Efficacy and Safety of Alogliptin Combined With Metformin in Participants With Type 2 Diabetes Mellitus

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00286442
• Collaborator: (none)
• Enrollment: 527
• Locations: 56
• Arms: 3
• Duration (Months): 15
• Patients Per Site: 9.4
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of alogliptin, once daily (QD), combined with metformin in adults with type 2 diabetes mellitus.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: Alogliptin and metformin; Drug: Alogliptin and metformin; Drug: Metformin	Phase 3

Detailed Description

There are approximately 19 million people in the United States who have been diagnosed with diabetes mellitus, of which 90% to 95% are type 2. The prevalence of type 2 diabetes varies among racial and ethnic populations and has been shown to correlate with age, obesity, family history, history of gestational diabetes, and physical inactivity. Over the next decade, a marked increase in the number of adults with diabetes mellitus is expected.

Takeda is developing SYR-322 (alogliptin) for the improvement of glycemic control in patients with type 2 diabetes mellitus. Alogliptin is an inhibitor of the dipeptidyl peptidase IV enzyme. Dipeptidyl peptidase IV is thought to be primarily responsible for the degradation of 2 peptide hormones released in response to nutrient ingestion. It is expected that inhibition of dipeptidyl peptidase IV will improve glycemic (glucose) control in patients with type 2 diabetes.

The aim of the current study is to evaluate the effectiveness of alogliptin in combination with metformin in individually who are inadequately controlled on metformin alone.

Individuals who participate in this study will be required to commit to a screening visit and up to 14 additional visits at the study center. Study participation is anticipated to be about 34 weeks (or 8.5 months).

Study Design

• Study Type: Interventional
• Actual Enrollment: 527 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, Placebo-Controlled Study to Determine the Efficacy and Safety of SYR110322 (SYR-322) When Used in Combination With Metformin in Subjects With Type 2 Diabetes
• Study Start Date: Mar 1, 2006
• Actual Primary Completion Date: Jun 1, 2007
• Actual Study Completion Date: Jun 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alogliptin 12.5 mg QD	Drug: Alogliptin and metformin; Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.; Other Names: alogliptin SYR110322 Glucophage SYR-322
Experimental: Alogliptin 25 mg QD	Drug: Alogliptin and metformin; Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.; Other Names: alogliptin SYR110322 Glucophage SYR-322
Placebo Comparator: Metformin	Drug: Metformin; Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.; Other Names: Glucophage

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26. [Baseline and Week 26.]

   The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 26 or final visit and glycosylated hemoglobin collected at baseline.

Secondary Outcome Measures

1. Change From Baseline in Glycosylated Hemoglobin (Week 4). [Baseline and Week 4.]

   The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 4 and Glycosylated Hemoglobin collected at baseline.

2. Change From Baseline in Glycosylated Hemoglobin (Week 8). [Baseline and Week 8.]

   The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 8 and Glycosylated Hemoglobin collected at baseline.

3. Change From Baseline in Glycosylated Hemoglobin (Week 12). [Baseline and Week 12.]

   The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 12 and Glycosylated Hemoglobin collected at baseline.

4. Change From Baseline in Glycosylated Hemoglobin (Week 16). [Baseline and Week 16.]

   The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 16 and Glycosylated Hemoglobin collected at baseline.

5. Change From Baseline in Glycosylated Hemoglobin (Week 20). [Baseline and Week 20.]

   The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 20 and Glycosylated Hemoglobin collected at baseline.

6. Change From Baseline in Fasting Plasma Glucose (Week 1). [Baseline and Week 1.]

   The change between the value of fasting plasma glucose collected at final visit or week 1 and fasting plasma glucose collected at baseline.

7. Change From Baseline in Fasting Plasma Glucose (Week 2). [Baseline and Week 2.]

   The change between the value of fasting plasma glucose collected at week 2 and fasting plasma glucose collected at baseline.

8. Change From Baseline in Fasting Plasma Glucose (Week 4). [Baseline and Week 4.]

   The change between the value of fasting plasma glucose collected at week 4 and fasting plasma glucose collected at baseline.

9. Change From Baseline in Fasting Plasma Glucose (Week 8). [Baseline and Week 8.]

   The change between the value of fasting plasma glucose collected at week 8 and fasting plasma glucose collected at baseline.

10. Change From Baseline in Fasting Plasma Glucose (Week 12). [Baseline and Week 12.]

    The change between the value of fasting plasma glucose collected at week 12 and fasting plasma glucose collected at baseline.

11. Change From Baseline in Fasting Plasma Glucose (Week 16). [Baseline and Week 16.]

    The change between the value of fasting plasma glucose collected at week 16 and fasting plasma glucose collected at baseline.

12. Change From Baseline in Fasting Plasma Glucose (Week 20). [Baseline and Week 20.]

    The change between the value of fasting plasma glucose collected at week 20 and fasting plasma glucose collected at baseline.

13. Change From Baseline in Fasting Plasma Glucose (Week 26). [Baseline and Week 26.]

    The change between the value of fasting plasma glucose collected at week 26 or final visit and fasting plasma glucose collected at baseline.

14. Number of Participants With Marked Hyperglycemia (Fasting Plasma Glucose ≥ 200 mg Per dL). [26 Weeks.]

    The number of participants with a fasting plasma glucose value greater than or equal to 200 mg per dL during the 26 week study.

15. Number of Participants Requiring Rescue. [26 Weeks.]

    The number of participants requiring rescue for failing to achieve pre-specified glycemic targets during the 26 week study.

16. Change From Baseline in Fasting Proinsulin (Week 4). [Baseline and Week 4.]

    The change between the value of fasting proinsulin collected at week 4 and fasting proinsulin collected at baseline.

17. Change From Baseline in Fasting Proinsulin (Week 8). [Baseline and Week 8.]

    The change between the value of fasting proinsulin collected at week 8 and fasting proinsulin collected at baseline.

18. Change From Baseline in Fasting Proinsulin (Week 12). [Baseline and Week 12.]

    The change between the value of fasting proinsulin collected at week 12 and fasting proinsulin collected at baseline.

19. Change From Baseline in Fasting Proinsulin (Week 16). [Baseline and Week 16.]

    The change between the value of fasting proinsulin collected at week 16 and fasting proinsulin collected at baseline.

20. Change From Baseline in Fasting Proinsulin (Week 20). [Baseline and Week 20.]

    The change between the value of fasting proinsulin collected at week 20 and fasting proinsulin collected at baseline.

21. Change From Baseline in Fasting Proinsulin (Week 26). [Baseline and Week 26.]

    The change between the value of fasting proinsulin collected at week 26 or final visit and fasting proinsulin collected at baseline.

