Efficacy and Safety of Alogliptin and Metformin Fixed-Dose Combination in Participants With Type 2 Diabetes

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01890122
• Collaborator: (none)
• Enrollment: 647
• Locations: 45
• Arms: 4
• Duration (Months): 25
• Patients Per Site: 14.4
• 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 and metformin fixed-dose combination (FDC) as compared with alogliptin alone or metformin alone on Type 2 Diabetes Mellitus (T2DM).

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: Alogliptin; Drug: Metformin HCl; Drug: Alogliptin and Metformin Fixed-Dose Combination (FDC); Drug: Alogliptin Placebo; Drug: Metformin Placebo; Drug: Alogliptin and Metformin FDC Placebo	Phase 3

Detailed Description

The drug being tested in this study is a fixed-dose combination tablet of alogliptin and metformin to treat people who have diabetes. This study will look at glycemic control in people who take alogliptin and metformin FDC compared with alogliptin or metformin alone. The study will enroll approximately 640 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the four treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

• Alogliptin 12.5 mg twice daily (BID)

• Metformin hydrochloride (HCl) 500 mg BID

• Alogliptin 12.5 mg and Metformin HCl 500 mg FDC BID

• Placebo (dummy inactive pill) - this is a tablet/capsule that looks like the study drug but has no active ingredient.

All participants will be asked to take 2 tablets and 1 capsule twice a day at the same time each day throughout the study. All participants will be asked to record any hypoglycemic events in a diary. This multi-center trial will be conducted in China, South Korea, Taiwan and Malaysia. The overall time to participate in this study is 34 weeks. Participants will make 11 visits to the clinic.

Study Design

• Study Type: Interventional
• Actual Enrollment: 647 participants
• Allocation: Randomized
• Intervention Model: Factorial 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 Alogliptin and Metformin Fixed Dose Combination, Alogliptin Alone, or Metformin Alone in Subjects With Type 2 Diabetes Mellitus
• Study Start Date: Sep 1, 2013
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Metformin HCl 500 mg Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Drug: Metformin HCl; Metformin HCl capsules; Other Names: Glucophage ; Drug: Alogliptin Placebo; Alogliptin placebo-matching tablets; Drug: Alogliptin and Metformin FDC Placebo; Alogliptin and metformin FDC placebo-matching tablets
Active Comparator: Alogliptin 12.5 mg Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Drug: Alogliptin; Alogliptin tablets; Other Names: SYR-322; Nesina ; Drug: Metformin Placebo; Metformin placebo-matching capsules; Drug: Alogliptin and Metformin FDC Placebo; Alogliptin and metformin FDC placebo-matching tablets
Experimental: Alogliptin 12.5 mg + Metformin HCl 500 mg FDC Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Drug: Alogliptin and Metformin Fixed-Dose Combination (FDC); Alogliptin and metformin FDC tablets; Other Names: Kazano ; Drug: Alogliptin Placebo; Alogliptin placebo-matching tablets; Drug: Metformin Placebo; Metformin placebo-matching capsules
Placebo Comparator: Placebo Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Drug: Alogliptin Placebo; Alogliptin placebo-matching tablets; Drug: Metformin Placebo; Metformin placebo-matching capsules; Drug: Alogliptin and Metformin FDC Placebo; Alogliptin and metformin FDC placebo-matching tablets

Outcome Measures

Primary Outcome Measures

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

   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 early termination relative to baseline. Negative change indicates better glycemic control.

Secondary Outcome Measures

1. Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20 [Baseline and Weeks 4, 8, 12, 16 and 20]

   The change in the value of HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Weeks 4, 8, 12, 16 and 20 relative to baseline. Negative change indicates better glycemic control.

2. Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26 [Baseline and Weeks 4, 8, 12, 16, 20 and 26]

   The change between the FPG value collected at Weeks 4, 8, 12, 16, 20 and 26 relative to baseline. Negative change indicates better glycemic control.

