, the subject may be rescreened within 1 week.
* 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 laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening.
* History of gastroparesis.
* Has New York Heart Association Class I to IV heart failure regardless of therapy.
* History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within 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 participant's ability to participate in the study.
* History of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors.
* Any alteration in angiotensin-II receptor inhibitors within 2 months prior to Randomization, if applicable.
* History of alcohol (defined as regular or daily consumption of more than 4 alcoholic drinks per day) or substance abuse (defined as illicit drug use) within 2 years prior to Screening.
* Received any investigational drug within 30 days prior to Screening or a history of receipt of an investigational antidiabetic drug within 3 months prior to Screening.
* Previously participated in an investigational study of SYR-322.
* Glycosylated hemoglobin concentration between 7.5-11%, inclusive, and a fasting plasma glucose less than 310 mg per dL.
* At least 75% compliant with the single-blind placebo regimen during the run-in/stabilization period.

Primary outcomes:
measure: Change From Baseline to Week 26 in Glycosylated Hemoglobin (HbA1c)
timeFrame: Baseline and Week 26
Secondary outcomes:
measure: Change From Baseline in HbA1c Over Time
timeFrame: Baseline and Weeks 4, 8, 12, 16 and 20.
measure: Change From Baseline in Fasting Plasma Glucose Over Time
timeFrame: Baseline and Weeks 1, 2, 4, 8, 12, 16, 20 and 26.
measure: Percentage of Participants With Marked Hyperglycemia
timeFrame: Weeks 1, 2, 4, 8, 12, 16, 20 and 26.
measure: Percentage of Participants Meeting Rescue Criteria
timeFrame: Weeks 4, 8, 12, 16, 20 and 26.
measure: Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5%
timeFrame: Week 26
measure: Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0%
timeFrame: Week 26
measure: Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.5%
timeFrame: Week 26
measure: Percentage of Participants With a Decrease in Glycosylated Hemoglobin Greater Than or Equal to 0.5%
timeFrame: Baseline and Week 26
measure: Percentage of Participants With a Decrease in Glycosylated Hemoglobin Greater Than or Equal to 1.0%
timeFrame: Baseline and Week 26
measure: Percentage of Participants With a Decrease in Glycosylated Hemoglobin Greater Than or Equal to 1.5%.
timeFrame: Baseline and Week 26
measure: Percentage of Participants With a Decrease in Glycosylated Hemoglobin Greater Than or Equal to 2.0%
timeFrame: Baseline and Week 26
measure: Change From Baseline in Fasting Proinsulin
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20 and 26.
measure: Change From Baseline in Insulin
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20 and 26.
measure: Change From Baseline in Proinsulin/Insulin Ratio
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20 and 26.
measure: Change From Baseline in C-peptide Levels
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20 and 26.
measure: Change From Baseline in Calculated Homeostatic Model Assessment Insulin Resistance
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Homeostatic Model Assessment Beta Cell Function
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Body Weight
timeFrame: Baseline and Weeks 8, 12, 20 and 26.
measure: Change From Baseline in Total Cholesterol Level
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20 and 26.
measure: Change From Baseline in Low-Density Lipoprotein Cholesterol
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20 and 26.
measure: Change From Baseline in High-Density Lipoprotein Cholesterol
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20 and 26.
measure: Change From Baseline in Triglyceride Levels
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20 and 26.
measure: Change From Baseline in Free Fatty Acids
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Plasminogen Activator Inhibitor-1
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in High-sensitivity C-Reactive Protein
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Adiponectin
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Apolipoprotein A1
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Apolipoprotein A2
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Apolipoprotein B
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Apolipoprotein C-III
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in VLDL / Chylomicron Triglycerides
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in VLDL Particles
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Mean VLDL Particle Size
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Low Density Lipoprotein (LDL) Particles
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Mean LDL Particle Size
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in High Density Lipoprotein (HDL) Particles
timeFrame: Baseline and Weeks 12 and 26.
measure: Change From Baseline in Mean HDL Particle Size
timeFrame: Baseline and Weeks 12 and 26.
