Comparative Study to Evaluate Efficacy and Safety When Metformin Hydrochloride 500 mg Once Daily is Added on to SYR-322 25 mg in Type 2 Diabetic Patients With Inadequate Glycemic Control Despite Treatment With SYR-322 25 mg in Addition to Diet and Exercise Therapy

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02068443
• Collaborator: (none)
• Enrollment: 374
• Locations: 27
• Arms: 3
• Duration (Months): 12
• Patients Per Site: 13.9
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the efficacy and safety of 24-week treatment with metformin hydrochloride 500 mg once daily added on to alogliptin (SYR-322) 25 mg in type 2 diabetic patients with inadequate glycemic control despite treatment with alogliptin 25 mg in addition to diet and exercise therapy.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Alogliptin; Drug: Metformin hydrochloride; Drug: Metformin hydrochloride Placebo	Phase 3

Detailed Description

The drugs being tested in this study are called alogliptin and metformin hydrochloride. Alogliptin in combination with metformin hydrochloride was being tested to treat people who have Type 2 diabetes mellitus (T2DM) with inadequate glycemic control despite treatment with alogliptin in addition to diet and exercise. This study looked at the efficacy and safety of alogliptin 25 mg once daily (QD) + metformin hydrochloride 500 mg QD compared to alogliptin 25 mg QD + metformin hydrochloride 250 mg twice daily (BID) and alogliptin 25 mg QD administered alone.

The study enrolled 374 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need):

• Alogliptin 25 mg QD + metformin hydrochloride 500 mg QD

• Alogliptin 25 mg QD + metformin hydrochloride 250 mg BID

• Alogliptin 25 mg QD

This multi-center trial was conducted in Japan. The overall time to participate in this study was 36 weeks (12-week screening period and 24-week treatment period). Participants made multiple visits to the clinic including a final visit 24 weeks after the start of study medication.

Study Design

• Study Type: Interventional
• Actual Enrollment: 374 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Multicenter, Randomized, Double-blind, Parallel-group, Comparative Study When Metformin Hydrochloride 500 mg is Added on to SYR-322 25 mg in Type 2 Diabetic Patients
• Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Alogliptin Alone Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Drug: Alogliptin; Alogliptin tablets; Other Names: SYR-322 Nesina® ; Drug: Metformin hydrochloride Placebo; Metformin hydrochloride placebo-matching tablets
Experimental: Alogliptin + Metformin Hydrochloride QD Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, once, daily, after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Drug: Alogliptin; Alogliptin tablets; Other Names: SYR-322 Nesina® ; Drug: Metformin hydrochloride; Metformin hydrochloride tablets; Other Names: Glycoran® ; Drug: Metformin hydrochloride Placebo; Metformin hydrochloride placebo-matching tablets
Active Comparator: Alogliptin + Metformin Hydrochloride BID Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.	Drug: Alogliptin; Alogliptin tablets; Other Names: SYR-322 Nesina® ; Drug: Metformin hydrochloride; Metformin hydrochloride tablets; Other Names: Glycoran® ; Drug: Metformin hydrochloride Placebo; Metformin hydrochloride placebo-matching tablets

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) National Glycohemoglobin Standardization Program (NGSP) at the End of Treatment (EOT) Period [Baseline and End of Treatment (EOT) (Up to Week 24)]

   The change in the value of HbA1c (NGSP) (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at End of Treatment Period relative to Baseline. A negative change from Baseline indicates improvement. An Analysis of Covariate (ANCOVA) model with change from Baseline as a dependent variable and Baseline and treatment as independent variables was used for main analyses.

Secondary Outcome Measures

1. Change From Baseline in HbA1c (NGSP) [Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 and EOT (Up to Week 24)]

   The change in the value of HbA1c (NGSP) (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Weeks 2, 4, 8, 12, 16, 20, 24, and EOT relative to Baseline. A negative change from Baseline indicates improvement.

2. HbA1c (NGSP) [Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 and EOT (Up to Week 24)]

   The value of HbA1c (NGSP) (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, and EOT.