3. Time to Hyperglycemic Rescue Event [From the date of randomization through Week 26]

   Rescue is defined as meeting one of the following criteria, confirmed by a second sample drawn within 7 days of first sample: After >1 week of treatment but prior to Week 4 visit: A single FPG ≥275 mg/dL (≥15.27 mmol/L); From the Week 4 but prior to the Week 8 visit: A single FPG ≥250 mg/dL (≥13.88 mmol/L); From the Week 8 visit but prior to the Week 12 visit: A single FPG ≥225 mg/dL (≥12.49 mmol/L); From the Week 12 visit through the end-of-treatment visit (week 26): HbA1c ≥8.5% and ≤0.5% reduction in HbA1c from baseline. Time to hyperglycemic rescue was censored if the participant did not experience a hyperglycemic rescue event.

4. Percentage of Participants Requiring Hyperglycemic Rescue [Baseline up to Week 26]

   Rescue is defined as meeting one of the following criteria, confirmed by a second sample drawn within 7 days of first sample: After >1 week of treatment but prior to Week 4 visit: A single FPG ≥275 mg/dL (≥15.27 mmol/L); From the Week 4 but prior to the Week 8 visit: A single FPG ≥250 mg/dL (≥13.88 mmol/L); From the Week 8 visit but prior to the Week 12 visit: A single FPG ≥225 mg/dL (≥12.49 mmol/L); From the Week 12 visit through the end-of-treatment visit (week 26): HbA1c ≥8.5% and ≤0.5% reduction in HbA1c from baseline.

5. Percentage of Participants With Marked Hyperglycemia [Baseline up to Week 26]

   Marked hyperglycemia is defined as FPG level ≥200 mg/dL (11.1 mmol/L).

6. Change From Baseline in Body Weight at Weeks 12 and 26 [Baseline and Weeks 12 and 26]

   Change in participant's body weight at Weeks 12 and 26 relative to baseline.

7. Percentage of Participants With Glycosylated Hemoglobin ≤6.5% [Week 26]

   Clinical response at Week 26 will be assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) ≤6.5%.

8. Percentage of Participants With Glycosylated Hemoglobin ≤7.0% [Week 26]

   Clinical response at Week 26 will be assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) ≤7%.

9. Percentage of Participants With Glycosylated Hemoglobin ≤7.5% [Week 26]

   Clinical response at Week 26 will be assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) ≤7.5%.

10. Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥0.5% [Baseline and Week 26]

    Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥0.5%.

11. Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.0% [Baseline and Week 26]

    Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥1.0%.

12. Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.5% [Baseline and Week 26]

    Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥1.5%.

13. Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥2.0% [Baseline and Week 26]

    Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥2.0%.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Capable of understanding and complying with protocol requirements.

2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

3. Has a historical diagnosis of Type 2 diabetes mellitus (T2DM).

4. Male or female and aged 18 to 75 years, inclusive.

5. Body mass index (BMI) between 20 and 45 kg/m^2, inclusive.

6. A female of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study.

7. Is experiencing inadequate glycemic control defined as glycosylated hemoglobin (HbA1c) concentration between 7.5% and 10%, inclusive, and has been treated with diet and exercise for at least 2 months prior to Screening. (Exception: a participant who has received any other diabetic therapy for less than 7 days in total within the 2 months prior to the screening, can be included).

8. If male, has a hemoglobin >12 g/dL (>120 g/L) at Screening or if female, has a hemoglobin >10 g/dL (>100 g/L) at Screening.

9. If male, has a serum creatinine <1.5 mg/dL at Screening or if female, has a serum creatinine <1.4 mg/dL at Screening, and estimated glomerular filtration rate (eGFR)

60 mL/min/1.73 m^2 based on calculation using the Modification of Diet in Renal Disease (MDRD) at Screening.

1. Willing and able to monitor their own blood glucose concentrations using a home glucose monitor and complete a subject diary.

Exclusion Criteria:

1. Participated in another clinical study within 90 days prior to Screening.

2. Received any investigational compound within 30 days prior to Randomization.

3. Received a dipeptidyl peptidase-4 (DPP-4) inhibitor within 3 months prior to screening.

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

5. History of treatment for diabetic gastric paresis, gastric banding, or gastric bypass surgery.

6. History of diabetic ketoacidosis or hyperosmolar non-ketotic coma.

7. Chronic pancreatitis and/or history of acute pancreatitis.

8. Systolic blood pressure >180 mm Hg and/or diastolic blood pressure >110 mm Hg at Screening.

9. History of any hemoglobinopathy or diagnosis of chronic anemia.

10. New York Heart Association Class III or IV heart failure. (Participants who are stable at Class I or II and are currently treated, are candidates for the study.)

