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

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00432276
• Collaborator: (none)
• Enrollment: 803
• Locations: 86
• Arms: 2
• Duration (Months): 29
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: Alogliptin; Drug: Pioglitazone; Drug: Metformin; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 803 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: Jan 1, 2007
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: Jun 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alogliptin 25 mg + Pioglitazone 30 mg add-on to Metformin Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322 ; Drug: Pioglitazone; Pioglitazone tablets.; Other Names: ACTOS® ; Drug: Metformin; Metformin HCl tablets (immediate-release, commercially available formulation) ≥1500 mg or maximum tolerated dose.; Drug: Placebo; Matching placebo tablets.
Active Comparator: Pioglitazone 45 mg add-on to Metformin Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Drug: Pioglitazone; Pioglitazone tablets.; Other Names: ACTOS® ; Drug: Metformin; Metformin HCl tablets (immediate-release, commercially available formulation) ≥1500 mg or maximum tolerated dose.; Drug: Placebo; Matching placebo tablets.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Glycosylated Hemoglobin (HbA1c) [Baseline and Weeks 26 and 52.]

   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).

Secondary Outcome Measures

1. Change From Baseline in HbA1c Over Time [Baseline and Weeks 4, 8, 12, 16, 20, 34 and 42.]

   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.

2. Percentage of Participants With Glycosylated Hemoglobin ≤ 6.5% [Weeks 26 and 52.]

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

3. Percentage of Participants With Glycosylated Hemoglobin ≤ 7.0% [Weeks 26 and 52.]

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

4. Percentage of Participants With Glycosylated Hemoglobin ≤ 7.5% [Weeks 26 and 52.]

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

5. Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 0.5% [Weeks 26 and 52.]

   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%.

6. Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.0% [Weeks 26 and 52.]

   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%.

7. Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.5% [Weeks 26 and 52.]

   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%.

8. Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 2.0% [Weeks 26 and 52.]

   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%.

9. Change From Baseline in Fasting Plasma Glucose [Baseline and Weeks 2, 4, 8, 12, 16, 20, 26, 34, 42 and 52.]

   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.

10. Percentage of Participants With Marked Hyperglycemia [Baseline to Week 52]

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

11. Percentage of Participants Meeting Hyperglycemic Rescue Criteria [Baseline to Week 52]

    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: After more than 2 weeks of treatment but prior to the Week 4 Visit: A single fasting plasma glucose (FPG) ≥275 mg/dL; From the Week 4 Visit but prior to the Week 8 Visit: A single FPG ≥250 mg/dL; From the Week 8 Visit but prior to the Week 12 Visit: A single FPG ≥225 mg/dL; 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.

12. Change From Baseline in Fasting Proinsulin [Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.]

    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.

13. Change From Baseline in Fasting Insulin [Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.]

    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.

14. Change From Baseline in Proinsulin/Insulin Ratio [Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.]

    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.

15. Change From Baseline in C-peptide [Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.]

    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.

16. Change From Baseline in Calculated HOMA Insulin Resistance [Baseline and Weeks 12, 26, 42 and 52.]

    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.

17. Change From Baseline in Calculated HOMA Beta-cell Function [Baseline and Weeks 12, 26, 42 and 52.]

    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.

18. Change From Baseline in Body Weight [Baseline and Weeks 4, 8, 12, 26, 42 and 52.]

    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.

19. Change From Baseline in Total Cholesterol [Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.]

    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.

20. Change From Baseline in High-Density Lipoprotein Cholesterol [Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.]

    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.

21. Change From Baseline in Low-Density Lipoprotein Cholesterol [Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.]

    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.

22. Change From Baseline in Triglycerides [Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.]

    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.

23. Change From Baseline in Free Fatty Acids [Baseline and Weeks 12, 26, 42, and 52.]

    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.

24. Change From Baseline in Apolipoprotein A1 [Baseline and Weeks 12, 26, 42 and 52.]

    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.

25. Change From Baseline in Apolipoprotein A2 [Baseline and Weeks 12, 26, 42 and 52.]

    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.

26. Change From Baseline in Apolipoprotein B [Baseline and Weeks 12, 26, 42 and 52.]

    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.

27. Change From Baseline in Apolipoprotein C-III [Baseline and Weeks 12, 26, 42 and 52.]

    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.

28. Change From Baseline in Plasminogen Activator Inhibitor-1 [Baseline and Weeks 12, 26, 42 and 52.]

    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.

29. Change From Baseline in High-sensitivity C-Reactive Protein [Baseline and Weeks 12, 26, 42 and 52.]

    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.

30. Change From Baseline in Adiponectin [Baseline and Weeks 12, 26, 42 and 52.]

    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.

31. Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides [Baseline and Weeks 12, 26, 42 and 52.]

    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.

32. Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles [Baseline and Weeks 12, 26, 42 and 52.]

    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.

33. Change From Baseline in VLDL / Chylomicron Triglycerides [Baseline and Weeks 12, 26, 42 and 52.]

    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.

34. Change From Baseline in VLDL Particles [Baseline and Weeks 12, 26, 42 and 52.]

    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.

35. Change From Baseline in Mean VLDL Particle Size [Baseline and Weeks 12, 26, 42 and 52.]

    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.

36. Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles [Baseline and Weeks 12, 26, 42 and 52.]

    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.

37. Change From Baseline in Low Density Lipoprotein (LDL) Particles [Baseline and Weeks 12, 26, 42 and 52.]

    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.

38. Change From Baseline in Mean LDL Particle Size [Baseline and Weeks 12, 26, 42 and 52.]

    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.

