AM7D: Efficacy and Safety of Alogliptin Plus Metformin in Patients With Type 2 Diabetes

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01023581
• Collaborator: (none)
• Enrollment: 784
• Locations: 201
• Arms: 7
• Duration (Months): 19
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and effectiveness of alogliptin combined with metformin, once daily (QD) or twice daily (BID), in participants with Type 2 Diabetes.

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

Detailed Description

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

Metformin is the usual choice of first-line therapy for type 2 diabetes. Metformin targets insulin resistance in type 2 diabetes by inhibiting hepatic glucose production and stimulating glucose uptake in skeletal muscle and adipose tissue, which results in a long-term glucose-lowering effect.

Alogliptin is an inhibitor of the dipeptidyl peptidase IV enzyme. Dipeptidyl peptidase-4 enzyme is thought to be primarily responsible for the in vivo degradation of 2 peptide hormones released in response to nutrient ingestion, namely glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. Both peptides exert important effects on islet beta cells to stimulate glucose-dependent insulin secretion as well as regulating beta cell proliferation and cytoprotection. Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits gastric emptying, glucagon secretion, and food intake. Glucose-dependent insulinotropic peptide has been shown to enhance insulin secretion by direct interaction with a glucose-dependent insulinotropic peptide -specific receptor on islet beta cells. The glucose-lowering actions of glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, are preserved in patients with type 2 diabetes mellitus. It is expected that inhibition of dipeptidyl peptidase IV will improve glycemic (glucose) control in patients with type 2 diabetes.

Based on the potential, complimentary mechanisms of action of alogliptin and metformin, this study will compare the safety and efficacy of alogliptin and metformin (SYR-322MET) on improving glycemic control in patients with type 2 diabetes mellitus who are inadequately controlled by diet adjustment and exercise alone.

Participants taking part in this study will receive dietary and exercise coaching, and will monitor their own blood glucose concentrations with a home glucose monitor. Participants will also be required to maintain a hypoglycemic diary throughout the course of the study. Participation in this study is expected to last up to 34 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 784 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of Alogliptin Plus Metformin, Alogliptin Alone, or Metformin Alone in Subjects With Type 2 Diabetes
• Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Alogliptin placebo-matching tablets, orally, twice daily and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Drug: Alogliptin Placebo; Alogliptin placebo-matching tablets.; Drug: Metformin Placebo; Metformin placebo-matching capsules.
Experimental: Alogliptin 25 QD Alogliptin 25 mg, tablets, orally, once daily (QD) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322 ; Drug: Metformin Placebo; Metformin placebo-matching capsules.
Experimental: Alogliptin 12.5 BID Alogliptin 12.5 mg, tablets, orally, twice daily (BID) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322 ; Drug: Metformin Placebo; Metformin placebo-matching capsules.
Active Comparator: Metformin 500 BID Alogliptin placebo-matching tablets, orally, twice daily and Metformin 500 mg capsules, orally, twice daily for up to 26 weeks.	Drug: Metformin; Metformin capsules; Other Names: Glucophage Glucophage XR Riomet Fortamet Glumetza Obimet Dianben Diabex Diaformin ; Drug: Alogliptin Placebo; Alogliptin placebo-matching tablets.
Active Comparator: Metformin 1000 BID Alogliptin placebo-matching tablets, orally, twice daily and Metformin 1000 mg capsules, orally, twice daily for up to 26 weeks.	Drug: Metformin; Metformin capsules; Other Names: Glucophage Glucophage XR Riomet Fortamet Glumetza Obimet Dianben Diabex Diaformin ; Drug: Alogliptin Placebo; Alogliptin placebo-matching tablets.
Experimental: Alogliptin 12.5 BID + Metformin 500 BID Alogliptin 12.5mg, tablets, orally, twice daily and Metformin 500 mg, capsules, orally, twice daily for up to 26 weeks.	Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322 ; Drug: Metformin; Metformin capsules; Other Names: Glucophage Glucophage XR Riomet Fortamet Glumetza Obimet Dianben Diabex Diaformin
Experimental: Alogliptin 12.5 BID + Metformin 1000 BID Alogliptin 12.5 mg, tablets, orally, twice daily and Metformin 1000 mg, capsules, orally, twice daily for up to 26 weeks.	Drug: Alogliptin; Alogliptin tablets.; Other Names: SYR-322 ; Drug: Metformin; Metformin capsules; Other Names: Glucophage Glucophage XR Riomet Fortamet Glumetza Obimet Dianben Diabex Diaformin

Outcome Measures

Primary Outcome Measures

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

   The change from Baseline to Week 26 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound).