11. History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within 6 months prior to Screening.

12. History of any cancer, other than squamous cell or basal cell carcinoma of the skin, which has not been in full remission for at least 5 years prior to Screening. Participants with a history of treated cervical intraepithelial neoplasia [CIN] I or CIN II are allowed.

13. Significant clinical sign or symptom of hepatopathy, acute or chronic hepatitis, human immunodeficiency virus or alanine aminotransferase (ALT) is 2.5 times above upper limit of normal value.

14. History of angioedema in association with use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB).

15. History of hypersensitivity or allergies to any DPP-4 inhibitor and/or metformin or related compounds.

16. Has used oral or systemically injected glucocorticoids (including intra-articular injection) or has used weight-loss drugs within 2 months prior to Screening. (Inhaled or topical corticosteroids were allowed.)

17. History of alcohol or substance abuse within 2 years prior to Screening.

18. Has used medicine for weight loss within 60 days prior to Screening (such as Xenical, Sibutramine, Phenylpropanolamine or similar nonprescription drugs).

19. History of organ transplantation.

20. Is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.

21. Has, in the judgment of the investigator, any major illness or debility that may prohibit the participant from completing the study.

22. If female, is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Beijing	Beijing	China
2		Fuzhou	Fujian	China
3		Xiamen	Fujian	China
4		Guangzhou	Guangdong	China
5		Nanning	Guangxi	China
6		Guiyang	Guizhou	China
7		Hengshui	Hebei	China
8		Shijiazhuang	Hebei	China
9		Shiyan	Hubei	China
10		Wuhan	Hubei	China
11		Changsha	Hunan	China
12		Yueyang	Hunan	China
13		Changzhou	Jiangsu	China
14		Nanjing	Jiangsu	China
15		Suzhou	Jiangsu	China
16		Nanchang	Jiangxi	China
17		Changchun	Jilin	China
18		Shenyang	Liaoning	China
19		Xi'an	Shanxi	China
20		Chengdu	Sichuan	China
21		Wenzhou	Zhejiang	China
22		Beijing		China
23		Shanghai		China
24		Tianjin		China
25		Goyang-si	Gyeonggi-do	Korea, Republic of
26		Seongnam-si	Gyeonggi-do	Korea, Republic of
27		Suwon	Gyeonggi-do	Korea, Republic of
28		Busan		Korea, Republic of
29		Seoul		Korea, Republic of
30		Johor Bahru	Johor	Malaysia
31		Alor Setar	Kedah Darul Aman	Malaysia
32		Alor Setar	Kedah	Malaysia
33		Kubang Kerian	Kelantan	Malaysia
34		Nilai	Negeri Sembilan	Malaysia
35		Seremban	Negeri Sembilan	Malaysia
36		Tampin	Negeri Sembilan	Malaysia
37		Bagan Serai	Perak	Malaysia
38		Ipoh	Perak	Malaysia
39		Petaling Jaya	Selangor	Malaysia
40		Shah Alam	Selangor	Malaysia
41		Putrajaya	WIlayah Persekutuan	Malaysia
42		Kaohsiung		Taiwan
43		New Taipei City		Taiwan
44		Taichung		Taiwan
45		Taipei		Taiwan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• The Alogliptin-Metformin Fixed Dose Combination (KAZANO) were approved in the United States (US) on 25 January 2013.

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01890122
• Other Study ID Numbers: SYR-322MET_303; U1111-1139-0497; NMRR-12-799-12754; CTR20130254; 1036022140
• First Posted: Jul 1, 2013
• Last Update Posted: Nov 28, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by Takeda: Drug therapy
• Additional relevant MeSH terms: Diabetes Mellitus; Metformin; Alogliptin

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 59 investigative sites in China, Malaysia, South Korea and Taiwan from 26 August 2013 to 05 October 2015.
Pre-assignment Detail	Participants with a diagnosis of type 2 diabetes mellitus were enrolled equally in 1 of 4 treatment groups, twice a day placebo, alogliptin 12.5 mg, metformin hydrochloride (HCl) 500 mg, or alogliptin 12.5 mg and metformin HCl 500 mg fixed dose combination (FDC).