39. Change From Baseline in High Density Lipoprotein (HDL) Particles [Baseline and Weeks 12, 26, 42 and 52.]

    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.

40. Change From Baseline in Mean HDL Particle Size [Baseline and Weeks 12, 26, 42 and 52.]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Huntsville	Alabama	United States
3		Lake Havasu City	Arizona	United States
4		Little Rock	Arkansas	United States
5		Foothill Ranch	California	United States
6		Los Alamitos	California	United States
7		Los Angeles	California	United States
8		Pismo Beach	California	United States
9		San Diego	California	United States
10		Golden	Colorado	United States
11		Clearwater	Florida	United States
12		Hialeah	Florida	United States
13		Lakeland	Florida	United States
14		Marianna	Florida	United States
15		Miami	Florida	United States
16		North Miami Beach	Florida	United States
17		Pembroke Pines	Florida	United States
18		Sebastian	Florida	United States
19		South Miami	Florida	United States
20		Tampa	Florida	United States
21		Winter Park	Florida	United States
22		Blue Ridge	Georgia	United States
23		Conyers	Georgia	United States
24		Decatur	Georgia	United States
25		Duluth	Georgia	United States
26		Dunwoody	Georgia	United States
27		Warner Robins	Georgia	United States
28		Boise	Idaho	United States
29		Coeur D'Alene	Idaho	United States
30		Burr Ridge	Illinois	United States
31		Chicago	Illinois	United States
32		Melrose Park	Illinois	United States
33		Naperville	Illinois	United States
34		O'Fallon	Illinois	United States
35		Bloomington	Indiana	United States
36		Mishawaka	Indiana	United States
37		Overland Park	Kansas	United States
38		Marrero	Louisiana	United States
39		Elkton	Maryland	United States
40		Rockville	Maryland	United States
41		Towson	Maryland	United States
42		Marlborough	Massachusetts	United States
43		Bay City	Michigan	United States
44		St. Clair Shores	Michigan	United States
45		McCook	Nebraska	United States
46		Las Vegas	Nevada	United States
47		Blackwood	New Jersey	United States
48		Trenton	New Jersey	United States
49		West Caldwell	New Jersey	United States
50		Asheboro	North Carolina	United States
51		Charlotte	North Carolina	United States
52		Mooresville	North Carolina	United States
53		Shelby	North Carolina	United States
54		Sparta	North Carolina	United States
55		Bismarck	North Dakota	United States
56		Orrville	Ohio	United States
57		Norman	Oklahoma	United States
58		Ashland	Oregon	United States
59		Aliquippa	Pennsylvania	United States
60		Altoona	Pennsylvania	United States
61		Dawningtown	Pennsylvania	United States
62		Fleetwood	Pennsylvania	United States
63		Kingston	Pennsylvania	United States
64		Norristown	Pennsylvania	United States
65		Pittsburgh	Pennsylvania	United States
66		Tipton	Pennsylvania	United States
67		Florence	South Carolina	United States
68		Taylors	South Carolina	United States
69		Williamston	South Carolina	United States
70		Watertown	South Dakota	United States
71		Kingsport	Tennessee	United States
72		Milan	Tennessee	United States
73		Nashville	Tennessee	United States
74		Arlington	Texas	United States
75		Austin	Texas	United States
76		Colleyville	Texas	United States
77		El Paso	Texas	United States
78		Garland	Texas	United States
79		Houston	Texas	United States
80		Hurst	Texas	United States
81		San Antonio	Texas	United States
82		Seguin	Texas	United States
83		Hampton	Virginia	United States
84		Norfolk	Virginia	United States
85		Richmond	Virginia	United States
86		Virginia Beach	Virginia	United States

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: VP Biological Sciences, Takeda

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• ACTOS® Package Insert

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT00432276
• Other Study ID Numbers: 01-06-TL-322OPI-004; 2006-006025-73; U1111-1112-3363
• First Posted: Feb 7, 2007
• Last Update Posted: Apr 4, 2013
• Last Verified: Apr 1, 2013

• Keywords provided by Takeda: Glucose Metabolism Disorder; Dysmetabolic Syndrome; Type II Diabetes; Diabetes Mellitus, Lipoatrophic; Dyslipidemia; Hyperglycemia; Drug Therapy
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Pioglitazone; Alogliptin

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 235 investigative sites in 16 countries worldwide from 30 January 2007 to 5 June 2009.
Pre-assignment Detail	Participants with a diagnosis of type 2 diabetes who were experiencing inadequate glycemic control on their existing treatment regimen of metformin HCl plus pioglitazone were randomized in a 1:1 ratio to 1 of 2 treatment arms: addition of alogliptin 25 mg versus titration of pioglitazone 30 mg to 45 mg.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Period Title: Overall Study
STARTED	404	399
Per Protocol Set	303	306
COMPLETED	283	243
NOT COMPLETED	121	156