22. Change From Baseline in Insulin (Week 4). [Baseline and Week 4.]

    The change between the value of insulin collected at week 4 and insulin collected at baseline.

23. Change From Baseline in Insulin (Week 8). [Baseline and Week 8.]

    The change between the value of insulin collected at week 8 and insulin collected at baseline.

24. Change From Baseline in Insulin (Week 12). [Baseline and Week 12.]

    The change between the value of insulin collected at week 12 and insulin collected at baseline.

25. Change From Baseline in Insulin (Week 16). [Baseline and Week 16.]

    The change between the value of insulin collected at week 16 and insulin collected at baseline.

26. Change From Baseline in Insulin (Week 20). [Baseline and Week 20.]

    The change between the value of insulin collected at week 20 and insulin collected at baseline.

27. Change From Baseline in Insulin (Week 26). [Baseline and Week 26.]

    The change between the value of insulin collected at week 26 and insulin collected at baseline.

28. Change From Baseline in Proinsulin/Insulin Ratio (Week 4). [Baseline and Week 4.]

    The change between the ratio value of proinsulin and insulin collected at week 4 and the ratio value of proinsulin and insulin collected at baseline.

29. Change From Baseline in Proinsulin/Insulin Ratio (Week 8). [Baseline and Week 8.]

    The change between the ratio value of proinsulin and insulin collected at week 8 and the ratio value of proinsulin and insulin collected at baseline.

30. Change From Baseline in Proinsulin/Insulin Ratio (Week 12). [Baseline and Week 12.]

    The change between the ratio value of proinsulin and insulin collected at week 12 and the ratio value of proinsulin and insulin collected at baseline.

31. Change From Baseline in Proinsulin/Insulin Ratio (Week 16). [Baseline and Week 16.]

    The change between the ratio value of proinsulin and insulin collected at week 16 and the ratio value of proinsulin and insulin collected at baseline.

32. Change From Baseline in Proinsulin/Insulin Ratio (Week 20). [Baseline and Week 20.]

    The change between the ratio value of proinsulin and insulin collected at week 20 and the ratio value of proinsulin and insulin collected at baseline.

33. Change From Baseline in Proinsulin/Insulin Ratio (Week 26). [Baseline and Week 26.]

    The change between the ratio value of proinsulin and insulin collected at week 26 or final visit and the ratio value of proinsulin and insulin collected at baseline.

34. Change From Baseline in C-peptide (Week 4). [Baseline and Week 4.]

    The change between the value of C-peptide collected at week 4 and C-peptide collected at baseline.

35. Change From Baseline in C-peptide (Week 8). [Baseline and Week 8.]

    The change between the value of C-peptide collected at week 8 and C-peptide collected at baseline.

36. Change From Baseline in C-peptide (Week 12). [Baseline and Week 12.]

    The change between the value of C-peptide collected at week 12 and C-peptide collected at baseline.

37. Change From Baseline in C-peptide (Week 16). [Baseline and Week 16.]

    The change between the value of C-peptide collected at week 16 and C-peptide collected at baseline.

38. Change From Baseline in C-peptide (Week 20). [Baseline and Week 20.]

    The change between the value of C-peptide collected at week 20 and C-peptide collected at baseline.

39. Change From Baseline in C-peptide (Week 26). [Baseline and Week 26.]

    The change between the value of C-peptide collected at week 26 or final visit and C-peptide collected at baseline.

40. Number of Participants With Glycosylated Hemoglobin ≤ 6.5%. [Baseline and Week 26.]

    The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 6.5% during the 26 week study.

41. Number of Participants With Glycosylated Hemoglobin ≤ 7.0%. [Baseline and Week 26.]

    The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 7.0% during the 26 week study.

42. Number of Participants With Glycosylated Hemoglobin ≤ 7.5%. [Baseline and Week 26.]

    The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 7.5% during the 26 week study.

43. Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 0.5%. [Baseline and Week 26.]

    The number of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 0.5% during the 26 week study.

44. Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 1.0%. [Baseline and Week 26.]

    The number of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 1.0% during the 26 week study.

45. Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 1.5%. [Baseline and Week 26.]

    The number of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 1.5% during the 26 week study.

46. Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 2.0%. [Baseline and Week 26.]

    The number of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 2.0% during the 26 week study.

47. Change From Baseline in Body Weight (Week 8). [Baseline and Week 8.]

    The change between Body Weight measured at week 8 and Body Weight measured at baseline.

48. Change From Baseline in Body Weight (Week 12). [Baseline and Week 12.]

    The change between Body Weight measured at week 12 and Body Weight measured at baseline.

49. Change From Baseline in Body Weight (Week 20). [Baseline and Week 20.]

    The change between Body Weight measured at week 20 and Body Weight measured at baseline.

50. Change From Baseline in Body Weight (Week 26). [Baseline and Week 26.]

    The change between Body Weight measured at week 26 or final visit and Body Weight measured at baseline.

Eligibility Criteria

Criteria

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

Inclusion Criteria

• Diagnosis of type 2 diabetes mellitus currently treated with metformin alone but, experiencing inadequate glycemic control. The participant should have received the metformin monotherapy for at least the 3 months prior to Screening; and must have a stable dose of greater than or equal to 1500 mg metformin for at least 8 weeks prior to randomization. Participants with a maximum tolerated dose that is documented to be less than 1500 mg of metformin may also be enrolled if this dose has been stable for 8 weeks prior to randomization.

• No treatment with antidiabetic agents other than metformin within the 3 months prior to Screening. (Exception: if a participant has received other antidiabetic therapy for less than 7 days within the 3 months prior to Screening.)

• Body mass index greater than or equal to 23 kg/m2 and less than or equal to 45 kg/m2

• Fasting C-peptide concentration greater than or equal to 0.8 ng per mL. (If this screening criterion is not met, the participant still qualifies if C-peptide is greater than or equal to 1.5 ng per mL after a challenge test.

• Glycosylated hemoglobin concentration between 7.0% and 10.0%, inclusive

• If regular use of other, non-excluded medications, must be on a stable dose for at least the 4 weeks prior to Screening. However, as needed use of prescription or over-the-counter medications is allowed at the discretion of the investigator.

• Systolic blood pressure less than or equal to 180 mm Hg and diastolic pressure less than or equal to 110 mm Hg

• Hemoglobin greater than or equal to 12 g per dL for males and greater than or equal to 10 g per dL for females

• Alanine aminotransferase less than or equal to 3 time the upper limit of normal

• Serum creatinine less than1.5 mg per dL for males and less than 1.4 mg per dL for females

• Thyroid-stimulating hormone level less than or equal to the upper limit of the normal range and the participant is clinically euthyroid.

• Neither pregnant nor lactating.