3. Percentage of Participants Achieving Target HbA1c (NGSP) Levels at the EOT Period [Baseline and EOT (Up to Week 24)]

   HbA1c (NGSP) is the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound. The percentage of participants with HbA1c levels of ≥6.0, ≥7.0 and ≥8.0 at the end of Screening (Baseline) with change to target values <6.0, <7.0 and <8.0 respectively at EOT.

4. Change From Baseline in Fasting Blood Glucose [Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 and EOT (Up to Week 24)]

   The change in the value of the fasting plasma glucose collected at Weeks 2, 4, 8, 12, 16, 20 and 24 relative to Baseline. A negative change from Baseline indicates improvement.

5. Fasting Blood Glucose [Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 and EOT (Up to Week 24)]

   The value of the fasting plasma glucose collected at Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 and EOT.

6. Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) [24 Weeks]

   An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

7. Percentage of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis [24 Weeks]

   The percentage of participants with any clinically relevant safety laboratory changes (chemistry, hematology and urinalysis) collected throughout study and recorded as AEs.

8. Percentage of Participants With TEAEs Related to Vital Signs [24 Weeks]

   Vital signs included sitting systolic and diastolic blood pressures (mmHg) (measured after resting for ≥ 5 minutes) and pulse rate (beats per minute [bpm]).

9. Number of Participants Who Had Clinically Relevant Changes in 12-Lead Electrocardiogram (ECG) Findings [Baseline and Weeks 12 and 24]

   Number of participants who had ECG findings changed from "normal" or "abnormal but not clinically relevant" at Baseline to "abnormal and clinically relevant".

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 74 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Has a diagnosis of type 2 diabetes mellitus.

2. Has a hemoglobin A1c (HbA1c) (National glycohemoglobin standardization program [NGSP]) of ≥6.9% to <10.5% at 8 weeks after the start of the screening period (Week -4).

3. Has an HbA1c (NGSP) difference between 4 weeks after the start of the screening period (Week -8) and 8 weeks after the start of the screening period (Week -4) being within 10.0% (rounded off to the first decimal place) of the value at 4 weeks after the start of the screening period (Week -8).

4. Has been on a certain diet therapy and exercise therapy (if any) during the screening period.

5. Has been receiving alogliptin on a stable dose and regimen (after breakfast, 25 mg/day) during the screening period.

6. In the opinion of investigator or subinvestigator, the participant is considered appropriate to receive a biguanide as an add-on to alogliptin, at the end of the screening period (Week 0).

7. In the opinion of investigator or subinvestigator, the participant is unlikely to require changes in the dose of antihypertensive agents (including discontinuation and suspension) or an additional antihypertensive agent during the study.

8. Is a male and female aged ≥20 years to <75 years. Participants aged ≥65 years to <75 years need to be considered eligible for the enrollment by the investigator or subinvestigator at the end of the screening period (Week 0) taking into consideration the cardiovascular disorders pulmonary function disorders, renal function, hepatic function, etc.

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

10. Is treated in outpatient settings during the screening period.

11. In the opinion of the investigator or subinvestigator, the participant is capable of understanding and complying with protocol requirements.

12. Signs and dates a written, informed consent form prior to the initiation of any study procedures.

Exclusion Criteria:

1. Has received other antidiabetic drugs than alogliptin (including insulin preparations and glucagon-like peptidase-1 [GLP-1] analog preparations) during the screening period.

2. Has clinical manifestations of hepatic impairment.

3. Has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 × upper limit of normal during the screening period.

4. Has clinical manifestations of renal impairment, including mild impairment.

5. Has a history of lactic acidosis.

6. Has any cardiovascular disease including shock, heart failure, myocardial infarction and pulmonary embolism, any serious pulmonary function disorder, or any other condition predisposing him/her to hypoxemia.

7. Has dehydration or gastrointestinal dysfunction such as diarrhea or vomiting, which may cause dehydrated state.

8. Has malnutrition, starved state, hyposthenia, pituitary gland dysfunction or adrenal insufficiency.

9. Has any serious cardiac disease, any serious cerebrovascular disorder, or any serious pancreatic or hematological disease (eg, the participant requiring inpatient treatment or having been hospitalized for treatment within 24 weeks prior to the start of the screening period).

10. In the opinion of the investigator or subinvestigator, the participant has clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes during the screening period.