Baseline Characteristics

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin	Total
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Total of all reporting groups
Overall Participants	404	399	803
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.3 (9.86)	55.9 (9.94)	55.1 (9.93)
Age, Customized (participants) [Number]
<65 years	339 83.9%	320 80.2%	659 82.1%
≥65 years	65 16.1%	79 19.8%	144 17.9%
Sex: Female, Male (Count of Participants)
Female	194 48%	195 48.9%	389 48.4%
Male	210 52%	204 51.1%	414 51.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	30 7.4%	31 7.8%	61 7.6%
Not Hispanic or Latino	374 92.6%	368 92.2%	742 92.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	2 0.5%	0 0%	2 0.2%
Asian	79 19.6%	78 19.5%	157 19.6%
Black or African American	41 10.1%	36 9%	77 9.6%
Native Hawaiian or Other Pacific Islander	2 0.5%	0 0%	2 0.2%
White	242 59.9%	256 64.2%	498 62%
Other	38 9.4%	29 7.3%	67 8.3%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	166.82 (9.884)	166.37 (10.856)	166.60 (10.375)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	88.16 (18.898)	87.98 (19.283)	88.07 (19.078)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	31.52 (5.248)	31.58 (5.177)	31.55 (5.210)
Duration of diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.47 (5.243)	6.85 (4.611)	7.16 (4.946)
Baseline daily metformin HCl use (mg) [Median (Full Range) ]
Median (Full Range) [mg]	1700.0	1700.0	1700.0
Current smoker (participants) [Number]
Yes	100 24.8%	99 24.8%	199 24.8%
No	304 75.2%	300 75.2%	604 75.2%
HbA1c (participants) [Number]
<8.0%	161 39.9%	163 40.9%	324 40.3%
≥8.0%	243 60.1%	236 59.1%	479 59.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (HbA1c)
Description	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.

Outcome Measure Data

Analysis Population Description

Per-protocol set included all randomized patients who received at least 1 dose of double-blind study medication and who had no major protocol violations. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	303	306
Change from Baseline at Week 26	-0.89 (0.042)	-0.42 (0.042)
Change from Baseline at Week 52	-0.70 (0.048)	-0.29 (0.048)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	The analysis was conducted at the 1-sided 0.025 significance level. Non-inferiority was demonstrated if the upper confidence limit for the LS mean difference was less than +0.3%.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The analysis was conducted at the 1-sided 0.025 significance level. Non-inferiority was demonstrated if the upper confidence limit for the LS mean difference was less than +0.3%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.47
	Confidence Interval	(1-Sided) 97.5%; to -0.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least squares means are from an ANCOVA model with treatment, study schedule, and geographic region as class variables, and baseline metformin dose and baseline HbA1c as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of Change from Baseline at Week 52. The null hypothesis was that the average change from Baseline in HbA1c at Week 52 for the alogliptin 25 mg addition group is inferior to the average change for the pioglitazone titration group. The alternative hypothesis was that the change from Baseline in HbA1c for the alogliptin 25 mg addition group was non-inferior to the change for the pioglitazone titration group for at Week 52.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The analysis was conducted at the 1-sided 0.025 significance level. Non-inferiority was demonstrated if the upper confidence limit for the LS mean difference was less than +0.3%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.42
	Confidence Interval	(1-Sided) 97.5%; to -0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least squares means are from an ANCOVA model with treatment, study schedule, and geographic region as class variables, and baseline metformin dose and baseline HbA1c as covariates.

2. Secondary Outcome

Title	Change From Baseline in HbA1c Over Time
Description	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.

Outcome Measure Data

Analysis Population Description

Per-protocol set. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	303	306
Change from Baseline at Week 4 (n=276, 277)	-0.42 (0.025)	-0.15 (0.025)
Change from Baseline at Week 8 (n=303, 306)	-0.71 (0.030)	-0.27 (0.030)
Change from Baseline at Week 12 (n=303, 306)	-0.85 (0.037)	-0.35 (0.037)
Change from Baseline at Week 16 (n=303, 306)	-0.91 (0.039)	-0.43 (0.038)
Change from Baseline at Week 20 (n=303, 306)	-0.91 (0.039)	-0.45 (0.039)
Change from Baseline at Week 34 (n=303, 306)	-0.82 (0.046)	-0.37 (0.045)
Change from Baseline at Week 42 (n=303, 306)	-0.80 (0.048)	-0.36 (0.048)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline in HbA1c at Week 42.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistical tests and resulting P-values are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	ANCOVA model with treatment, study schedule, and geographic region as class variables, and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -0.57 to -0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With Glycosylated Hemoglobin ≤ 6.5%
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 26	13.9 3.4%	7.8 2%
Week 52	8.7 2.2%	4.3 1.1%

4. Secondary Outcome

Title	Percentage of Participants With Glycosylated Hemoglobin ≤ 7.0%
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 26	39.1 9.7%	25.8 6.5%
Week 52	33.2 8.2%	21.3 5.3%

5. Secondary Outcome

Title	Percentage of Participants With Glycosylated Hemoglobin ≤ 7.5%
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 26	64.9 16.1%	47.1 11.8%
Week 52	59.9 14.8%	44.1 11.1%

6. Secondary Outcome

Title	Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 0.5%
Description	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%.
Time Frame	Weeks 26 and 52.

Outcome Measure Data

Analysis Population Description

The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 26	72.0 17.8%	42.1 10.6%
Week 52	60.9 15.1%	37.6 9.4%

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 26	42.3 10.5%	20.3 5.1%
Week 52	35.6 8.8%	17.3 4.3%

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 26	18.6 4.6%	7.5 1.9%
Week 52	17.1 4.2%	8.0 2%

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 26	8.2 2%	3.0 0.8%
Week 52	7.9 2%	3.3 0.8%

10. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set, which included all randomized patients who received at least 1 dose of double-blind study drug and where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 2 (n=360, 345)	-15.5 (1.56)	-0.5 (1.59)
Week 4 (n=397, 394)	-17.7 (1.48)	-1.4 (1.49)
Week 8 (n=399, 396)	-19.1 (1.56)	-5.7 (1.57)
Week 12 (n=399, 396)	-19.6 (1.60)	-4.8 (1.61)
Week 16 (n=399, 396)	-18.0 (1.60)	-4.5 (1.60)
Week 20 (n=399, 396)	-16.4 (1.65)	-5.8 (1.66)
Week 26 (n=399, 396)	-17.1 (1.79)	-4.9 (1.79)
Week 34 (n=399, 396)	-13.6 (1.88)	-6.2 (1.88)
Week 42 (n=399, 396)	-15.9 (1.87)	-4.9 (1.88)
Week 52 (n=399, 396)	-14.6 (1.89)	-3.7 (1.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and FPG as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-10.9
	Confidence Interval	(2-Sided) 95%; -16.2 to -5.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Percentage of Participants With Marked Hyperglycemia
Description	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set including patients with at least one non-missing fasting plasma glucose result in each treatment group.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	399	396
Number [percentage of participants]	27.3 6.8%	36.1 9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of incidence of marked hyperglycemia through Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	Extended Mantel Haenszel Test
	Comments	Treatment comparison was performed using nonparametric, covariance-adjusted, extended Mantel-Haenszel test.

12. Secondary Outcome

Title	Percentage of Participants Meeting Hyperglycemic Rescue Criteria
Description	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: After more than 2 weeks of treatment but prior to the Week 4 Visit: A single fasting plasma glucose (FPG) ≥275 mg/dL; From the Week 4 Visit but prior to the Week 8 Visit: A single FPG ≥250 mg/dL; From the Week 8 Visit but prior to the Week 12 Visit: A single FPG ≥225 mg/dL; 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

Outcome Measure Data

Analysis Population Description

Full Analysis Set including patients with a postbaseline visit.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	402	397
Number [percentage of participants]	10.9 2.7%	21.7 5.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of incidence of hyperglycemic rescue through Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	Extended Mantel Haenszel Test
	Comments	Treatment comparison was performed using nonparametric, covariance-adjusted, extended Mantel-Haenszel test.