Secondary Outcome Measures

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

   The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) was assessed at Weeks 4, 8, 12, 16 and 20. Least squares means are from an analysis of covariance (ANCOVA) model with treatment and geographic region as fixed effects, and baseline HbA1c as a covariate.

2. Change From Baseline in Fasting Plasma Glucose Over Time [Baseline and Weeks 1, 2, 4, 8, 12, 16, 20 and 26.]

   The change from Baseline in fasting plasma glucose was assessed at Weeks 1, 2, 4, 8, 12, 16, 20 and 26. Least Squares Means were from an ANCOVA model with treatment and geographic region as fixed effects, and baseline fasting plasma glucose as a covariate.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Has historical diagnosis of Type 2 Diabetes Mellitus.

• Has been treated with diet and exercise for at least 2 months prior to Screening, and has a Glycosylated Hemoglobin concentration between 7.5% and 10.0%, inclusive at Screening.

• Has received less than 7 days of any antidiabetic medication within 2 months prior to Screening.

• Body mass index greater than or equal to 23 kg/m^{2 and less than or equal to 45 kg/m}2 (except for Asian or Asian-descendant subjects for whom the range is between 20 and 35 kg/ m^2, inclusive).

• Fasting C-peptide concentration greater than or equal to 0.8 ng/mL.

• Regularly using other, non-excluded, medications must be on a stable dose for at least the 4 weeks prior to Screening.

• Females of childbearing potential and males who are sexually active agree to routinely use adequate contraception from Screening throughout the duration of the study.

• Able and willing to monitor their own blood glucose concentrations with a home glucose monitor and complete patient diaries.

Exclusion Criteria:

• Hemoglobin less than 12 g/dL for males and less than 10 g/dL for females at Screening Visit.

• Has a history of any hemoglobinopathy that may affect determination of Glycosylated Hemoglobin.

• Has a history of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening.

• Has a history of treatment for diabetic gastric paresis, gastric banding, or gastric bypass surgery.

• Has a history of diabetic ketoacidosis or hyperosmolar non-ketotic coma.

• Has systolic blood pressure greater than or equal to 150 mmHg and /or diastolic pressure greater than or equal to 90 mmHg at Screening visit.

• Has New York Heart Association Class III to IV heart failure.

• Has a history of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within the 90 days prior to Screening.

• Has Alanine aminotransferase greater than 3 times the upper limit of normal at Screening.

• Has a history of alcohol or substance abuse with the 2 years prior to Screening.

• Serum creatinine greater than or equal to 1.5 mg/dL for males and greater than or equal to 1.4 mg/dL for females.

• Has history of cancer, other than squamous cell or basal cell carcinoma of the skin that has not been in full remission for at least 5 years prior to Screening.

• Has a history of infection with human immunodeficiency virus, hepatitis B virus or hepatitis C virus.

• Has any major illness or debility that in the investigator's opinion prohibits the subject from completing the study.

• Has received any investigational drug within the 90 days prior to Screening.

• Has a history of hypersensitivity or allergy to alogliptin, other DPP-4 inhibitors, metformin or related compounds.