• Female participants of childbearing potential must be practicing adequate contraception. Adequate contraception must be practiced for the duration of participation in 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 participant from completing the study

• Able and willing to provide written informed consent Exclusion Criteria

• Urine albumin to creatinine ratio of greater than 1000 μg per mg at Screening. If elevated, the participant may be rescreened within 1 week.

• History of cancer, other than squamous cell or basal cell carcinoma of the skin, that has not been in full remission for at least 5 years prior to Screening. (A history of treated cervical intraepithelial neoplasia I or cervical intraepithelial neoplasia II is allowed.)

• History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening

• History of treated diabetic gastric paresis

• New York Heart Association Class III or IV heart failure regardless of therapy. Currently treated participants who are stable at Class I or II are candidates for the study.

• 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 participant's ability to participate in the study

• History of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors

• History of alcohol 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

• Excluded Medications:

• Treatment with antidiabetic agents other than study drug or metformin is not allowed within the 3 months prior to Screening and through the completion of the end-of treatment/early termination procedures.

• Treatment with weight-loss drugs, any investigational antidiabetics, or oral or systemically injected glucocorticoids is not allowed from 3 months prior to randomization through the completion of the end-of-treatment/early termination procedures. Inhaled corticosteroids are allowed.

• Participants must be instructed not to take any medications, including over-the-counter products, without first consulting with the investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Phoenix	Arizona	United States
2		Anaheim	California	United States
3		Artesia	California	United States
4		Fresno	California	United States
5		Los Angeles	California	United States
6		Mission Viejo	California	United States
7		Northridge	California	United States
8		Orange	California	United States
9		San Diego	California	United States
10		Walnut Creek	California	United States
11		Denver	Colorado	United States
12		Washington	District of Columbia	United States
13		Cocoa Beach	Florida	United States
14		Longwood	Florida	United States
15		Ocala	Florida	United States
16		Ocoee	Florida	United States
17		St. Cloud	Florida	United States
18		Honolulu	Hawaii	United States
19		Avon	Indiana	United States
20		Elkhart	Indiana	United States
21		Evansville	Indiana	United States
22		St. Louis	Missouri	United States
23		Omaha	Nebraska	United States
24		Berlin	New Jersey	United States
25		Burlington	North Carolina	United States
26		Hickory	North Carolina	United States
27		Morehead City	North Carolina	United States
28		Pinehurst	North Carolina	United States
29		Winston Salem	North Carolina	United States
30		Cincinnati	Ohio	United States
31		Medford	Oregon	United States
32		Lansdale	Pennsylvania	United States
33		Charleston	South Carolina	United States
34		Columbia	South Carolina	United States
35		Simpsonville	South Carolina	United States
36		Corpus Christi	Texas	United States
37		Dallas	Texas	United States
38		San Antonio	Texas	United States
39		Texarkana	Texas	United States
40		Burlington	Vermont	United States
41		Multiple Cities		Argentina
42		Multiple Cities		Australia
43		Multiple Cities		Brazil
44		Multiple Cities		Chile
45		Multiple Cities		Czech Republic
46		Multiple Cities		Germany
47		Multiple Cities		Guatemala
48		Multiple Cities		Hungary
49		Multiple Cities		India
50		Multiple Cities		Mexico
51		Multiple Cities		Netherlands
52		Multiple Cities		New Zealand
53		Multiple Cities		Peru
54		Multiple Cities		Poland
55		Multiple Cities		South Africa
56		Multiple Cities		United Kingdom

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: VP Biological Sciences, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT00286442
• Other Study ID Numbers: SYR-322-MET-008; 2005-004668-22; U1111-1113-8393
• First Posted: Feb 3, 2006
• Last Update Posted: Feb 3, 2012
• Last Verified: Feb 1, 2012

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

Study Results

Participant Flow

Recruitment Details	Participants enrolled at 115 investigative sites in Australia, Brazil, Chile, Germany, Guatemala, Hungary, India, Mexico, New Zealand, The Netherlands, Poland, South Africa, Spain, and the United States from 10 March 2006 to 12 June 2007.
Pre-assignment Detail	Participants with a historical diagnosis of type 2 diabetes mellitus who were inadequately controlled while receiving a stable dose of metformin monotherapy were enrolled in one of 3, once-daily (QD) treatment groups.

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Period Title: Overall Study
STARTED	213	210	104
COMPLETED	176	165	72
NOT COMPLETED	37	45	32

Baseline Characteristics

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo	Total
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.	Total of all reporting groups
Overall Participants	213	210	104	527
Age, Customized (participants) [Number]
<65 years	173 81.2%	179 85.2%	83 79.8%	435 82.5%
≥65 years	40 18.8%	31 14.8%	21 20.2%	92 17.5%
Sex: Female, Male (Count of Participants)
Female	112 52.6%	96 45.7%	54 51.9%	262 49.7%
Male	101 47.4%	114 54.3%	50 48.1%	265 50.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26.
Description	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 26 or final visit and glycosylated hemoglobin collected at baseline.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had an HbA1c measurement at baseline and at Week 26.

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	210	203	103
Least Squares Mean (Standard Error) [percentage of Glycosylated Hemoglobin]	-0.61 (0.053)	-0.59 (0.054)	-0.10 (0.076)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments	Null Hypothesis: No difference between treatment and placebo arms in change from baseline in glycosylated hemoglobin at wk 26. Sample size calculated based on normally distributed means. For comparison of either dose vs. placebo (2-sample t-test), study sample size >=500 participants had 95% power to detect a treatment difference as small as 0.4% in the supportive per protocol analysis set assuming SD=0.8%, 2-sided >0.05 significance level and >=80% of participants meeting per protocol criteria.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	A step-down strategy was used for the primary analysis. First, the 25mg dose was compared to placebo at the 2-sided 0.05 significance level. The 12.5 mg dose was compared to placebo only if the comparison of the 25mg dose to placebo was significant.
	Method	ANCOVA
	Comments	Analysis of covariance (ANCOVA) with treatment and geographic region as class variables and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -0.68 to -0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments	Null Hypothesis: No difference between treatment and placebo arms in change from baseline in glycosylated hemoglobin at week 26. Sample size calculated based on normally distributed means. For comparison of either dose vs. placebo (2-sample t-test), study sample size >=500 participants had 95% power to detect a treatment difference as small as 0.4% in the per protocol analysis set assuming SD=0.8%, 2-sided test at 0.05 significance level and >=80% of participants meeting per protocol criteria.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	A step-down strategy was used for the primary analysis. First, the 25mg dose was compared to placebo at the 2-sided 0.05 significance level. The 12.5 mg dose was compared to placebo only if the comparison of the 25mg dose to placebo was significant.
	Method	ANCOVA
	Comments	ANCOVA on change from baseline with treatment and geographic region as class variables and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -0.67 to -0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

2. Secondary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (Week 4).
Description	The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 4 and Glycosylated Hemoglobin collected at baseline.
Time Frame	Baseline and Week 4.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had an HbA1c measurement at baseline and at Week 4. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	188	187	91
Least Squares Mean (Standard Error) [percentage of Glycosylated Hemoglobin]	-0.36 (0.031)	-0.40 (0.031)	-0.10 (0.044)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	ANCOVA on change from baseline with treatment and geographic region as class variables and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.37 to -0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	ANCOVA on change from baseline with treatment and geographic region as class variables and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.40 to -0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

3. Secondary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (Week 8).
Description	The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 8 and Glycosylated Hemoglobin collected at baseline.
Time Frame	Baseline and Week 8.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had an HbA1c measurement at baseline and at Week 8.