13. Secondary Outcome

Title	Change From Baseline in Fasting Proinsulin
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 4 (n=342, 325)	-2.0 (0.67)	-0.8 (0.69)
Week 8 (n=380, 376)	-2.3 (0.77)	-0.5 (0.77)
Week 12 (n=380, 376)	-1.3 (0.89)	1.6 (0.89)
Week 16 (n=381, 376)	-0.2 (1.01)	0.6 (1.02)
Week 20 (n=381, 376)	-0.5 (0.67)	0.3 (0.68)
Week 26 (n=381, 376)	0.6 (0.82)	0.7 (0.83)
Week 34 (n=381, 376)	0.9 (0.86)	0.3 (0.86)
Week 42 (n=381, 376)	-0.1 (0.80)	1.1 (0.81)
Week 52 (n=381, 376)	-0.5 (0.74)	1.2 (0.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.116
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and proinsulin as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95%; -3.7 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline in Fasting Insulin
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 4 (n=344, 328)	0.53 (0.346)	-0.54 (0.355)
Week 8 (n=382, 378)	0.72 (0.393)	0.05 (0.395)
Week 12 (n=382, 378)	1.21 (0.505)	1.22 (0.507)
Week 16 (n=383, 378)	1.19 (0.414)	0.56 (0.416)
Week 20 (n=383, 378)	1.60 (0.414)	0.38 (0.417)
Week 26 (n=383, 378)	1.94 (0.479)	0.88 (0.482)
Week 34 (n=383, 378)	1.41 (0.430)	0.83 (0.433)
Week 42 (n=383, 378)	1.79 (0.441)	1.10 (0.443)
Week 52 (n=383, 378)	1.91 (0.470)	1.18 (0.473)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.276
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and fasting insulin as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; -0.58 to 2.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Change From Baseline in Proinsulin/Insulin Ratio
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 4 (n=341, 325)	-0.046 (0.0095)	-0.005 (0.0097)
Week 8 (n=380, 375)	-0.049 (0.0148)	-0.001 (0.0149)
Week 12 (n=380, 375)	-0.053 (0.0105)	0.004 (0.0106)
Week 16 (n=381, 375)	-0.044 (0.0100)	0.002 (0.0101)
Week 20 (n=381, 375)	-0.037 (0.0085)	-0.004 (0.0085)
Week 26 (n=381, 375)	-0.036 (0.0081)	-0.015 (0.0081)
Week 34 (n=381, 375)	-0.038 (0.0084)	-0.004 (0.0085)
Week 42 (n=381, 375)	-0.047 (0.0083)	-0.010 (0.0083)
Week 52 (n=381, 375)	-0.048 (0.0080)	-0.007 (0.0081)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.041
	Confidence Interval	(2-Sided) 95%; -0.063 to -0.018
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Change From Baseline in C-peptide
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 4 (n=349, 333)	0.110 (0.0350)	-0.033 (0.0358)
Week 8 (n=393, 389)	0.074 (0.0387)	-0.038 (0.0389)
Week 12 (n=394, 390)	0.070 (0.0459)	0.030 (0.0462)
Week 16 (n=395, 390)	0.064 (0.0380)	0.010 (0.0382)
Week 20 (n=395, 390)	0.104 (0.0384)	-0.001 (0.0386)
Week 26 (n=395, 390)	0.102 (0.0407)	-0.013 (0.0409)
Week 34 (n=395, 390)	0.118 (0.0403)	0.003 (0.0406)
Week 42 (n=395, 390)	0.140 (0.0413)	0.037 (0.0415)
Week 52 (n=395, 390)	0.182 (0.0430)	0.108 (0.0433)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.230
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline fasting C-peptide as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.073
	Confidence Interval	(2-Sided) 95%; -0.047 to 0.193
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Change From Baseline in Calculated HOMA Insulin Resistance
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=380, 378)	0.007 (0.2339)	0.350 (0.2345)
Week 26 (n=381, 378)	0.336 (0.2446)	0.312 (0.2455)
Week 42 (n=381, 378)	0.200 (0.2103)	0.431 (0.2111)
Week 52 (n=381, 378)	0.353 (0.2310)	0.541 (0.2319)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.567
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline HOMA insulin resistance as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.188
	Confidence Interval	(2-Sided) 95%; -0.830 to 0.455
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Change From Baseline in Calculated HOMA Beta-cell Function
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=380, 377)	14.770 (3.6543)	4.580 (3.6689)
Week 26 (n=381, 377)	30.012 (8.6151)	3.242 (8.6608)
Week 42 (n=381, 377)	15.397 (2.7628)	2.400 (2.7774)
Week 52 (n=381, 377)	15.020 (2.7396)	2.057 (2.7541)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline HOMA beta cell function as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	12.963
	Confidence Interval	(2-Sided) 95%; 5.333 to 20.592
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 4 (n=354, 344)	0.18 (0.094)	0.32 (0.095)
Week 8 (n=394, 394	0.31 (0.107)	0.51 (0.107)
Week 12 (n=395, 394)	0.35 (0.124)	0.64 (0.124)
Week 26 (n=395, 394)	0.73 (0.150)	0.97 (0.150)
Week 42 (n=395, 394)	1.09 (0.179)	1.52 (0.179)
Week 52 (n=395, 394)	1.10 (0.194)	1.60 (0.194)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.071
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline body weight as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -1.03 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Change From Baseline in Total Cholesterol
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 4 (n=397, 393)	-5.2 (1.28)	-1.9 (1.29)
Week 8 (n=399, 395)	-4.0 (1.40)	0.3 (1.40)
Week 12 (n=399, 395)	-3.6 (1.44)	1.1 (1.45)
Week 16 (n=399, 395)	-4.3 (1.56)	-0.4 (1.57)
Week 20 (n=399, 395)	-3.9 (1.55)	-0.5 (1.56)
Week 26 (n=399, 395)	-2.1 (1.62)	1.0 (1.63)
Week 34 (n=399, 395)	-3.5 (1.61)	-0.7 (1.62)
Week 42 (n=399, 395)	-3.8 (1.62)	0.0 (1.62)
Week 52 (n=399, 395)	-4.4 (1.58)	-0.1 (1.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline total cholesterol as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.2
	Confidence Interval	(2-Sided) 95%; -8.6 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Change From Baseline in High-Density Lipoprotein Cholesterol
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 4 (n=397, 392)	-0.7 (0.33)	0.4 (0.34)
Week 8 (n=399, 395)	-0.8 (0.35)	0.6 (0.35)
Week 12 (n=399, 395)	-0.2 (0.42)	1.1 (0.42)
Week 16 (n=399, 395)	-0.5 (0.37)	0.9 (0.38)
Week 20 (n=399, 395)	-0.2 (0.37)	0.7 (0.37)
Week 26 (n=399, 395)	0.0 (0.37)	0.6 (0.37)
Week 34 (n=399, 395)	-0.6 (0.38)	0.3 (0.38)
Week 42 (n=399, 395)	-0.3 (0.38)	0.6 (0.38)
Week 52 (n=395, 395)	-0.3 (0.37)	0.3 (0.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.228
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline HDL cholesterol as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -1.7 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	Change From Baseline in Low-Density Lipoprotein Cholesterol
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 4 (n=388, 383)	-2.4 (1.11)	0.0 (1.12)
Week 8 (n=390, 386)	-0.6 (1.18)	2.1 (1.19)
Week 12 (n=390, 386)	-1.2 (1.21)	1.4 (1.22)
Week 16 (n=390, 386)	-1.7 (1.31)	-0.1 (1.32)
Week 20 (n=390, 386)	-2.0 (1.24)	0.1 (1.25)
Week 26 (n=390, 386)	-0.6 (1.36)	1.6 (1.37)
Week 34 (n=390, 386)	-1.9 (1.33)	1.2 (1.33)
Week 42 (n=390, 386)	-1.6 (1.35)	0.7 (1.36)
Week 52 (n=390, 386)	-1.9 (1.32)	1.0 (1.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.132
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline LDL cholesterol as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.8
	Confidence Interval	(2-Sided) 95%; -6.5 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Change From Baseline in Triglycerides
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 4 (n=397, 393)	-16.4 (2.98)	-12.2 (3.00)
Week 8 (n=399, 395)	-17.9 (3.61)	-12.3 (3.63)
Week 12 (n=399, 395)	-16.1 (3.69)	-4.5 (3.71)
Week 16 (n=399, 395)	-16.3 (3.36)	-9.4 (3.38)
Week 20 (n=399, 395)	-12.7 (3.68)	-8.5 (3.70)
Week 26 (n=399, 395)	-11.9 (3.98)	-6.3 (4.00)
Week 34 (n=399, 395)	-7.4 (3.98)	-8.1 (4.00)
Week 42 (n=399, 395)	-14.6 (3.67)	-7.0 (3.69)
Week 52 (n=399, 395)	-16.4 (3.47)	-7.8 (3.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.080
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline triglycerides as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-8.6
	Confidence Interval	(2-Sided) 95%; -18.3 to 1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Change From Baseline in Free Fatty Acids
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=355, 360)	-0.0526 (0.01037)	-0.0332 (0.01031)
Week 26 (n=366, 368)	-0.0364 (0.01231)	-0.0162 (0.01228)
Week 42 (n=367, 368)	-0.0243 (0.01083)	-0.0222 (0.01081)
Week 52 (n=367, 368)	-0.0294 (0.01173)	0.0019 (0.01171)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline free fatty acid as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.0314
	Confidence Interval	(2-Sided) 95%; -0.0640 to 0.0012
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Change From Baseline in Apolipoprotein A1
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=348, 355)	0.5 (0.99)	0.0 (0.98)
Week 26 (n=359, 363)	0.1 (0.95)	-0.9 (0.95)
Week 42 (n=360, 363)	-2.1 (0.95)	-2.2 (0.95)
Week 52 (n=360, 363)	-4.5 (0.99)	-4.4 (0.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.934
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein A1 as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -2.9 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Secondary Outcome