11. Has a systolic blood pressure ≥ 180 mmHg or a diastolic blood pressure ≥ 110 mmHg during the screening period.

12. Has a condition requiring insulin for blood glucose control (eg, severe ketosis, diabetic coma or precoma, type 1 diabetes, severe infection, pre- or post-operative condition, or serious trauma).

13. Has any malignancy.

14. Has a history of hypersensitivity or allergies to dipeptidyl-peptidase-4 (DPP-4) inhibitors or biguanides.

15. Is a habitual drinker consuming more than 100 mL of alcohol on average daily.

16. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol dependence.

17. Requires an excluded medication or a prohibited matter during the study.

18. Has received combination therapy of alogliptin benzoate and metformin hydrochloride in a previous clinical study or as a therapeutic agent.

19. Has received any investigational compound within 12 weeks prior to the start of the screening period (Week -12).

20. Is a participant in another clinical study at the time of signing informed consent.

21. If female, the participant is pregnant or lactating; intending to become pregnant between the time of signing informed consent and the end of the study; or intending to donate ova during such period.

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

23. Is considered ineligible for the study for any other reason by the investigator or subinvestigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Nagoya-shi	Aichi	Japan
2		Chiba-shi	Chiba	Japan
3		Fukuoka-shi	Fukuoka	Japan
4		Kitakyushu-shi	Fukuoka	Japan
5		Kurume-shi	Fukuoka	Japan
6		Aki-gun	Hiroshima	Japan
7		Hiroshima-shi	Hiroshima	Japan
8		Koga-shi	Ibaraki	Japan
9		Mito-shi	Ibaraki	Japan
10		Tushiura-shi	Ibaraki	Japan
11		Ushiku-shi	Ibaraki	Japan
12		Kanazawa-shi	Ishikawa	Japan
13		Takamatsu-chi	Kagawa	Japan
14		Sendai-shi	Miyagi	Japan
15		Ohita-shi	Ohita	Japan
16		Okinawa-shi	Okinawa	Japan
17		Shimajiri-gun	Okinawa	Japan
18		Kashiwara-shi	Osaka	Japan
19		Osaka-shi	Osaka	Japan
20		Hiki-gun	Saitama	Japan
21		Oyama-shi	Tochigi	Japan
22		Shimotsuke-shi	Tochigi	Japan
23		Koutoh-ku	Tokyo	Japan
24		Meguro-ku	Tokyo	Japan
25		Sagae-shi	Yamagata	Japan
26		Yamagata-shi	Yamagata	Japan
27		Yamaguchi-shi	Yamaguchi	Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02068443
• Other Study ID Numbers: SYR-322-MET/CCT-001; JapicCTI-132377; U1111-1151-6515
• First Posted: Feb 21, 2014
• Last Update Posted: Jun 6, 2016
• Last Verified: Feb 1, 2016

• Keywords provided by Takeda: Drug therapy
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Metformin; Alogliptin

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 34 investigative sites in Japan from 06 February 2014 (first patient to sign the informed consent form) to 28 February 2015.
Pre-assignment Detail	Participants with a diagnosis of Type 2 Diabetes Mellitus were enrolled equally in a 2:2:1 ratio to 1 of 3 treatment groups: alogliptin in combination with 500 mg total dose metformin hydrochloride administered either once a day (QD) or twice a day (BID) and alogliptin alone.

Arm/Group Title	Alogliptin Alone	Alogliptin + Metformin Hydrochloride QD	Alogliptin + Metformin Hydrochloride BID
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.
Period Title: Overall Study
STARTED	71	152	151
COMPLETED	64	146	148
NOT COMPLETED	7	6	3