Other outcomes:
Locations:
city: Columbiana
country: United States
state: Alabama
city: Hueytown
country: United States
state: Alabama
city: Huntsville
country: United States
state: Alabama
city: Northport
country: United States
state: Alabama
city: Tucson
country: United States
state: Arizona
city: Jonesboro
country: United States
state: Arkansas
city: Little Rock
country: United States
state: Arkansas
city: Searcy
country: United States
state: Arkansas
city: Foothill Ranch
country: United States
state: California
city: Irvine
country: United States
state: California
city: Northridge
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Mateo
country: United States
state: California
city: Santa Monica
country: United States
state: California
city: Jacksonville
country: United States
state: Florida
city: Melbourne
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Port Charlotte
country: United States
state: Florida
city: Sebastian
country: United States
state: Florida
city: South Miami
country: United States
state: Florida
city: Winter Haven
country: United States
state: Florida
city: Augusta
country: United States
state: Georgia
city: Barnesville
country: United States
state: Georgia
city: Columbus
country: United States
state: Georgia
city: Savannah
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Libertyville
country: United States
state: Illinois
city: South Bend
country: United States
state: Indiana
city: Bossier City
country: United States
state: Louisiana
city: Elkton
country: United States
state: Maryland
city: Prince Frederick
country: United States
state: Maryland
city: Towson
country: United States
state: Maryland
city: North Dartmouth
country: United States
state: Massachusetts
city: Bay City
country: United States
state: Michigan
city: Benzonia
country: United States
state: Michigan
city: Portage
country: United States
state: Michigan
city: St Clair Shores
country: United States
state: Michigan
city: Picayune
country: United States
state: Mississippi
city: St Louis
country: United States
state: Missouri
city: Billings
country: United States
state: Montana
city: Las Vegas
country: United States
state: Nevada
city: Elizabeth
country: United States
state: New Jersey
city: Hamilton
country: United States
state: New Jersey
city: Cicero
country: United States
state: New York
city: Charlotte
country: United States
state: North Carolina
city: Mooresville
country: United States
state: North Carolina
city: Northeast
country: United States
state: North Dakota
city: Franklin
country: United States
state: Ohio
city: Ashland
country: United States
state: Oregon
city: Altoona
country: United States
state: Pennsylvania
city: Fleetwood
country: United States
state: Pennsylvania
city: Harleysville
country: United States
state: Pennsylvania
city: Havertown
country: United States
state: Pennsylvania
city: Norristown
country: United States
state: Pennsylvania
city: Northern Cambria
country: United States
state: Pennsylvania
city: Penndel
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Charleston
country: United States
state: South Carolina
city: Florence
country: United States
state: South Carolina
city: Orangeburg
country: United States
state: South Carolina
city: Taylors
country: United States
state: South Carolina
city: Williamston
country: United States
state: South Carolina
city: Morristown
country: United States
state: Tennessee
city: Arlington
country: United States
state: Texas
city: Colleyville
country: United States
state: Texas
city: Conroe
country: United States
state: Texas
city: Corpus Christi
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Euless
country: United States
state: Texas
city: Fort Worth
country: United States
state: Texas
city: Garland
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Katy
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Seguin
country: United States
state: Texas
city: Sugarland
country: United States
state: Texas
city: Tomball
country: United States
state: Texas
city: Ogden
country: United States
state: Utah
city: Arlington
country: United States
state: Virginia
city: Norfolk
country: United States
state: Virginia
city: Richmond
country: United States
state: Virginia
city: Lewisburg
country: United States
state: West Virginia
city: Milwaukee
country: United States
state: Wisconsin
city: Cap. Fed.