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Period Title: Overall Study
STARTED	162	163	159	163
Treated	161	162	159	163
COMPLETED	135	126	146	104
NOT COMPLETED	27	37	13	59

Baseline Characteristics

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo	Total
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Total of all reporting groups
Overall Participants	162	163	159	163	647
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.6 (9.91)	55.4 (9.62)	53.4 (10.46)	52.2 (10.17)	53.6 (10.08)
Sex: Female, Male (Count of Participants)
Female	80 49.4%	65 39.9%	68 42.8%	68 41.7%	281 43.4%
Male	82 50.6%	98 60.1%	91 57.2%	95 58.3%	366 56.6%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaskan Native	0 0%	1 0.6%	0 0%	2 1.2%	3 0.5%
Asian	161 99.4%	162 99.4%	159 100%	161 98.8%	643 99.4%
Multiracial	1 0.6%	0 0%	0 0%	0 0%	1 0.2%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino (Yes)	0 0%	0 0%	1 0.6%	0 0%	1 0.2%
Hispanic or Latino (No)	162 100%	163 100%	158 99.4%	163 100%	646 99.8%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	163.8 (8.72)	165.0 (8.06)	164.3 (7.66)	164.2 (9.19)	164.3 (8.42)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	70.79 (12.357)	71.21 (11.669)	70.73 (11.489)	71.79 (13.949)	71.13 (12.388)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.30 (3.566)	26.16 (3.923)	26.16 (3.508)	26.56 (4.218)	26.30 (3.811)
Smoking Classification (participants) [Number]
Has Never Smoked	125 77.2%	112 68.7%	113 71.1%	112 68.7%	462 71.4%
Is a Current Smoker	27 16.7%	35 21.5%	38 23.9%	36 22.1%	136 21%
Is an Ex-smoker	10 6.2%	16 9.8%	8 5%	15 9.2%	49 7.6%
Female Reproductive Status (participants) [Number]
Postmenopausal	47 29%	45 27.6%	37 23.3%	45 27.6%	174 26.9%
Surgically Sterile	8 4.9%	8 4.9%	10 6.3%	5 3.1%	31 4.8%
Female of Childbearing Potential	25 15.4%	12 7.4%	21 13.2%	18 11%	76 11.7%
Not Applicable (Participant is Male)	82 50.6%	98 60.1%	91 57.2%	95 58.3%	366 56.6%
Region of Enrollment (participants) [Number]
China	129 79.6%	129 79.1%	128 80.5%	130 79.8%	516 79.8%
Korea, Republic of	9 5.6%	10 6.1%	10 6.3%	10 6.1%	39 6%
Malaysia	19 11.7%	19 11.7%	18 11.3%	19 11.7%	75 11.6%
Taiwan, Province of China	5 3.1%	5 3.1%	3 1.9%	4 2.5%	17 2.6%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26 (or Early Termination)
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 early termination relative to baseline. Negative change indicates better glycemic control.
Time Frame	Baseline and Week 26 (or Early termination)

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. Last observation carried forward (LOCF) imputation was utilized.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	160	160	158	157
Mean (Standard Deviation) [percentage of glycosylated hemoglobin]	-0.32 (1.067)	-1.23 (0.877)	-1.06 (0.970)	-1.72 (1.024)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metformin HCl 500 mg, Alogliptin 12.5 mg + Metformin HCl 500 mg FDC
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	An analysis of covariance (ANCOVA) model was used with treatment and country as fixed effects, and Baseline HbA1c as a continuous covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -0.700 to -0.278
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.107
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 mg, Alogliptin 12.5 mg + Metformin HCl 500 mg FDC
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	An ANCOVA model was used with treatment and country as fixed effects, and Baseline HbA1c as a continuous covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.68
	Confidence Interval	(2-Sided) 95%; -0.889 to -0.467
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.108
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in HbA1c at Weeks 4, 8, 12, 16 and 20
Description	The change in the value of HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Weeks 4, 8, 12, 16 and 20 relative to baseline. Negative change indicates better glycemic control.
Time Frame	Baseline and Weeks 4, 8, 12, 16 and 20