Title	Change From Baseline in Apolipoprotein A2
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=348, 355)	-0.4 (0.22)	0.6 (0.22)
Week 26 (n=359, 363)	0.4 (0.23)	0.7 (0.22)
Week 42 (n=360, 363)	0.8 (0.25)	1.1 (0.25)
Week 52 (n=360, 363)	0.3 (0.24)	1.0 (0.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.070
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein A2 as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -1.3 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

27. Secondary Outcome

Title	Change From Baseline in Apolipoprotein B
Description	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.

Outcome Measure Data

Analysis Population Description

Full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 [N=348, 355]	-3.1 (1.02)	0.1 (1.01)
Week 26 [N=359, 363]	-0.6 (1.09)	1.1 (1.08)
Week 42 [N=360, 363]	-0.4 (1.15)	1.8 (1.15)
Week 52 [N=360, 363]	-1.2 (1.10)	1.7 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.064
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein B as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.9
	Confidence Interval	(2-Sided) 95%; -5.9 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

28. Secondary Outcome

Title	Change From Baseline in Apolipoprotein C-III
Description	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.

Outcome Measure Data

Analysis Population Description

Full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=352, 361)	-0.6 (0.15)	0.1 (0.15)
Week 26 (n=365, 369)	-0.1 (0.17)	0.2 (0.17)
Week 42 (n=366, 369)	-0.3 (0.17)	0.2 (0.17)
Week 52 (n=366, 369)	-0.5 (0.16)	0.0 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein C-III as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -1.0 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

29. Secondary Outcome

Title	Change From Baseline in Plasminogen Activator Inhibitor-1
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=322, 330)	-3.23 (1.483)	-3.59 (1.464)
Week 26 (n=342, 343)	-2.83 (1.523)	-3.63 (1.520)
Week 42 (n=346, 344)	-2.08 (1.429)	-4.89 (1.434)
Week 52 (n=346, 344)	-2.92 (1.234)	-4.70 (1.237)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.308
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline PAI-1 as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.78
	Confidence Interval	(2-Sided) 95%; -1.65 to 5.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

30. Secondary Outcome

Title	Change From Baseline in High-sensitivity C-Reactive Protein
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=357, 366)	0.2989 (0.53213)	0.7049 (0.52569)
Week 26 (n=366, 373)	-0.0632 (0.49229)	0.9706 (0.48763)
Week 42 (n=367, 373)	0.7251 (0.48203)	0.6443 (0.47813)
Week 52 (n=367, 373)	0.5875 (0.54194)	1.4085 (0.53755)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.283
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline hsCRP as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.8209
	Confidence Interval	(2-Sided) 95%; -2.3209 to 0.6790
	Parameter Dispersion	Type: Value:
	Estimation Comments

31. Secondary Outcome

Title	Change From Baseline in Adiponectin
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=355, 361)	1.15 (0.453)	2.97 (0.449)
Week 26 (n=366, 371)	1.17 (0.599)	4.19 (0.595)
Week 42 (n=367, 371)	-0.41 (0.529)	3.04 (0.526)
Week 52 (n=367, 371)	-0.70 (0.595)	2.21 (0.591)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments	Treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline adiponectin as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.92
	Confidence Interval	(2-Sided) 95%; -4.57 to -1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

32. Secondary Outcome

Title	Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=357, 361)	-8.7 (3.24)	0.2 (3.23)
Week 26 (n=367, 368)	-1.7 (3.58)	0.8 (3.58)
Week 42 (n=367, 369)	-6.4 (3.60)	0.7 (3.59)
Week 52 (n=367, 369)	-6.9 (3.35)	-0.7 (3.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin, Pioglitazone 45 mg + Metformin
	Comments	Comparison of change from Baseline at Week 52.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.197
	Comments	Statistical test and resulting P-value are 2-sided and was evaluated at the 0.05 significance level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-6.1
	Confidence Interval	(2-Sided) 95%; -15.4 to 3.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

33. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Total Particles - Week 12 (n=357, 361)	-0.59 (1.814)	2.39 (1.805)
Total Particles - Week 26 (n=367, 368)	1.27 (1.940)	3.09 (1.937)
Total Particles - Week 42 (n=367, 369)	-1.35 (1.916)	1.64 (1.911)
Total Particles - Week 52 (n=367, 369)	-1.20 (1.890)	3.03 (1.885)
Large Particles - Week 12 (n=357, 361)	-0.83 (0.247)	-0.27 (0.246)
Large Particles - Week 26 (n=367, 368)	-0.39 (0.282)	-0.32 (0.281)
Large Particles - Week 42 (n=367, 369)	-0.72 (0.277)	-0.38 (0.277)
Large Particles - Week 52 (n=367, 369)	-0.66 (0.260)	-0.46 (0.260)