• Has used oral or systematically injected glucocorticoids or weight loss drugs prior to 2 months to screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Dothan	Alabama	United States
2		Muscle Shoals	Alabama	United States
3		Pell City	Alabama	United States
4		Chandler	Arizona	United States
5		Mesa	Arizona	United States
6		Phoenix	Arizona	United States
7		Sierra Vista	Arizona	United States
8		Tempe	Arizona	United States
9		Little Rock	Arkansas	United States
10		Searcy	Arkansas	United States
11		Tempe	Arkansas	United States
12		Anaheim	California	United States
13		Buena Park	California	United States
14		Cathedral City	California	United States
15		National City	California	United States
16		Pismo Beach	California	United States
17		Roseville	California	United States
18		Santa Ana	California	United States
19		Colorado Springs	Colorado	United States
20		Boca Raton	Florida	United States
21		Bradenton	Florida	United States
22		Cutler Bay	Florida	United States
23		Hialeah	Florida	United States
24		Lauderdale Lakes	Florida	United States
25		Miami	Florida	United States
26		Ocala	Florida	United States
27		Opa Locka	Florida	United States
28		Orlando	Florida	United States
29		Panama City	Florida	United States
30		Pembroke Pines	Florida	United States
31		Atlanta	Georgia	United States
32		Blue Ridge	Georgia	United States
33		Decatur	Georgia	United States
34		Lawrenceville	Georgia	United States
35		Hayden Lake	Idaho	United States
36		Chicago	Illinois	United States
37		Melrose Park	Illinois	United States
38		La Porte	Indiana	United States
39		Mishawaka	Indiana	United States
40		Council Bluffs	Iowa	United States
41		Dubuque	Iowa	United States
42		Topeka	Kansas	United States
43		Lexington	Kentucky	United States
44		Louisville	Kentucky	United States
45		Marrero	Louisiana	United States
46		Oxon Hill	Maryland	United States
47		North Dartmouth	Massachusetts	United States
48		Dearborn	Michigan	United States
49		Flint	Michigan	United States
50		Kalamazoo	Michigan	United States
51		Picayune	Mississippi	United States
52		St. Louis	Missouri	United States
53		Omaha	Nebraska	United States
54		Henderson	Nevada	United States
55		Las Vegas	Nevada	United States
56		Brick	New Jersey	United States
57		Elizabeth	New Jersey	United States
58		North Massapequa	New York	United States
59		Asheville	North Carolina	United States
60		Charlotte	North Carolina	United States
61		Greensboro	North Carolina	United States
62		Mooresville	North Carolina	United States
63		Fargo	North Dakota	United States
64		Cincinnati	Ohio	United States
65		Cleveland	Ohio	United States
66		Gallipolis	Ohio	United States
67		Mason	Ohio	United States
68		Maumee	Ohio	United States
69		Norman	Oklahoma	United States
70		Oklahoma City	Oklahoma	United States
71		Tulsa	Oklahoma	United States
72		Altoona	Pennsylvania	United States
73		Bensalem	Pennsylvania	United States
74		Downingtown	Pennsylvania	United States
75		Fleetwood	Pennsylvania	United States
76		Perkasie	Pennsylvania	United States
77		Shippensburg	Pennsylvania	United States
78		Tipton	Pennsylvania	United States
79		Uniontown	Pennsylvania	United States
80		Columbia	South Carolina	United States
81		Greenville	South Carolina	United States
82		Murrells Inlet	South Carolina	United States
83		North Myrtle Beach	South Carolina	United States
84		Taylors	South Carolina	United States