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized. "n" in the category is the number of participants with data available at the given time-point.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	161	162	158	161
Week 4 (n=157,156,154,156)	-0.57 (0.483)	-0.41 (0.570)	-0.80 (0.489)	-0.18 (0.503)
Week 8 (n=160,160,158,157)	-0.90 (0.682)	-0.78 (0.756)	-1.29 (0.732)	-0.29 (0.738)
Week 12 (n=160,160,158,157)	-1.06 (0.793)	-1.01 (0.839)	-1.57 (0.873)	-0.27 (0.895)
Week 16 (n=160,160,158,157)	-1.18 (0.816)	-1.06 (0.900)	-1.71 (0.937)	-0.33 (0.957)
Week 20 (n=160.160,158,157)	-1.24 (0.852)	-1.11 (0.925)	-1.74 (0.969)	-0.33 (1.006)

3. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, 16, 20 and 26
Description	The change between the FPG value collected at Weeks 4, 8, 12, 16, 20 and 26 relative to baseline. Negative change indicates better glycemic control.
Time Frame	Baseline and Weeks 4, 8, 12, 16, 20 and 26

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized. "n" in the category is the number of participants with data available at the given time-point.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	161	162	158	161
Week 4 (n=157,154,155,156)	-1.42 (1.344)	-1.01 (1.794)	-2.01 (2.157)	0.02 (1.532)
Week 8 (n=160,158,158,157)	-1.50 (1.571)	-1.17 (1.788)	-2.13 (1.808)	-0.08 (1.682)
Week 12 (n=160,158,158,157)	-1.48 (1.527)	-1.33 (1.938)	-2.14 (1.779)	-0.08 (2.112)
Week 16 (n=160,158,158,157)	-1.62 (1.599)	-1.25 (2.148)	-2.17 (1.923)	-0.07 (2.020)
Week 20 (n=160,158,158,157)	-1.57 (1.634)	-1.19 (2.248)	-2.26 (1.995)	-0.12 (2.092)
Week 26 (n=160,158,158,157)	-1.45 (1.674)	-1.06 (2.307)	-2.06 (2.274)	-0.04 (2.060)

4. Secondary Outcome

Title	Time to Hyperglycemic Rescue Event
Description	Rescue is defined as meeting one of the following criteria, confirmed by a second sample drawn within 7 days of first sample: After >1 week of treatment but prior to Week 4 visit: A single FPG ≥275 mg/dL (≥15.27 mmol/L); From the Week 4 but prior to the Week 8 visit: A single FPG ≥250 mg/dL (≥13.88 mmol/L); From the Week 8 visit but prior to the Week 12 visit: A single FPG ≥225 mg/dL (≥12.49 mmol/L); From the Week 12 visit through the end-of-treatment visit (week 26): HbA1c ≥8.5% and ≤0.5% reduction in HbA1c from baseline. Time to hyperglycemic rescue was censored if the participant did not experience a hyperglycemic rescue event.
Time Frame	From the date of randomization through Week 26

Outcome Measure Data

Analysis Population Description

Randomized set consisted of all enrolled participants who were randomized.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	162	162	159	163
Median (Inter-Quartile Range) [days]	NA	NA	NA	NA

5. Secondary Outcome

Title	Percentage of Participants Requiring Hyperglycemic Rescue
Description	Rescue is defined as meeting one of the following criteria, confirmed by a second sample drawn within 7 days of first sample: After >1 week of treatment but prior to Week 4 visit: A single FPG ≥275 mg/dL (≥15.27 mmol/L); From the Week 4 but prior to the Week 8 visit: A single FPG ≥250 mg/dL (≥13.88 mmol/L); From the Week 8 visit but prior to the Week 12 visit: A single FPG ≥225 mg/dL (≥12.49 mmol/L); From the Week 12 visit through the end-of-treatment visit (week 26): HbA1c ≥8.5% and ≤0.5% reduction in HbA1c from baseline.
Time Frame	Baseline up to Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	161	162	158	161
Number [percentage of participants]	8.7 5.4%	14.8 9.1%	4.4 2.8%	25.5 15.6%