Baseline Characteristics

Arm/Group Title	Alogliptin Alone	Alogliptin + Metformin Hydrochloride QD	Alogliptin + Metformin Hydrochloride BID	Total
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.	Total of all reporting groups
Overall Participants	71	152	151	374
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.2 (10.07)	56.9 (8.79)	57.6 (9.72)	57.2 (9.40)
Age, Customized (participants) [Number]
< 65 years	52 73.2%	119 78.3%	109 72.2%	280 74.9%
≥ 65 years	19 26.8%	33 21.7%	42 27.8%	94 25.1%
Sex: Female, Male (Count of Participants)
Female	19 26.8%	42 27.6%	45 29.8%	106 28.3%
Male	52 73.2%	110 72.4%	106 70.2%	268 71.7%
Region of Enrollment (participants) [Number]
Japan	71 100%	152 100%	151 100%	374 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	165.3 (8.89)	164.6 (8.82)	164.6 (9.12)	164.8 (8.94)
Body Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	68.00 (13.702)	69.48 (13.074)	69.55 (14.927)	69.23 (13.943)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	24.72 (3.764)	25.61 (4.231)	25.52 (4.344)	25.41 (4.196)
Duration of Type 2 Diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.73 (4.666)	7.02 (5.257)	7.04 (5.380)	7.16 (5.195)
Estimated Glomerular Filtration Rate (eGFR) (mL/min/1.73 m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min/1.73 m^2]	88.2 (15.99)	91.0 (16.82)	87.9 (17.86)	89.2 (17.11)
Hemoglobin A1c (HbA1c) [National Glycohemoglobin Standardization Program (NGSP)] (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	7.77 (0.780)	7.82 (0.820)	7.89 (0.791)	7.84 (0.800)
Fasting Blood Glucose (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	162.4 (31.03)	164.7 (31.02)	165.9 (30.92)	164.7 (30.92)
Fasting Insulin (μU/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [μU/mL]	9.918 (6.8797)	9.464 (6.7691)	9.342 (6.0645)	9.501 (6.4990)
Fasting Glucagon (pg/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/mL]	91.7 (30.03)	86.8 (21.27)	89.3 (27.98)	88.8 (25.89)
Homeostasis Model Assessment of Insulin Resistance (HOMA-R) (unitless) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [unitless]	4.05 (3.238)	3.87 (2.869)	3.92 (2.820)	3.93 (2.916)
Homeostasis Model Assessment Beta Cell Index (HOMA-β) (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	38.64 (29.181)	36.05 (27.848)	34.27 (23.638)	35.82 (26.464)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) National Glycohemoglobin Standardization Program (NGSP) at the End of Treatment (EOT) Period
Description	The change in the value of HbA1c (NGSP) (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at End of Treatment Period relative to Baseline. A negative change from Baseline indicates improvement. An Analysis of Covariate (ANCOVA) model with change from Baseline as a dependent variable and Baseline and treatment as independent variables was used for main analyses.
Time Frame	Baseline and End of Treatment (EOT) (Up to Week 24)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Alogliptin Alone	Alogliptin + Metformin Hydrochloride QD	Alogliptin + Metformin Hydrochloride BID
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.
Measure Participants	71	152	151
Least Squares Mean (Standard Error) [percent]	0.16 (0.072)	-0.49 (0.049)	-0.60 (0.049)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin Alone, Alogliptin + Metformin Hydrochloride QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.65
	Confidence Interval	(2-Sided) 95%; -0.821 to -0.480
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.087
	Estimation Comments	Estimated Value was for the difference between Alogliptin + Metformin Hydrochloride QD and Alogliptin alone (Metformin QD - Alogliptin alone).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alogliptin + Metformin Hydrochloride QD, Alogliptin + Metformin Hydrochloride BID
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority of Alogliptin + Metformin Hydrochloride QD to Alogliptin + Metformin Hydrochloride BID.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.026 to 0.247
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.069
	Estimation Comments	Estimated Value was for the difference between Alogliptin + Metformin Hydrochloride QD and Alogliptin + Metformin Hydrochloride BID (Metformin QD - Metformin BID).

2. Secondary Outcome

Title	Change From Baseline in HbA1c (NGSP)
Description	The change in the value of HbA1c (NGSP) (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Weeks 2, 4, 8, 12, 16, 20, 24, and EOT relative to Baseline. A negative change from Baseline indicates improvement.
Time Frame	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 and EOT (Up to Week 24)

Outcome Measure Data

Analysis Population Description

FAS, all randomized participants who received at least 1 dose of study drug, with data available for analyses.