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	210	201	103
Least Squares Mean (Standard Error) [percentage of Glycosylated Hemoglobin]	-0.59 (0.041)	-0.59 (0.042)	-0.21 (0.058)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	ANCOVA on change from baseline with treatment and geographic region as class variables and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.52 to -0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	ANCOVA on change from baseline with treatment and geographic region as class variables and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.52 to -0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

4. Secondary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (Week 12).
Description	The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 12 and Glycosylated Hemoglobin collected at baseline.
Time Frame	Baseline and Week 12.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had an HbA1c measurement at baseline and at Week 12.

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	210	203	103
Least Squares Mean (Standard Error) [percentage of Glycosylated Hemoglobin]	-0.66 (0.047)	-0.66 (0.048)	-0.16 (0.067)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	ANCOVA on change from baseline with treatment and geographic region as class variables and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -0.66 to -0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments
	Method	ANCOVA
	Comments	ANCOVA on change from baseline with treatment and geographic region as class variables and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -0.66 to -0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

5. Secondary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (Week 16).
Description	The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 16 and Glycosylated Hemoglobin collected at baseline.
Time Frame	Baseline and Week 16.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had an HbA1c measurement at baseline and at Week 16.

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	210	203	103
Least Squares Mean (Standard Error) [percentage of Glycosylated Hemoglobin]	-0.66 (0.050)	-0.64 (0.051)	-0.13 (0.072)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	ANCOVA on change from baseline with treatment and geographic region as class variables and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.53
	Confidence Interval	(2-Sided) 95%; -0.70 to -0.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	ANCOVA on change from baseline with treatment and geographic region as class variables and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.51
	Confidence Interval	(2-Sided) 95%; -0.69 to -0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

6. Secondary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (Week 20).
Description	The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 20 and Glycosylated Hemoglobin collected at baseline.
Time Frame	Baseline and Week 20.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had an HbA1c measurement at baseline and at Week 20.

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	210	203	103
Least Squares Mean (Standard Error) [percentage of Glycosylated Hemoglobin]	-0.63 (0.051)	-0.63 (0.052)	-0.12 (0.073)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	ANCOVA on change from baseline with treatment and geographic region as class variables and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 95%; -0.69 to -0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	ANCOVA on change from baseline with treatment and geographic region as class variables and baseline metformin dose and baseline HbA1c as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 95%; -0.69 to -0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

7. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (Week 1).
Description	The change between the value of fasting plasma glucose collected at final visit or week 1 and fasting plasma glucose collected at baseline.
Time Frame	Baseline and Week 1.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a fasting plasma glucose measurement at baseline and at Week 1.

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	193	186	98
Least Squares Mean (Standard Error) [mg/dL]	-14.3 (2.05)	-12.5 (2.09)	-0.6 (2.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates. Missing data imputed with LOCF.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.7
	Confidence Interval	(2-Sided) 95%; -20.7 to -6.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the metformin arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates. Missing data imputed with LOCF.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.9
	Confidence Interval	(2-Sided) 95%; -18.9 to -4.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the metformin arm.

8. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (Week 2).
Description	The change between the value of fasting plasma glucose collected at week 2 and fasting plasma glucose collected at baseline.
Time Frame	Baseline and Week 2.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a fasting plasma glucose measurement at baseline and at Week 2.

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	208	199	104
Least Squares Mean (Standard Error) [mg/dL]	-17.4 (2.11)	-17.6 (2.16)	-0.7 (2.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates. Missing data imputed with LOCF.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.7
	Confidence Interval	(2-Sided) 95%; -23.9 to -9.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates. Missing data imputed with LOCF.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.8
	Confidence Interval	(2-Sided) 95%; -24.1 to -9.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

9. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (Week 4).
Description	The change between the value of fasting plasma glucose collected at week 4 and fasting plasma glucose collected at baseline.
Time Frame	Baseline and Week 4.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a fasting plasma glucose measurement at baseline and at Week 2. Missing data imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	211	204	104
Least Squares Mean (Standard Error) [mg/dL]	-18.4 (1.98)	-18.1 (2.01)	-0.6 (2.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.8
	Confidence Interval	(2-Sided) 95%; -24.6 to -11.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.5
	Confidence Interval	(2-Sided) 95%; -24.3 to -10.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

10. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (Week 8).
Description	The change between the value of fasting plasma glucose collected at week 8 and fasting plasma glucose collected at baseline.
Time Frame	Baseline and Week 8.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a fasting plasma glucose measurement at baseline and at Week 8. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	211	204	104
Least Squares Mean (Standard Error) [mg/dL]	-19.6 (2.30)	-17.2 (2.34)	0.4 (3.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-20.1
	Confidence Interval	(2-Sided) 95%; -28.0 to -12.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.6
	Confidence Interval	(2-Sided) 95%; -25.6 to -9.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

11. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (Week 12).
Description	The change between the value of fasting plasma glucose collected at week 12 and fasting plasma glucose collected at baseline.
Time Frame	Baseline and Week 12.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a fasting plasma glucose measurement at baseline and at Week 12. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	211	204	104
Least Squares Mean (Standard Error) [mg/dL]	-16.9 (2.44)	-16.8 (2.47)	0.3 (3.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.2
	Confidence Interval	(2-Sided) 95%; -25.6 to -8.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.0
	Confidence Interval	(2-Sided) 95%; -25.4 to -8.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

12. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (Week 16).
Description	The change between the value of fasting plasma glucose collected at week 16 and fasting plasma glucose collected at baseline.
Time Frame	Baseline and Week 16.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a fasting plasma glucose measurement at baseline and at Week 16. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	211	204	104
Least Squares Mean (Standard Error) [mg/dL]	-17.8 (2.43)	-15.4 (2.46)	1.3 (3.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.1
	Confidence Interval	(2-Sided) 95%; -27.4 to -10.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.7
	Confidence Interval	(2-Sided) 95%; -25.0 to -8.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

13. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (Week 20).
Description	The change between the value of fasting plasma glucose collected at week 20 and fasting plasma glucose collected at baseline.
Time Frame	Baseline and Week 20.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a fasting plasma glucose measurement at baseline and at Week 20. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	211	204	104
Least Squares Mean (Standard Error) [mg/dL]	-18.1 (2.53)	-15.6 (2.57)	-0.1 (3.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-18.1
	Confidence Interval	(2-Sided) 95%; -26.7 to -9.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.5
	Confidence Interval	(2-Sided) 95%; -24.2 to -6.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

14. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (Week 26).
Description	The change between the value of fasting plasma glucose collected at week 26 or final visit and fasting plasma glucose collected at baseline.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a fasting plasma glucose measurement at baseline and at Week 26. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	211	204	104
Least Squares Mean (Standard Error) [mg/dL]	-18.7 (2.49)	-17.4 (2.53)	0.0 (3.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-18.7
	Confidence Interval	(2-Sided) 95%; -27.3 to -10.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.4
	Confidence Interval	(2-Sided) 95%; -25.9 to -8.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

15. Secondary Outcome

Title	Number of Participants With Marked Hyperglycemia (Fasting Plasma Glucose ≥ 200 mg Per dL).
Description	The number of participants with a fasting plasma glucose value greater than or equal to 200 mg per dL during the 26 week study.
Time Frame	26 Weeks.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had at least 1 fasting plasma glucose measurement after baseline.

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	211	206	104
Number [participants]	61 28.6%	65 31%	53 51%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	no multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.372
	Confidence Interval	(2-Sided) 95%; 0.213 to 0.650
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) is alogliptin arm versus placebo. OR <1.0 indicates lower incidence compared to placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.405
	Confidence Interval	(2-Sided) 95%; 0.231 to 0.708
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) is alogliptin arm versus placebo. OR <1.0 indicates lower incidence compared to placebo.

16. Secondary Outcome

Title	Number of Participants Requiring Rescue.
Description	The number of participants requiring rescue for failing to achieve pre-specified glycemic targets during the 26 week study.
Time Frame	26 Weeks.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who completed at least 1 study visit after baseline.

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	211	207	104
Number [participants]	19 8.9%	17 8.1%	25 24%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	no multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.302
	Confidence Interval	(2-Sided) 95%; 0.143 to 0.635
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) is alogliptin arm versus placebo. OR <1.0 indicates lower incidence compared to placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.236
	Confidence Interval	(2-Sided) 95%; 0.109 to 0.510
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) is alogliptin arm versus placebo. OR <1.0 indicates lower incidence compared to placebo.

17. Secondary Outcome

Title	Change From Baseline in Fasting Proinsulin (Week 4).
Description	The change between the value of fasting proinsulin collected at week 4 and fasting proinsulin collected at baseline.
Time Frame	Baseline and Week 4.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a fasting plasma glucose measurement at baseline and at Week 4. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	178	174	90
Least Squares Mean (Standard Error) [pmol/L]	-1.9 (1.76)	-5.0 (1.77)	-0.5 (2.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.634
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -7.4 to 4.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.136
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.5
	Confidence Interval	(2-Sided) 95%; -10.5 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

18. Secondary Outcome

Title	Change From Baseline in Fasting Proinsulin (Week 8).
Description	The change between the value of fasting proinsulin collected at week 8 and fasting proinsulin collected at baseline.
Time Frame	Baseline and Week 8.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a proinsulin measurement at baseline and at Week 8. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	201	189	100
Least Squares Mean (Standard Error) [pmol/L]	-2.9 (1.30)	-5.0 (1.34)	-0.4 (1.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.274
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -6.9 to 2.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.046
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.6
	Confidence Interval	(2-Sided) 95%; -9.1 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

19. Secondary Outcome

Title	Change From Baseline in Fasting Proinsulin (Week 12).
Description	The change between the value of fasting proinsulin collected at week 12 and fasting proinsulin collected at baseline.
Time Frame	Baseline and Week 12.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a proinsulin measurement at baseline and at Week 12. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	201	191	100
Least Squares Mean (Standard Error) [pmol/L]	-2.6 (1.76)	-2.7 (1.8)	-1.3 (2.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.655
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -7.4 to 4.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.645
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline FPG as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -7.4 to 4.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

20. Secondary Outcome

Title	Change From Baseline in Fasting Proinsulin (Week 16).
Description	The change between the value of fasting proinsulin collected at week 16 and fasting proinsulin collected at baseline.
Time Frame	Baseline and Week 16.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a proinsulin measurement at baseline and at Week 16. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	201	191	100
Least Squares Mean (Standard Error) [pmol/L]	-1.4 (1.60)	-2.7 (1.64)	-0.5 (2.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.748
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -6.3 to 4.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.432
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -7.7 to 3.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

21. Secondary Outcome

Title	Change From Baseline in Fasting Proinsulin (Week 20).
Description	The change between the value of fasting proinsulin collected at week 20 and fasting proinsulin collected at baseline.
Time Frame	Baseline and Week 20.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a proinsulin measurement at baseline and at Week 20. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	201	191	100
Least Squares Mean (Standard Error) [pmol/L]	-4.2 (1.62)	-1.1 (1.66)	-2.0 (2.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.427
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -7.8 to 3.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.746
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; -4.6 to 6.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

22. Secondary Outcome

Title	Change From Baseline in Fasting Proinsulin (Week 26).
Description	The change between the value of fasting proinsulin collected at week 26 or final visit and fasting proinsulin collected at baseline.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a PROINSULIN measurement at baseline and at Week 26. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	201	191	100
Least Squares Mean (Standard Error) [pmol/L]	-2.1 (1.80)	-1.6 (1.84)	-3.2 (2.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.727
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; -5.0 to 7.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.6
	Comments	No multiplicity adjustments
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.601
	Confidence Interval	(2-Sided) 95%; -4.5 to 7.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

23. Secondary Outcome

Title	Change From Baseline in Insulin (Week 4).
Description	The change between the value of insulin collected at week 4 and insulin collected at baseline.
Time Frame	Baseline and Week 4.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had an insulin measurement at baseline and at Week 4. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	177	170	89
Least Squares Mean (Standard Error) [mcIU/mL]	1.11 (0.684)	0.52 (0.695)	-1.07 (0.965)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.066
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline insulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.19
	Confidence Interval	(2-Sided) 95%; -0.15 to 4.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.180
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline insulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.60
	Confidence Interval	(2-Sided) 95%; -0.74 to 3.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