6. Secondary Outcome

Title	Percentage of Participants With Marked Hyperglycemia
Description	Marked hyperglycemia is defined as FPG level ≥200 mg/dL (11.1 mmol/L).
Time Frame	Baseline up to Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	161	162	158	161
Number [percentage of participants]	8.8 5.4%	12.7 7.8%	5.7 3.6%	15.9 9.8%

7. Secondary Outcome

Title	Change From Baseline in Body Weight at Weeks 12 and 26
Description	Change in participant's body weight at Weeks 12 and 26 relative to baseline.
Time Frame	Baseline and Weeks 12 and 26

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized. "n" in the category is the number of participants with data available at the given time-point.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	161	162	158	158
Week 12 (n=153,151,149,145)	-0.71 (1.735)	-0.19 (1.696)	-0.14 (1.730)	-0.32 (1.837)
Week 26 (n=156,156,156,152)	-0.93 (2.240)	-0.22 (2.291)	-0.57 (2.336)	-0.33 (2.220)

8. Secondary Outcome

Title	Percentage of Participants With Glycosylated Hemoglobin ≤6.5%
Description	Clinical response at Week 26 will be assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) ≤6.5%.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	161	162	158	161
Number [percentage of participants]	27.3 16.9%	21.6 13.3%	55.1 34.7%	11.8 7.2%

9. Secondary Outcome

Title	Percentage of Participants With Glycosylated Hemoglobin ≤7.0%
Description	Clinical response at Week 26 will be assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) ≤7%.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	161	162	158	161
Number [percentage of participants]	55.9 34.5%	44.4 27.2%	77.2 48.6%	30.4 18.7%

10. Secondary Outcome

Title	Percentage of Participants With Glycosylated Hemoglobin ≤7.5%
Description	Clinical response at Week 26 will be assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) ≤7.5%.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	161	162	158	161
Number [percentage of participants]	73.3 45.2%	60.5 37.1%	84.8 53.3%	46.0 28.2%

11. Secondary Outcome

Title	Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥0.5%
Description	Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥0.5%.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	161	162	158	161
Number [percentage of participants]	81.4 50.2%	74.1 45.5%	89.2 56.1%	42.9 26.3%

12. Secondary Outcome

Title	Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.0%
Description	Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥1.0%.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	161	162	158	161
Number [percentage of participants]	63.4 39.1%	53.7 32.9%	83.5 52.5%	25.5 15.6%

13. Secondary Outcome

Title	Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥1.5%
Description	Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥1.5%.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	161	162	158	161
Number [percentage of participants]	37.3 23%	36.4 22.3%	62.0 39%	14.9 9.1%

14. Secondary Outcome

Title	Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥2.0%
Description	Clinical response at Week 26 will be assessed by the percentage of participants with a decrease from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) of ≥2.0%.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all randomized participants in the safety set (participants who received at least 1 dose of study drug) who had baseline and at least 1 post baseline assessment. LOCF imputation was utilized.

Arm/Group Title	Metformin HCl 500 mg	Alogliptin 12.5 mg	Alogliptin 12.5 mg + Metformin HCl 500 mg FDC	Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.	Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.	Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
Measure Participants	161	162	158	161
Number [percentage of participants]	17.4 10.7%	17.3 10.6%	34.8 21.9%	6.2 3.8%