Arm/Group Title	Alogliptin Alone	Alogliptin + Metformin Hydrochloride QD	Alogliptin + Metformin Hydrochloride BID
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.
Measure Participants	71	152	151
Week 2 (n=71, 152, 151)	0.01 (0.197)	-0.14 (0.203)	-0.19 (0.212)
Week 4 (n=70, 150, 150)	0.01 (0.316)	-0.28 (0.279)	-0.35 (0.298)
Week 8 (n=68, 149, 149)	-0.01 (0.402)	-0.50 (0.408)	-0.60 (0.454)
Week 12 (n=67, 148, 148)	-0.02 (0.518)	-0.61 (0.530)	-0.75 (0.565)
Week 16 (n=66, 148, 147)	0.01 (0.543)	-0.64 (0.553)	-0.81 (0.602)
Week 20 (n=65, 146, 148)	0.11 (0.568)	-0.58 (0.585)	-0.71 (0.626)
Week 24 (n=64, 146, 148)	0.17 (0.628)	-0.49 (0.629)	-0.62 (0.659)
EOT (n=71, 152, 151)	0.17 (0.616)	-0.49 (0.620)	-0.62 (0.654)

3. Secondary Outcome

Title	HbA1c (NGSP)
Description	The value of HbA1c (NGSP) (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, and EOT.
Time Frame	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 and EOT (Up to Week 24)

Outcome Measure Data

Analysis Population Description

FAS, all randomized participants who received at least 1 dose of study drug, with data available for analyses.

Arm/Group Title	Alogliptin Alone	Alogliptin + Metformin Hydrochloride QD	Alogliptin + Metformin Hydrochloride BID
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.
Measure Participants	71	152	151
Baseline (n=71, 152, 151)	7.77 (0.780)	7.82 (0.820)	7.89 (0.791)
Week 2 (n=71, 152, 151)	7.78 (0.824)	7.67 (0.796)	7.70 (0.787)
Week 4 (n=70, 150, 150)	7.78 (0.913)	7.55 (0.773)	7.54 (0.735)
Week 8 (n=68, 149, 149)	7.72 (0.889)	7.32 (0.725)	7.28 (0.707)
Week 12 (n=67, 148, 148)	7.70 (0.987)	7.19 (0.721)	7.13 (0.706)
Week 16 (n=66, 148, 147)	7.70 (0.990)	7.16 (0.725)	7.08 (0.717)
Week 20 (n=65, 146, 148)	7.81 (1.023)	7.23 (0.749)	7.18 (0.780)
Week 24 (n=64, 146, 148)	7.86 (0.983)	7.32 (0.798)	7.27 (0.805)
EOT (n=71, 152, 151)	7.95 (1.018)	7.33 (0.819)	7.28 (0.804)

4. Secondary Outcome

Title	Percentage of Participants Achieving Target HbA1c (NGSP) Levels at the EOT Period
Description	HbA1c (NGSP) is the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound. The percentage of participants with HbA1c levels of ≥6.0, ≥7.0 and ≥8.0 at the end of Screening (Baseline) with change to target values <6.0, <7.0 and <8.0 respectively at EOT.
Time Frame	Baseline and EOT (Up to Week 24)

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Alogliptin Alone	Alogliptin + Metformin Hydrochloride QD	Alogliptin + Metformin Hydrochloride BID
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.
Measure Participants	71	152	151
≥6.0 at Baseline to <6.0 at EOT (n=71, 152, 151)	0.0 (0.197) 0%	0.7 (0.203) 0.5%	1.3 (0.212) 0.9%
≥7.0 at Baseline to <7.0 at EOT ( n=63, 137, 140)	4.8 (0.316) 6.8%	35.0 (0.279) 23%	34.3 (0.298) 22.7%
≥8.0 at Baseline to <8.0 at EOT (n=26, 59, 64)	23.1 (0.402) 32.5%	47.5 (0.408) 31.3%	60.9 (0.454) 40.3%

5. Secondary Outcome

Title	Change From Baseline in Fasting Blood Glucose
Description	The change in the value of the fasting plasma glucose collected at Weeks 2, 4, 8, 12, 16, 20 and 24 relative to Baseline. A negative change from Baseline indicates improvement.
Time Frame	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 and EOT (Up to Week 24)

Outcome Measure Data

Analysis Population Description

FAS, all randomized participants who received at least 1 dose of study drug, with data available for analyses.