85		Brentwood	Tennessee	United States
86		Bristol	Tennessee	United States
87		Crossville	Tennessee	United States
88		Johnson City	Tennessee	United States
89		McKenzie	Tennessee	United States
90		Spring Hill	Tennessee	United States
91		Carrollton	Texas	United States
92		Dallas	Texas	United States
93		Deer Park	Texas	United States
94		El Paso	Texas	United States
95		Houston	Texas	United States
96		Hurst	Texas	United States
97		Katy	Texas	United States
98		Odessa	Texas	United States
99		San Antonio	Texas	United States
100		Schertz	Texas	United States
101		Spring	Texas	United States
102		Sugarland	Texas	United States
103		Temple	Texas	United States
104		Bountiful	Utah	United States
105		Ogden	Utah	United States
106		Salt Lake City	Utah	United States
107		South Burlington	Vermont	United States
108		Petersburg	Virginia	United States
109		Milwaukee	Wisconsin	United States
110		Hradec Kralove		Czech Republic
111		Olomouc		Czech Republic
112		Ostrava		Czech Republic
113		Praha 10		Czech Republic
114		Zlin		Czech Republic
115		Znojmo		Czech Republic
116		Budaors		Hungary
117		Debrecen		Hungary
118		Gyongyos		Hungary
119		Gyor		Hungary
120		Gyula		Hungary
121		Komarom		Hungary
122		Szolnok		Hungary
123		Zalaegerszeg		Hungary
124		Haifa		Israel
125		Holon		Israel
126		Kfar Saba		Israel
127		Nahariya		Israel
128		Safed		Israel
129		Kaunas		Lithuania
130		Kedainiai		Lithuania
131		Klaipeda		Lithuania
132		Vilnius		Lithuania
133		Acapulco, Guerrero		Mexico
134		Cuernavaca		Mexico
135		Culiacan, Sinoloa		Mexico
136		Distrito Federal		Mexico
137		Durango, Durango		Mexico
138		Durango		Mexico
139		Guadalajara		Mexico
140		Mexico City, Mexico		Mexico
141		Mexico City		Mexico
142		Mexico, DF		Mexico
143		Monclova, Coahuila		Mexico
144		Monterrey, NL		Mexico
145		Monterrey		Mexico
146		Pachuca, Hidalgo		Mexico
147		Pachuca		Mexico
148		Saltillo		Mexico
149		Tijuana, Baja California		Mexico
150		Zapopan, Jalisco		Mexico
151		Bialystok		Poland
152		Bytom		Poland
153		Gniewkowo		Poland
154		Grodzisk Mazowiecki		Poland
155		Kamieniec Zabkowicki		Poland
156		Leczyca		Poland
157		Warszawa		Poland
158		Wroclaw		Poland
159		Caguas		Puerto Rico
160		Cidra		Puerto Rico
161		Ponce		Puerto Rico
162		Salinas		Puerto Rico
163		San Juan		Puerto Rico
164		Santurce		Puerto Rico
165		Trujilo Alto		Puerto Rico
166		Bacau		Romania
167		Baia Mare		Romania
168		Bucharest		Romania
169		Constanta		Romania
170		Iasi		Romania
171		Ploiesti		Romania
172		Arkhangelsk		Russian Federation
173		Irkutsk		Russian Federation
174		Kemerovo		Russian Federation
175		Moscow		Russian Federation
176		Perm		Russian Federation
177		St. Petersburg		Russian Federation
178		Ufa		Russian Federation
179		Banska Bystrica		Slovakia
180		Kosice		Slovakia
181		Lucenec		Slovakia
182		Nitra		Slovakia
183		Presov		Slovakia
184		Prievidza		Slovakia
185		Sahy		Slovakia
186		Zilina		Slovakia
187		Centurion	Gauteng	South Africa
188		Johannesburg	Gauteng	South Africa
189		Pretoria	Gauteng	South Africa
190		Durban	Kwazulu-Natal	South Africa
191		Cape Town	Western Cape	South Africa
192		Pretoria		South Africa
193		Dnipropetrovsk		Ukraine
194		Donetsk		Ukraine
195		Ivano-Frankivsk		Ukraine
196		Kharkiv		Ukraine
197		Kyiv		Ukraine
198		Lviv		Ukraine
199		Odesa		Ukraine
200		Vinnytsya		Ukraine
201		Zaporizhzhya		Ukraine