24. Secondary Outcome

Title	Change From Baseline in Insulin (Week 8).
Description	The change between the value of insulin collected at week 8 and insulin collected at baseline.
Time Frame	Baseline and Week 8.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a Insulin measurement at baseline and at Week 8. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	200	186	99
Least Squares Mean (Standard Error) [mcIU/mL]	2.50 (1.416)	0.18 (1.466)	2.68 (2.015)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.944
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline insulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -5.02 to 4.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.316
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline insulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.50
	Confidence Interval	(2-Sided) 95%; -7.40 to 2.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

25. Secondary Outcome

Title	Change From Baseline in Insulin (Week 12).
Description	The change between the value of insulin collected at week 12 and insulin collected at baseline.
Time Frame	Baseline and Week 12.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a Insulin measurement at baseline and at Week 12. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	200	188	99
Least Squares Mean (Standard Error) [mcIU/mL]	1.6 (1.488)	0.46 (1.532)	1.92 (2.118)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.901
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline insulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -5.42 to 4.77
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.578
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline insulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.45
	Confidence Interval	(2-Sided) 95%; -6.59 to 3.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

26. Secondary Outcome

Title	Change From Baseline in Insulin (Week 16).
Description	The change between the value of insulin collected at week 16 and insulin collected at baseline.
Time Frame	Baseline and Week 16.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a Insulin measurement at baseline and at Week 16. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	200	188	99
Least Squares Mean (Standard Error) [mcIU/mL]	1.27 (0.964)	1.53 (0.993)	0.64 (1.372)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.708
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline insulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; -2.67 to 3.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.601
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline insulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; -2.44 to 4.21
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

27. Secondary Outcome

Title	Change From Baseline in Insulin (Week 20).
Description	The change between the value of insulin collected at week 20 and insulin collected at baseline.
Time Frame	Baseline and Week 20.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a Insulin measurement at baseline and at Week 20. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	200	188	99
Least Squares Mean (Standard Error) [mcIU/mL]	0.91 (0.760)	0.86 (0.782)	-0.21 (1.081)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.398
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline insulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; -1.48 to 3.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.425
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline insulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; -1.56 to 3.69
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

28. Secondary Outcome

Title	Change From Baseline in Insulin (Week 26).
Description	The change between the value of insulin collected at week 26 and insulin collected at baseline.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had a Insulin measurement at baseline and at Week 26. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	200	188	99
Least Squares Mean (Standard Error) [mcIU/mL]	0.63 (0.690)	-0.01 (0.710)	-2.23 (0.981)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline insulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.87
	Confidence Interval	(2-Sided) 95%; 0.50 to 5.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.067
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline insulin as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.22
	Confidence Interval	(2-Sided) 95%; -0.15 to 4.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

29. Secondary Outcome

Title	Change From Baseline in Proinsulin/Insulin Ratio (Week 4).
Description	The change between the ratio value of proinsulin and insulin collected at week 4 and the ratio value of proinsulin and insulin collected at baseline.
Time Frame	Baseline and Week 4.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had insulin and proinsulin measurements at baseline and at Week 4. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	177	170	89
Least Squares Mean (Standard Error) [ratio]	-0.045 (0.0082)	-0.056 (0.0083)	-0.008 (0.0115)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.036
	Confidence Interval	(2-Sided) 95%; -0.064 to -0.009
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.047
	Confidence Interval	(2-Sided) 95%; -0.075 to -0.019
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

30. Secondary Outcome

Title	Change From Baseline in Proinsulin/Insulin Ratio (Week 8).
Description	The change between the ratio value of proinsulin and insulin collected at week 8 and the ratio value of proinsulin and insulin collected at baseline.
Time Frame	Baseline and Week 8.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had insulin and proinsulin measurements at baseline and at Week 8. Missing data are imputed using last observation carried forward (LOCF.

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	200	186	99
Least Squares Mean (Standard Error) [ratio]	-0.055 (0.0073)	-0.046 (0.0075)	-0.009 (0.0103)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.045
	Confidence Interval	(2-Sided) 95%; -0.070 to -0.021
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.037
	Confidence Interval	(2-Sided) 95%; -0.062 to -0.012
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

31. Secondary Outcome

Title	Change From Baseline in Proinsulin/Insulin Ratio (Week 12).
Description	The change between the ratio value of proinsulin and insulin collected at week 12 and the ratio value of proinsulin and insulin collected at baseline.
Time Frame	Baseline and Week 12.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had insulin and proinsulin measurements at baseline and at Week 12. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	200	188	99
Least Squares Mean (Standard Error) [ratio]	-0.044 (0.0083)	-0.042 (0.0085)	-0.005 (0.0118)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.039
	Confidence Interval	(2-Sided) 95%; -0.068 to -0.011
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.037
	Confidence Interval	(2-Sided) 95%; -0.066 to -0.008
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm

32. Secondary Outcome

Title	Change From Baseline in Proinsulin/Insulin Ratio (Week 16).
Description	The change between the ratio value of proinsulin and insulin collected at week 16 and the ratio value of proinsulin and insulin collected at baseline.
Time Frame	Baseline and Week 16.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had insulin and proinsulin measurements at baseline and at Week 16. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	200	188	99
Least Squares Mean (Standard Error) [ratio]	-0.051 (0.0082)	-0.043 (0.0085)	0.001 (0.0117)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.052
	Confidence Interval	(2-Sided) 95%; -0.080 to -0.024
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.044
	Confidence Interval	(2-Sided) 95%; -0.072 to -0.015
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

33. Secondary Outcome

Title	Change From Baseline in Proinsulin/Insulin Ratio (Week 20).
Description	The change between the ratio value of proinsulin and insulin collected at week 20 and the ratio value of proinsulin and insulin collected at baseline.
Time Frame	Baseline and Week 20.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had insulin and proinsulin measurements at baseline and at Week 20. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	200	188	99
Least Squares Mean (Standard Error) [ratio]	-0.53 (0.0150)	-0.011 (0.0155)	-0.007 (0.0213)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.078
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.046
	Confidence Interval	(2-Sided) 95%; -0.097 to 0.005
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.860
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.005
	Confidence Interval	(2-Sided) 95%; -0.056 to 0.047
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

34. Secondary Outcome

Title	Change From Baseline in Proinsulin/Insulin Ratio (Week 26).
Description	The change between the ratio value of proinsulin and insulin collected at week 26 or final visit and the ratio value of proinsulin and insulin collected at baseline.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had insulin and proinsulin measurements at baseline and at Week 26. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	200	188	99
Least Squares Mean (Standard Error) [ratio]	-0.049 (0.0154)	0.000 (0.0159)	0.004 (0.0219)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.053
	Confidence Interval	(2-Sided) 95%; -0.106 to -0.001
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.889
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline proinsulin/insulin ratio as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.004
	Confidence Interval	(2-Sided) 95%; -0.057 to 0.050
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