Arm/Group Title	Alogliptin Alone	Alogliptin + Metformin Hydrochloride QD	Alogliptin + Metformin Hydrochloride BID
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.
Measure Participants	71	152	151
Week 2 (n=71, 152, 151)	0.4 (16.62)	-16.6 (18.99)	-23.7 (20.50)
Week 4 (n=70, 150, 150)	-0.9 (26.32)	-16.4 (20.79)	-25.2 (20.73)
Week 8 (n=68, 149, 149)	-2.1 (23.30)	-18.4 (20.90)	-23.4 (24.13)
Week 12 (n=67, 148, 148)	1.5 (20.42)	-15.2 (23.83)	-22.9 (24.36)
Week 16 (n=66, 148, 148)	0.4 (22.63)	-13.0 (24.70)	-22.6 (25.50)
Week 20 (n=65, 146, 148)	6.6 (23.87)	-11.3 (23.34)	-17.6 (25.25)
Week 24 (n=64, 146, 148)	8.0 (21.85)	-7.2 (26.53)	-18.2 (25.28)
EOT (n=71, 152, 151)	7.4 (26.89)	-7.6 (26.41)	-18.2 (25.41)

6. Secondary Outcome

Title	Fasting Blood Glucose
Description	The value of the fasting plasma glucose collected at Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 and EOT.
Time Frame	Baseline and Weeks 2, 4, 8, 12, 16, 20, 24 and EOT (Up to Week 24)

Outcome Measure Data

Analysis Population Description

FAS, all randomized participants who received at least 1 dose of study drug, with data available for analyses.

Arm/Group Title	Alogliptin Alone	Alogliptin + Metformin Hydrochloride QD	Alogliptin + Metformin Hydrochloride BID
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.
Measure Participants	71	152	151
Baseline (n=71, 152, 151)	162.4 (31.03)	164.7 (31.02)	165.9 (30.92)
Week 2 (n=71, 152, 151)	162.8 (33.42)	148.1 (26.70)	142.3 (25.24)
Week 4 (n=70, 150, 150)	161.4 (37.17)	148.7 (27.56)	140.7 (23.74)
Week 8 (n=68, 149, 149)	158.9 (33.15)	146.5 (25.21)	142.0 (25.35)
Week 12 (n=67, 148, 148)	161.1 (33.43)	149.2 (30.70)	142.5 (27.85)
Week 16 (n=66, 148, 148)	158.5 (29.71)	151.4 (32.52)	142.9 (26.16)
Week 20 (n=65, 146, 148)	164.6 (31.64)	153.2 (30.92)	147.8 (28.21)
Week 24 (n=64, 146, 148)	165.9 (31.19)	157.4 (33.21)	147.3 (26.85)
EOT (n=71, 152, 151)	169.8 (36.03)	157.1 (32.82)	147.7 (27.20)

7. Secondary Outcome

Title	Percentage of Participants With Treatment-Emergent Adverse Events (TEAE)
Description	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	24 Weeks

Outcome Measure Data

Analysis Population Description

Safety Analysis Set included all participants who received at least 1 dose of study drug.

Arm/Group Title	Alogliptin Alone	Alogliptin + Metformin Hydrochloride QD	Alogliptin + Metformin Hydrochloride BID
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.
Measure Participants	71	152	151
Number [percentage of participants]	57.7 81.3%	50.7 33.4%	52.3 34.6%

8. Secondary Outcome

Title	Percentage of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis
Description	The percentage of participants with any clinically relevant safety laboratory changes (chemistry, hematology and urinalysis) collected throughout study and recorded as AEs.
Time Frame	24 Weeks

Outcome Measure Data

Analysis Population Description

Safety Analysis Set included all participants who received at least 1 dose of study drug.