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Vice President, Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01023581
• Other Study ID Numbers: SYR-322MET_302; 2009-012652-24; U1111-1112-1912; DOH-27-0910-3155; CTRI/2010/091/000253
• First Posted: Dec 2, 2009
• Last Update Posted: Mar 26, 2013
• Last Verified: Feb 1, 2013

• Keywords provided by Takeda: Type 2 Diabetes mellitus; Non-insulin dependent diabetes mellitus; Drug Therapy; Hypoglycemia,; Hyperglycemia
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Alogliptin

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 198 investigative sites worldwide from 16 November 2009 to 30 June 2011.
Pre-assignment Detail	Participants with a diagnosis of type 2 diabetes and glycemia inadequately controlled on diet and exercise alone were randomly assigned with equal probability to 1 of 7 treatment groups, including placebo, alogliptin alone, metformin alone or a combination of alogliptin and metformin.

Arm/Group Title	Placebo	Alogliptin 25 QD	Alogliptin 12.5 BID	Metformin 500 BID	Metformin 1000 BID	Alogliptin 12.5 BID + Metformin 500 BID	Alogliptin 12.5 BID + Metformin 1000 BID
Arm/Group Description	Alogliptin placebo-matching tablets, orally, twice daily and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily (QD) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice daily (BID) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, twice daily and Metformin 500 mg capsules, orally, twice daily for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, twice daily and Metformin 1000 mg capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5mg, tablets, orally, twice daily and Metformin 500 mg, capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice daily and Metformin 1000 mg, capsules, orally, twice daily for up to 26 weeks.
Period Title: Overall Study
STARTED	109	112	113	114	111	111	114
Received Study Treatment	106	112	110	109	111	106	114
COMPLETED	74	89	71	94	95	92	94
NOT COMPLETED	35	23	42	20	16	19	20

Baseline Characteristics

Arm/Group Title	Placebo	Alogliptin 25 QD	Alogliptin 12.5 BID	Metformin 500 BID	Metformin 1000 BID	Alogliptin 12.5 BID + Metformin 500 BID	Alogliptin 12.5 BID + Metformin 1000 BID	Total
Arm/Group Description	Alogliptin placebo-matching tablets, orally, twice daily and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily (QD) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice daily (BID) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, twice daily and Metformin 500 mg capsules, orally, twice daily for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, twice daily and Metformin 1000 mg capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5mg, tablets, orally, twice daily and Metformin 500 mg, capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice daily and Metformin 1000 mg, capsules, orally, twice daily for up to 26 weeks.	Total of all reporting groups
Overall Participants	109	112	113	114	111	111	114	784
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.1 (9.60)	52.6 (9.38)	53.7 (9.70)	54.6 (10.20)	52.6 (11.30)	53.7 (11.59)	54.6 (10.42)	53.5 (10.33)
Age, Customized (participants) [Number]
<65 years	100 91.7%	103 92%	96 85%	95 83.3%	94 84.7%	91 82%	96 84.2%	675 86.1%
≥65 years	9 8.3%	9 8%	17 15%	19 16.7%	17 15.3%	20 18%	18 15.8%	109 13.9%
Sex: Female, Male (Count of Participants)
Female	54 49.5%	64 57.1%	50 44.2%	67 58.8%	60 54.1%	63 56.8%	52 45.6%	410 52.3%
Male	55 50.5%	48 42.9%	63 55.8%	47 41.2%	51 45.9%	48 43.2%	62 54.4%	374 47.7%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	45 41.3%	43 38.4%	43 38.1%	45 39.5%	42 37.8%	45 40.5%	39 34.2%	302 38.5%
Not Hispanic or Latino	64 58.7%	69 61.6%	70 61.9%	69 60.5%	69 62.2%	66 59.5%	75 65.8%	482 61.5%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	5 4.6%	8 7.1%	5 4.4%	3 2.6%	6 5.4%	9 8.1%	5 4.4%	41 5.2%
Asian	20 18.3%	17 15.2%	21 18.6%	19 16.7%	20 18%	20 18%	26 22.8%	143 18.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	1 0.9%	0 0%	0 0%	0 0%	0 0%	1 0.1%
Black or African American	8 7.3%	3 2.7%	3 2.7%	6 5.3%	6 5.4%	6 5.4%	5 4.4%	37 4.7%
White	76 69.7%	84 75%	83 73.5%	85 74.6%	79 71.2%	76 68.5%	78 68.4%	561 71.6%
Multiracial	0 0%	0 0%	0 0%	1 0.9%	0 0%	0 0%	0 0%	1 0.1%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	31.15 (5.269)	30.81 (5.219)	30.36 (5.159)	30.19 (4.842)	30.51 (5.043)	30.92 (5.353)	31.04 (5.375)	30.71 (5.173)
Diabetes Duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.25 (4.778)	3.65 (4.119)	3.97 (4.800)	3.78 (3.904)	4.08 (4.587)	4.13 (4.777)	4.22 (4.972)	4.01 (4.563)
Baseline HbA1c (participants) [Number]
≤8.5%	65 59.6%	67 59.8%	67 59.3%	67 58.8%	66 59.5%	66 59.5%	67 58.8%	465 59.3%
>8.5%	44 40.4%	45 40.2%	46 40.7%	47 41.2%	45 40.5%	45 40.5%	47 41.2%	319 40.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26
Description	The change from Baseline to Week 26 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound).
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Full analysis set (patients who took at least 1 dose of study medication) where baseline and at least 1 postbaseline assessment were available. Analysis includes only data collected on or after baseline and within 7 days after last dose of study medication or hyperglycemic rescue, whichever came first. Last observation carried forward was utilized.