35. Secondary Outcome

Title	Change From Baseline in C-peptide (Week 4).
Description	The change between the value of C-peptide collected at week 4 and C-peptide collected at baseline.
Time Frame	Baseline and Week 4.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had C-peptide measurements at baseline and at Week 4. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	186	184	92
Least Squares Mean (Standard Error) [ng/mL]	0.222 (0.0893)	0.190 (0.0897)	-0.114 (0.1273)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline C-peptide as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.336
	Confidence Interval	(2-Sided) 95%; 0.030 to 0.642
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.051
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline C-peptide as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.304
	Confidence Interval	(2-Sided) 95%; -0.002 to 0.611
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

36. Secondary Outcome

Title	Change From Baseline in C-peptide (Week 8).
Description	The change between the value of C-peptide collected at week 8 and C-peptide collected at baseline.
Time Frame	Baseline and Week 8.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had C-peptide measurements at baseline and at Week 8. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	210	200	103
Least Squares Mean (Standard Error) [ng/mL]	0.215 (0.0864)	0.238 (0.0884)	0.127 (0.1236)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.563
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline C-peptide as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.088
	Confidence Interval	(2-Sided) 95%; -0.209 to 0.384
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.467
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline C-peptide as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.111
	Confidence Interval	(2-Sided) 95%; -0.188 to 0.410
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

37. Secondary Outcome

Title	Change From Baseline in C-peptide (Week 12).
Description	The change between the value of C-peptide collected at week 12 and C-peptide collected at baseline.
Time Frame	Baseline and Week 12.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had C-peptide measurements at baseline and at Week 12. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	210	202	103
Least Squares Mean (Standard Error) [ng/mL]	0.154 (0.0915)	0.246 (0.0932)	-0.033 (0.1309)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.243
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline C-peptide as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.187
	Confidence Interval	(2-Sided) 95%; -0.127 to 0.501
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.083
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline C-peptide as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.279
	Confidence Interval	(2-Sided) 95%; -0.037 to 0.595
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

38. Secondary Outcome

Title	Change From Baseline in C-peptide (Week 16).
Description	The change between the value of C-peptide collected at week 16 and C-peptide collected at baseline.
Time Frame	Baseline and Week 16.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had C-peptide measurements at baseline and at Week 16. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	210	202	103
Least Squares Mean (Standard Error) [ng/mL]	0.138 (0.0894)	0.250 (0.0910)	-0.018 (0.1280)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.321
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline C-peptide as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.155
	Confidence Interval	(2-Sided) 95%; -0.152 to 0.463
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.089
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline C-peptide as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.268
	Confidence Interval	(2-Sided) 95%; -0.041 to 0.577
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

39. Secondary Outcome

Title	Change From Baseline in C-peptide (Week 20).
Description	The change between the value of C-peptide collected at week 20 and C-peptide collected at baseline.
Time Frame	Baseline and Week 20.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had C-peptide measurements at baseline and at Week 20. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	210	202	103
Least Squares Mean (Standard Error) [ng/mL]	0.007 (0.0803)	0.054 (0.0818)	-0.137 (0.1149)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.305
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline C-peptide as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.144
	Confidence Interval	(2-Sided) 95%; -0.132 to 0.420
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.177
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline C-peptide as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.191
	Confidence Interval	(2-Sided) 95%; -0.086 to 0.468
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

40. Secondary Outcome

Title	Change From Baseline in C-peptide (Week 26).
Description	The change between the value of C-peptide collected at week 26 or final visit and C-peptide collected at baseline.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had C-peptide measurements at baseline and at Week 26. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	210	202	103
Least Squares Mean (Standard Error) [ng/mL]	-0.083 (0.0833)	-0.214 (0.0848)	-0.476 (0.1192)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline C-peptide as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.394
	Confidence Interval	(2-Sided) 95%; 0.107 to 0.680
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline C-peptide as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.263
	Confidence Interval	(2-Sided) 95%; -0.025 to 0.550
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

41. Secondary Outcome

Title	Number of Participants With Glycosylated Hemoglobin ≤ 6.5%.
Description	The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 6.5% during the 26 week study.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	213	207	104
Number [participants]	42 19.7%	36 17.1%	4 3.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	no multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	6.150
	Confidence Interval	(2-Sided) 95%; 2.117 to 17.864
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) is alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.322
	Confidence Interval	(2-Sided) 95%; 1.820 to 15.564
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) is alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

42. Secondary Outcome

Title	Number of Participants With Glycosylated Hemoglobin ≤ 7.0%.
Description	The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 7.0% during the 26 week study.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	213	207	104
Number [participants]	110 51.6%	92 43.8%	19 18.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	6.092
	Confidence Interval	(2-Sided) 95%; 3.271 to 11.345
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) compares alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.451
	Confidence Interval	(2-Sided) 95%; 2.388 to 8.296
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) compares alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

43. Secondary Outcome

Title	Number of Participants With Glycosylated Hemoglobin ≤ 7.5%.
Description	The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 7.5% during the 26 week study.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	213	207	104
Number [participants]	153 71.8%	137 65.2%	47 45.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.238
	Confidence Interval	(2-Sided) 95%; 2.327 to 7.717
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) compares alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.293
	Confidence Interval	(2-Sided) 95%; 1.814 to 5.979
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) compares alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

44. Secondary Outcome

Title	Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 0.5%.
Description	The number of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 0.5% during the 26 week study.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	213	207	104
Number [participants]	123 57.7%	122 58.1%	28 26.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.103
	Confidence Interval	(2-Sided) 95%; 2.428 to 6.934
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) compares alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.314
	Confidence Interval	(2-Sided) 95%; 2.545 to 7.312
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) compares alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

45. Secondary Outcome

Title	Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 1.0%.
Description	The number of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 1.0% during the 26 week study.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	213	207	104
Number [participants]	61 28.6%	62 29.5%	9 8.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.601
	Confidence Interval	(2-Sided) 95%; 2.554 to 12.282
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) compares alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.793
	Confidence Interval	(2-Sided) 95%; 2.645 to 12.684
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) compares alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

46. Secondary Outcome

Title	Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 1.5%.
Description	The number of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 1.5% during the 26 week study.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	213	207	104
Number [participants]	20 9.4%	24 11.4%	6 5.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.085
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.449
	Confidence Interval	(2-Sided) 95%; 0.883 to 6.797
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) compares alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.958
	Confidence Interval	(2-Sided) 95%; 1.087 to 8.046
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) compares alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

47. Secondary Outcome

Title	Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 2.0%.
Description	The number of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 2.0% during the 26 week study.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	213	207	104
Number [participants]	7 3.3%	5 2.4%	4 3.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.639
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.404
	Confidence Interval	(2-Sided) 95%; 0.340 to 5.803
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) compares alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.956
	Comments	No multiplicity adjustments.
	Method	Regression, Logistic
	Comments	Logistic regression model includes effects for treatment, geographic region, baseline metformin dose and baseline HbA1c.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.959
	Confidence Interval	(2-Sided) 95%; 0.218 to 4.223
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odd's Ratio (OR) compares alogliptin arm versus placebo. OR >1.0 indicates higher incidence of response compared to placebo.