34. Secondary Outcome

Title	Change From Baseline in VLDL / Chylomicron Triglycerides
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=357, 361)	-7.6 (3.22)	-0.2 (3.20)
Week 26 (n=367, 368)	-1.3 (3.54)	0.2 (3.54)
Week 42 (n=367, 369)	-5.4 (3.60)	0.2 (3.59)
Week 52 (n=367, 369)	-6.1 (3.30)	-1.5 (3.29)

35. Secondary Outcome

Title	Change From Baseline in VLDL Particles
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Medium Particles - Week 12 (n=357, 361)	-0.09 (1.152)	1.74 (1.146)
Medium Particles - Week 26 (n=367, 368)	1.30 (1.208)	2.23 (1.207)
Medium Particles - Week 42 (n=367, 369)	1.03 (1.307)	2.43 (1.303)
Medium Particles - Week 52 (n=367, 369)	0.26 (1.166)	2.12 (1.163)
Small Particles - Week 12 (n=357, 361)	-0.04 (1.077)	1.30 (1.072)
Small Particles - Week 26 (n=367, 368)	0.07 (1.121)	1.47 (1.119)
Small Particles - Week 42 (n=367, 369)	-1.86 (1.120)	-0.21 (1.117)
Small Particles - Week 52 (n=367, 369)	-1.02 (1.192)	1.58 (1.189)

36. Secondary Outcome

Title	Change From Baseline in Mean VLDL Particle Size
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=355, 361)	-0.67 (0.369)	-0.79 (0.366)
Week 26 (n=365, 368)	0.11 (0.391)	-0.87 (0.389)
Week 42 (n=365, 369)	0.44 (0.445)	-0.79 (0.442)
Week 52 (n=365, 369)	-0.12 (0.395)	-1.04 (0.393)

37. Secondary Outcome

Title	Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=357, 361)	-4.9 (2.24)	3.2 (2.23)
Week 26 (n=367, 368)	-4.1 (2.39)	1.0 (2.39)
Week 42 (n=367, 369)	-5.6 (2.26)	2.0 (2.26)
Week 52 (n=367, 369)	-4.5 (2.22)	3.2 (2.21)

38. Secondary Outcome

Title	Change From Baseline in Low Density Lipoprotein (LDL) Particles
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Total Particles - Week 12 (n=357, 361)	-46.9 (14.88)	-22.3 (14.81)
Total Particles - Week 26 (n=367, 368)	-14.0 (15.83)	-8.2 (15.81)
Total Particles - Week 42 (n=367, 369)	-11.7 (16.86)	-10.7 (16.81)
Total Particles - Week 52 (n=367, 369)	-13.0 (15.98)	-2.7 (15.94)
Large Particles - Week 12 (n=357, 361)	-4.4 (9.29)	-5.0 (9.24)
Large Particles - Week 26 (n=367, 368)	1.1 (10.37)	8.8 (10.36)
Large Particles - Week 42 (n=367, 369)	-20.8 (9.68)	0.0 (9.65)
Large Particles - Week 52 (n=367, 369)	-19.2 (10.03)	-2.4 (10.00)
Medium-small Particles - Week 12 (n=357, 361)	-7.0 (3.45)	-0.3 (3.43)
Medium-small Particles - Week 26 (n=367, 368)	-0.7 (3.57)	-0.7 (3.57)
Medium-small Particles - Week 42 (n=367, 369)	4.1 (3.82)	1.8 (3.81)
Medium-small Particles - Week 52 (n=367, 369)	2.4 (3.54)	1.2 (3.53)
Total Small Particles - Week 12 (n=357, 361)	-37.6 (16.93)	-20.8 (16.84)
Total Small Particles - Week 26 (n=367, 368)	-10.9 (17.80)	-18.2 (17.77)
Total Small Particles - Week 42 (n=367, 369)	15.0 (18.63)	-13.0 (18.58)
Total Small Particles - Week 52 (n=367, 369)	10.9 (17.84)	-3.5 (17.79)
Very Small Particles - Week 12 (n=357, 361)	-30.6 (13.84)	-20.6 (13.77)
Very Small Particles - Week 26 (n=367, 368)	-10.1 (14.49)	-17.5 (14.47)
Very Small Particles - Week 42 (n=367, 369)	11.0 (15.13)	-14.9 (15.09)
Very Small Particles - Week 52 (n=367, 369)	8.6 (14.56)	-4.8 (14.52)

39. Secondary Outcome

Title	Change From Baseline in Mean LDL Particle Size
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=357, 361)	0.05 (0.031)	0.06 (0.031)
Week 26 (n=367, 368)	0.03 (0.032)	0.07 (0.032)
Week 42 (n=367, 369)	-0.02 (0.032)	0.05 (0.032)
Week 52 (n=367, 369)	-0.04 (0.032)	0.03 (0.032)