Arm/Group Title	Alogliptin Alone	Alogliptin + Metformin Hydrochloride QD	Alogliptin + Metformin Hydrochloride BID
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.
Measure Participants	71	152	151
Blood Creatine Phosphokinase increased	0 0%	2.0 1.3%	0.7 0.5%
Blood Lactic Acid increased	0 0%	1.3 0.9%	0 0%
Amylase increased	0 0%	0 0%	2.0 1.3%
Lipase increased	0 0%	0 0%	2.0 1.3%
Blood Albumin decreased	0 0%	0 0%	0.7 0.5%
Gamma-glutamyltransferase increased	0 0%	0 0%	0.7 0.5%

9. Secondary Outcome

Title	Percentage of Participants With TEAEs Related to Vital Signs
Description	Vital signs included sitting systolic and diastolic blood pressures (mmHg) (measured after resting for ≥ 5 minutes) and pulse rate (beats per minute [bpm]).
Time Frame	24 Weeks

Outcome Measure Data

Analysis Population Description

Safety Analysis Set included all participants who received at least 1 dose of study drug.

Arm/Group Title	Alogliptin Alone	Alogliptin + Metformin Hydrochloride QD	Alogliptin + Metformin Hydrochloride BID
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.
Measure Participants	71	152	151
Hypertension	1.4 2%	0 0%	0 0%
Blood Pressure increased	0 0%	0 0%	0.7 0.5%

10. Secondary Outcome

Title	Number of Participants Who Had Clinically Relevant Changes in 12-Lead Electrocardiogram (ECG) Findings
Description	Number of participants who had ECG findings changed from "normal" or "abnormal but not clinically relevant" at Baseline to "abnormal and clinically relevant".
Time Frame	Baseline and Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

Safety Analysis Set, all participants who received at least 1 dose of study drug, with ECG values "normal" or "abnormal not clinically significant" at Baseline.

Arm/Group Title	Alogliptin Alone	Alogliptin + Metformin Hydrochloride QD	Alogliptin + Metformin Hydrochloride BID
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.
Measure Participants	71	151	151
Week 12	0 0%	0 0%	0 0%
Week 24	0 0%	0 0%	2 1.3%

Adverse Events

Time Frame	24 Weeks
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 Alone		Alogliptin + Metformin Hydrochloride QD		Alogliptin + Metformin Hydrochloride BID
Arm/Group Description	Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride placebo-matching, tablets, orally, 2 tablets after breakfast and 1 tablet after dinner for 24 weeks.		Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 500 mg QD (250 mg x 2 tablets, once daily), tablets, orally, QD (once daily), after breakfast and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after dinner for 24 weeks.		Alogliptin 25 mg, tablets, orally, once, daily, after breakfast and metformin hydrochloride 250 mg BID (twice daily), tablets, orally, 1 tablet after breakfast and 1 tablet after dinner and 1 metformin hydrochloride placebo-matching, tablet, orally, once, daily, after breakfast for 24 weeks.
All Cause Mortality
	Alogliptin Alone		Alogliptin + Metformin Hydrochloride QD		Alogliptin + Metformin Hydrochloride BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Alogliptin Alone		Alogliptin + Metformin Hydrochloride QD		Alogliptin + Metformin Hydrochloride BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/71 (1.4%)		3/152 (2%)		0/151 (0%)
Infections and infestations
Diverticulitis	1/71 (1.4%)		0/152 (0%)		0/151 (0%)
Injury, poisoning and procedural complications
Brain contusion	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Contusion	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Fall	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Fibula fracture	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Limb crushing injury	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Pulmonary contusion	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Rib fracture	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Road traffic accident	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Scapula fracture	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Spinal compression fracture	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Splenic injury	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Nervous system disorders
Subarachnoid haemorrhage	0/71 (0%)		1/152 (0.7%)		0/151 (0%)
Other (Not Including Serious) Adverse Events
	Alogliptin Alone		Alogliptin + Metformin Hydrochloride QD		Alogliptin + Metformin Hydrochloride BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/71 (21.1%)		25/152 (16.4%)		27/151 (17.9%)
Infections and infestations
Nasopharyngitis	8/71 (11.3%)		22/152 (14.5%)		19/151 (12.6%)
Pharyngitis	3/71 (4.2%)		3/152 (2%)		9/151 (6%)
Nervous system disorders
Hypoaesthesia	4/71 (5.6%)		1/152 (0.7%)		0/151 (0%)

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.