48. Secondary Outcome

Title	Change From Baseline in Body Weight (Week 8).
Description	The change between Body Weight measured at week 8 and Body Weight measured at baseline.
Time Frame	Baseline and Week 8.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had weight measurements at baseline and at Week 8. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	198	193	102
Least Squares Mean (Standard Error) [kg]	-0.30 (0.134)	-0.53 (0.135)	-0.12 (0.186)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.439
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline weight as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.63 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.075
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline weight as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.41
	Confidence Interval	(2-Sided) 95%; -0.86 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

49. Secondary Outcome

Title	Change From Baseline in Body Weight (Week 12).
Description	The change between Body Weight measured at week 12 and Body Weight measured at baseline.
Time Frame	Baseline and Week 12.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had weight measurements at baseline and at Week 12. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	205	198	103
Least Squares Mean (Standard Error) [kg]	-0.28 (0.161)	-0.64 (0.164)	-0.57 (0.227)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.305
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline weight as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.788
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline weight as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.63 to 0.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

50. Secondary Outcome

Title	Change From Baseline in Body Weight (Week 20).
Description	The change between Body Weight measured at week 20 and Body Weight measured at baseline.
Time Frame	Baseline and Week 20.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had weight measurements at baseline and at Week 20. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	205	198	103
Least Squares Mean (Standard Error) [kg]	-0.38 (0.178)	-0.58 (0.182)	-0.40 (0.252)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.930
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline weight as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.58 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.559
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline weight as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.79 to 0.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

51. Secondary Outcome

Title	Change From Baseline in Body Weight (Week 26).
Description	The change between Body Weight measured at week 26 or final visit and Body Weight measured at baseline.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug (Full Analysis Set), and who had weight measurements at baseline and at Week 26. Missing data are imputed using last observation carried forward (LOCF).

Arm/Group Title	Alogliptin 12.5 mg QD	Alogliptin 25 mg QD	Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
Measure Participants	206	198	103
Least Squares Mean (Standard Error) [kg]	-0.39 (0.194)	-0.67 (0.198)	-0.39 (0.274)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.996
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline weight as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.66 to 0.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 25 mg QD, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.407
	Comments	No multiplicity adjustments.
	Method	ANCOVA
	Comments	Treatment and geographic region as class variables; baseline metformin dose and baseline weight as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.94 to 0.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative mean treatment difference indicates larger decrease from baseline (more negative change from baseline) in the alogliptin arm compared to the placebo arm.

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious adverse event) after the last dose of double-blind study drug.
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Alogliptin 12.5 mg QD		Alogliptin 25 mg QD		Placebo
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.		Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.		Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
All Cause Mortality
	Alogliptin 12.5 mg QD		Alogliptin 25 mg QD		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Alogliptin 12.5 mg QD		Alogliptin 25 mg QD		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/213 (2.8%)		8/207 (3.9%)		4/104 (3.8%)
Cardiac disorders
Angina unstable	0/213 (0%)		0/207 (0%)		1/104 (1%)
Bradycardia	1/213 (0.5%)		0/207 (0%)		0/104 (0%)
Cardiac failure congestive	0/213 (0%)		1/207 (0.5%)		0/104 (0%)
Hypertensive heart disease	1/213 (0.5%)		0/207 (0%)		0/104 (0%)
Congenital, familial and genetic disorders
Hydrocele	0/213 (0%)		0/207 (0%)		1/104 (1%)
General disorders
Non-cardiac chest pain	0/213 (0%)		2/207 (1%)		0/104 (0%)
Hepatobiliary disorders
Cholelithiasis	0/213 (0%)		1/207 (0.5%)		0/104 (0%)
Infections and infestations
Appendicitis	1/213 (0.5%)		0/207 (0%)		0/104 (0%)
Cellulitis	0/213 (0%)		0/207 (0%)		1/104 (1%)
Postoperative wound infection	0/213 (0%)		1/207 (0.5%)		0/104 (0%)
Pyelonephritis	0/213 (0%)		0/207 (0%)		1/104 (1%)
Urinary tract infection	0/213 (0%)		1/207 (0.5%)		0/104 (0%)
Injury, poisoning and procedural complications
Burns third degree	0/213 (0%)		0/207 (0%)		1/104 (1%)
Fall	1/213 (0.5%)		0/207 (0%)		0/104 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/213 (0%)		1/207 (0.5%)		0/104 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial cancer	1/213 (0.5%)		0/207 (0%)		0/104 (0%)
Non-secretory adenoma of the pituitary	1/213 (0.5%)		0/207 (0%)		0/104 (0%)
Prostate cancer	1/213 (0.5%)		0/207 (0%)		0/104 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/213 (0%)		1/207 (0.5%)		0/104 (0%)
Other (Not Including Serious) Adverse Events
	Alogliptin 12.5 mg QD		Alogliptin 25 mg QD		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	62/213 (29.1%)		41/207 (19.8%)		37/104 (35.6%)
Gastrointestinal disorders
Diarrhoea	6/213 (2.8%)		7/207 (3.4%)		6/104 (5.8%)
General disorders
Pain in extremity	5/213 (2.3%)		3/207 (1.4%)		4/104 (3.8%)
Infections and infestations
Upper respiratory tract infection	10/213 (4.7%)		5/207 (2.4%)		7/104 (6.7%)
Urinary tract infection	14/213 (6.6%)		5/207 (2.4%)		4/104 (3.8%)
Nasopharyngitis	12/213 (5.6%)		7/207 (3.4%)		6/104 (5.8%)
Sinusitis	5/213 (2.3%)		4/207 (1.9%)		5/104 (4.8%)
Bronchitis	9/213 (4.2%)		6/207 (2.9%)		2/104 (1.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/213 (1.9%)		3/207 (1.4%)		5/104 (4.8%)
Nervous system disorders
Headache	8/213 (3.8%)		4/207 (1.9%)		2/104 (1.9%)
Vascular disorders
Hypertension	4/213 (1.9%)		6/207 (2.9%)		5/104 (4.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

No publication related to study results will be published prior to publication of a multi-center report submitted for publication within 18 months after conclusion or termination of a study at all study sites. Results publications will be submitted to sponsor for review 60 days in advance of publication. Sponsor can require removal of confidential information unrelated to study results. Sponsor can embargo a proposed publication for another 60 days to preserve intellectual property.