country: Argentina
state: Buenos Aires
city: Chacabuco
country: Argentina
state: Buenos Aires
city: La Plata
country: Argentina
state: Buenos Aires
city: Mar del Plata
country: Argentina
state: Buenos Aires
city: Morón
country: Argentina
state: Buenos Aires
city: Córdoba
country: Argentina
city: Kingswood
country: Australia
state: New South Wales
city: Fitzroy
country: Australia
state: Victoria
city: Frankston
country: Australia
state: Victoria
city: Fortaleza
country: Brazil
state: CE
city: Goiás
country: Brazil
state: GO
city: Belém
country: Brazil
state: PA
city: Curitiba
country: Brazil
state: PR
city: Maringá
country: Brazil
state: RP
city: Marília
country: Brazil
state: SP
city: Mogi das Cruzes
country: Brazil
state: SP
city: Pleven
country: Bulgaria
city: Santiago
country: Chile
city: Slavonski Brod
country: Croatia
city: Pärnu
country: Estonia
city: Guatemala
country: Guatemala
city: Budapest
country: Hungary
city: Eger
country: Hungary
city: Gyula
country: Hungary
city: Mako
country: Hungary
city: Nyiregyhaza
country: Hungary
city: Pecs
country: Hungary
city: Hyderabad
country: India
state: Andhra Pradesh
city: Bangalore
country: India
state: Karnataka
city: Aurangabad
country: India
state: Maharashtra
city: Mumbai
country: India
state: Maharashtra
city: Nagpur
country: India
state: Maharashtra
city: Chennai
country: India
state: Tamil Nadu
city: Hadera
country: Israel
city: Haifa
country: Israel
city: Holon
country: Israel
city: Jaffa Tel Aviv
country: Israel
city: Jerusalem
country: Israel
city: Nahariya
country: Israel
city: Riga
country: Latvia
city: Kaunas
country: Lithuania
city: Kedainiai
country: Lithuania
city: Aguascalientes
country: Mexico
city: Mexico City
country: Mexico
city: Monterrey
country: Mexico
city: Christchurch
country: New Zealand
city: Hamilton
country: New Zealand
city: Bialystok
country: Poland
city: Bytom
country: Poland
city: Gdansk
country: Poland
city: Gniewkowo
country: Poland
city: Kamieniec Zabkowicki
country: Poland
city: Krakow
country: Poland
city: Leczyca
country: Poland
city: Brasov
country: Romania
city: Bucharest
country: Romania
city: Galati
country: Romania
city: Ekaterinburg
country: Russian Federation
city: Kazan
country: Russian Federation
city: Moscow
country: Russian Federation
city: Belgrade
country: Serbia
city: Kragujevac
country: Serbia
city: Nis
country: Serbia
city: Interna klinika II
country: Slovakia
state: Nitra
city: Banska Bysterica
country: Slovakia
city: Lucenec
country: Slovakia
city: Riverside
country: Slovakia
city: Sahy
country: Slovakia
city: Port Elizabeth
country: South Africa
state: Eastern Cape
city: Johannesburg
country: South Africa
state: Gauteng
city: Durban
country: South Africa
state: Kwa-Zulu Natal
city: East Lynne
country: South Africa
state: Pretoria
city: Bellville
country: South Africa
state: Western Province
city: Cape Town
country: South Africa
state: Western Province
city: Dnipropetrovsk
country: Ukraine
city: Kharkiv
country: Ukraine
city: Lviv
country: Ukraine
city: Odesa
country: Ukraine
Study officials:
affiliation: Takeda
name: VP, Biological Sciences
role: STUDY_DIRECTOR
References:
citation: Rosenstock J, Inzucchi SE, Seufert J, Fleck PR, Wilson CA, Mekki Q. Initial combination therapy with alogliptin and pioglitazone in drug-naive patients with type 2 diabetes. Diabetes Care. 2010 Nov;33(11):2406-8. doi: 10.2337/dc10-0159. Epub 2010 Aug 19.