Adverse Events

Time Frame	Week 1 up to Week 28
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. Safety set, all participants who took at least 1 dose of double-blind study drug.
Arm/Group Title	Metformin HCl 500 mg		Alogliptin 12.5 mg		Alogliptin 12.5 mg + Metformin HCl 500 mg FDC		Placebo
Arm/Group Description	Metformin hydrochloride (HCl) 500 mg, capsules, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; alogliptin and metformin HCl fixed dose combination (FDC) placebo-matching tablets, orally, twice a day for up to 26 weeks.		Alogliptin 12.5 mg, tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day; alogliptin and metformin HCl FDC placebo-matching tablets, orally, twice a day for up to 26 weeks.		Alogliptin 12.5 mg and metformin HCl 500 mg FDC, tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.		Alogliptin and metformin FDC placebo-matching tablets, orally, twice a day; alogliptin placebo-matching tablets, orally, twice a day; metformin placebo-matching capsules, orally, twice a day for up to 26 weeks.
All Cause Mortality
	Metformin HCl 500 mg		Alogliptin 12.5 mg		Alogliptin 12.5 mg + Metformin HCl 500 mg FDC		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Metformin HCl 500 mg		Alogliptin 12.5 mg		Alogliptin 12.5 mg + Metformin HCl 500 mg FDC		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/161 (3.1%)		4/162 (2.5%)		4/158 (2.5%)		5/161 (3.1%)
Cardiac disorders
Coronary artery disease	0/161 (0%)		1/162 (0.6%)		0/158 (0%)		0/161 (0%)
Angina unstable	0/161 (0%)		1/162 (0.6%)		1/158 (0.6%)		0/161 (0%)
Angina pectoris	0/161 (0%)		0/162 (0%)		0/158 (0%)		1/161 (0.6%)
Prinzmetal angina	0/161 (0%)		0/162 (0%)		1/158 (0.6%)		0/161 (0%)
Supraventricular tachycardia	1/161 (0.6%)		0/162 (0%)		0/158 (0%)		0/161 (0%)
Ear and labyrinth disorders
Vertigo	1/161 (0.6%)		0/162 (0%)		0/158 (0%)		0/161 (0%)
Gastrointestinal disorders
Umbilical hernia	0/161 (0%)		0/162 (0%)		1/158 (0.6%)		0/161 (0%)
General disorders
Pyrexia	0/161 (0%)		1/162 (0.6%)		0/158 (0%)		0/161 (0%)
Chest discomfort	1/161 (0.6%)		0/162 (0%)		0/158 (0%)		0/161 (0%)
Infections and infestations
Gastroenteritis	1/161 (0.6%)		0/162 (0%)		0/158 (0%)		1/161 (0.6%)
Lung infection	0/161 (0%)		1/162 (0.6%)		0/158 (0%)		0/161 (0%)
Pneumonia	0/161 (0%)		0/162 (0%)		0/158 (0%)		1/161 (0.6%)
Erysipelas	0/161 (0%)		1/162 (0.6%)		0/158 (0%)		0/161 (0%)
Injury, poisoning and procedural complications
Muscle strain	0/161 (0%)		0/162 (0%)		0/158 (0%)		1/161 (0.6%)
Road traffic accident	0/161 (0%)		0/162 (0%)		1/158 (0.6%)		0/161 (0%)
Traumatic intracranial haemorrhage	0/161 (0%)		0/162 (0%)		0/158 (0%)		1/161 (0.6%)
Musculoskeletal and connective tissue disorders
Bone cyst	0/161 (0%)		0/162 (0%)		1/158 (0.6%)		0/161 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm	1/161 (0.6%)		0/162 (0%)		0/158 (0%)		0/161 (0%)
Other (Not Including Serious) Adverse Events
	Metformin HCl 500 mg		Alogliptin 12.5 mg		Alogliptin 12.5 mg + Metformin HCl 500 mg FDC		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/161 (20.5%)		26/162 (16%)		25/158 (15.8%)		35/161 (21.7%)
Gastrointestinal disorders
Diarrhoea	5/161 (3.1%)		4/162 (2.5%)		1/158 (0.6%)		4/161 (2.5%)
Infections and infestations
Upper respiratory tract infection	11/161 (6.8%)		8/162 (4.9%)		8/158 (5.1%)		9/161 (5.6%)
Nasopharyngitis	6/161 (3.7%)		3/162 (1.9%)		2/158 (1.3%)		6/161 (3.7%)
Investigations
Protein urine present	5/161 (3.1%)		2/162 (1.2%)		7/158 (4.4%)		6/161 (3.7%)
Metabolism and nutrition disorders
Hyperlipidaemia	6/161 (3.7%)		9/162 (5.6%)		7/158 (4.4%)		10/161 (6.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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