40. Secondary Outcome

Title	Change From Baseline in High Density Lipoprotein (HDL) Particles
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Total Particles - Week 12 (n=357, 361)	-0.18 (0.224)	-0.14 (0.223)
Total Particles - Week 26 (n=367, 368)	0.37 (0.228)	0.03 (0.227)
Total Particles - Week 42 (n=367, 369)	0.09 (0.227)	-0.11 (0.227)
Total Particles - Week 52 (n=367, 369)	0.38 (0.227)	0.02 (0.226)
Large Particles - Week 12 (n=357, 361)	0.08 (0.102)	0.35 (0.101)
Large Particles - Week 26 (n=367, 368)	0.19 (0.103)	0.53 (0.103)
Large Particles - Week 42 (n=367, 369)	0.06 (0.102)	0.51 (0.101)
Large Particles - Week 52 (n=367, 369)	0.19 (0.105)	0.57 (0.105)
Medium Particles - Week 12 (n=357, 361)	0.10 (0.165)	0.43 (0.164)
Medium Particles - Week 26 (n=367, 368)	0.71 (0.178)	0.90 (0.178)
Medium Particles - Week 42 (n=367, 369)	0.57 (0.172)	0.70 (0.171)
Medium Particles - Week 52 (n=367, 369)	0.66 (0.180)	0.96 (0.179)
Small Particles - Week 12 (n=357, 361)	-0.38 (0.243)	-0.92 (0.242)
Small Particles - Week 26 (n=367, 368)	-0.53 (0.250)	-1.39 (0.250)
Small Particles - Week 42 (n=367, 369)	-0.54 (0.247)	-1.31 (0.246)
Small Particles - Week 52 (n=367, 369)	-0.47 (0.251)	-1.49 (0.250)

41. Secondary Outcome

Title	Change From Baseline in Mean HDL Particle Size
Description	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.

Outcome Measure Data

Analysis Population Description

The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin	Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Measure Participants	404	399
Week 12 (n=357, 361)	0.04 (0.012)	0.05 (0.012)
Week 26 (n=367, 368)	0.04 (0.012)	0.07 (0.012)
Week 42 (n=367, 369)	0.02 (0.012)	0.07 (0.012)
Week 52 (n=367, 369)	0.03 (0.012)	0.08 (0.012)

Adverse Events

Time Frame	Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug.
Adverse Event Reporting Description	At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Arm/Group Title	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin		Pioglitazone 45 mg + Metformin
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.		Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
All Cause Mortality
	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin		Pioglitazone 45 mg + Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin		Pioglitazone 45 mg + Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/404 (5%)		20/399 (5%)
Cardiac disorders
Acute myocardial infarction	0/404 (0%)		2/399 (0.5%)
Angina unstable	1/404 (0.2%)		1/399 (0.3%)
Coronary artery disease	1/404 (0.2%)		1/399 (0.3%)
Myocardial infarction	1/404 (0.2%)		0/399 (0%)
Ear and labyrinth disorders
Acute vestibular syndrome	1/404 (0.2%)		0/399 (0%)
Eye disorders
Cataract	0/404 (0%)		2/399 (0.5%)
Ocular myasthenia	0/404 (0%)		1/399 (0.3%)
Gastrointestinal disorders
Upper gastrointestinal haemorrhage	0/404 (0%)		1/399 (0.3%)
General disorders
Non-cardiac chest pain	2/404 (0.5%)		0/399 (0%)
Infections and infestations
Abdominal abscess	0/404 (0%)		1/399 (0.3%)
Appendicitis	1/404 (0.2%)		0/399 (0%)
Gastroenteritis viral	0/404 (0%)		1/399 (0.3%)
Hepatitis B	0/404 (0%)		1/399 (0.3%)
Lobar pneumonia	1/404 (0.2%)		0/399 (0%)
Osteomyelitis	1/404 (0.2%)		0/399 (0%)
Pneumonia	0/404 (0%)		1/399 (0.3%)
Pneumonia primary atypical	1/404 (0.2%)		0/399 (0%)
Sepsis	0/404 (0%)		1/399 (0.3%)
Injury, poisoning and procedural complications
Fall	0/404 (0%)		2/399 (0.5%)
Frostbite	1/404 (0.2%)		0/399 (0%)
Injury	1/404 (0.2%)		0/399 (0%)
Road traffic accident	1/404 (0.2%)		0/399 (0%)
Wound dehiscence	1/404 (0.2%)		0/399 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	2/404 (0.5%)		1/399 (0.3%)
Intervertebral disc protrusion	0/404 (0%)		1/399 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	1/404 (0.2%)		0/399 (0%)
Rectosigmoid cancer	0/404 (0%)		1/399 (0.3%)
Nervous system disorders
Cerebrovascular accident	1/404 (0.2%)		0/399 (0%)
Ischaemic stroke	0/404 (0%)		1/399 (0.3%)
Migraine	1/404 (0.2%)		0/399 (0%)
Psychiatric disorders
Mania	1/404 (0.2%)		0/399 (0%)
Renal and urinary disorders
Calculus urinary	0/404 (0%)		1/399 (0.3%)
Renal colic	1/404 (0.2%)		0/399 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/404 (0.2%)		0/399 (0%)
Respiratory failure	0/404 (0%)		1/399 (0.3%)
Vascular disorders
Hypotension	0/404 (0%)		2/399 (0.5%)
Arteriosclerosis obliterans	1/404 (0.2%)		0/399 (0%)
Hypertension	0/404 (0%)		1/399 (0.3%)
Peripheral vascular disorder	0/404 (0%)		1/399 (0.3%)
Other (Not Including Serious) Adverse Events
	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin		Pioglitazone 45 mg + Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	116/404 (28.7%)		104/399 (26.1%)
Gastrointestinal disorders
Diarrhoea	11/404 (2.7%)		24/399 (6%)
Infections and infestations
Nasopharyngitis	28/404 (6.9%)		21/399 (5.3%)
Upper respiratory tract infection	29/404 (7.2%)		16/399 (4%)
Influenza	18/404 (4.5%)		23/399 (5.8%)
Urinary tract infection	22/404 (5.4%)		13/399 (3.3%)
Vascular disorders
Hypertension	24/404 (5.9%)		21/399 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.