Arm/Group Title	Placebo	Alogliptin 25 QD	Alogliptin 12.5 BID	Metformin 500 BID	Metformin 1000 BID	Alogliptin 12.5 BID + Metformin 500 BID	Alogliptin 12.5 BID + Metformin 1000 BID
Arm/Group Description	Alogliptin placebo-matching tablets, orally, twice daily and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily (QD) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice daily (BID) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, twice daily and Metformin 500 mg capsules, orally, twice daily for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, twice daily and Metformin 1000 mg capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5mg, tablets, orally, twice daily and Metformin 500 mg, capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice daily and Metformin 1000 mg, capsules, orally, twice daily for up to 26 weeks.
Measure Participants	102	104	104	103	108	102	111
Least Squares Mean (Standard Error) [percentage glycosylated hemoglobin]	0.15 (0.094)	-0.52 (0.094)	-0.56 (0.093)	-0.65 (0.094)	-1.11 (0.092)	-1.22 (0.094)	-1.55 (0.090)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 BID, Alogliptin 12.5 BID + Metformin 500 BID
	Comments	The primary efficacy analysis consisted of 2 separate sets of comparisons between each BID combination of alogliptin and metformin (alogliptin/metformin 12.5/500 mg BID and 12.5/1000 mg BID) and its constituent doses of alogliptin and metformin. The null hypothesis was that the combination of alogliptin and metformin had no additional effect on glycemic control at Week 26 either when compared with the constituent dose of alogliptin or with the constituent dose of metformin.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	For each set of comparisons in the primary analysis, the null hypothesis was rejected only if both comparisons between a combination and its constituent doses were statistically significant at the 2-sided 2.5% level.
	Method	ANCOVA
	Comments	ANCOVA model with treatment and geographic region as fixed effects and baseline HbA1c as a covariate.
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.67
	Confidence Interval	(2-Sided) 95%; -0.96 to -0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Metformin 500 BID, Alogliptin 12.5 BID + Metformin 500 BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments	ANCOVA model with treatment and geographic region as fixed effects and baseline HbA1c as a covariate
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.57
	Confidence Interval	(2-Sided) 95%; -0.87 to -0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Alogliptin 12.5 BID, Alogliptin 12.5 BID + Metformin 1000 BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments	ANCOVA model with treatment and geographic region as fixed effects and baseline HbA1c as a covariate.
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.00
	Confidence Interval	(2-Sided) 95%; -1.29 to -0.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Metformin 1000 BID, Alogliptin 12.5 BID + Metformin 1000 BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments	ANCOVA model with treatment and geographic region as fixed effects and baseline HbA1c as a covariate.
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -0.73 to -0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in HbA1c Over Time
Description	The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) was assessed at Weeks 4, 8, 12, 16 and 20. Least squares means are from an analysis of covariance (ANCOVA) model with treatment and geographic region as fixed effects, and baseline HbA1c as a covariate.
Time Frame	Baseline and Weeks 4, 8, 12, 16, and 20.

Outcome Measure Data

Analysis Population Description

The full analysis set where a baseline assessment and at least 1 valid postbaseline assessment were available. The analysis includes only data collected on or after baseline and within 7 days after the last dose of study medication or hyperglycemic rescue, whichever came first. Last observation carried forward was utilized.

Arm/Group Title	Placebo	Alogliptin 25 QD	Alogliptin 12.5 BID	Metformin 500 BID	Metformin 1000 BID	Alogliptin 12.5 BID + Metformin 500 BID	Alogliptin 12.5 BID + Metformin 1000 BID
Arm/Group Description	Alogliptin placebo-matching tablets, orally, twice daily and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily (QD) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice daily (BID) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, twice daily and Metformin 500 mg capsules, orally, twice daily for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, twice daily and Metformin 1000 mg capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5mg, tablets, orally, twice daily and Metformin 500 mg, capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice daily and Metformin 1000 mg, capsules, orally, twice daily for up to 26 weeks.
Measure Participants	106	112	110	109	111	106	114
Week 4 (n=95, 97, 89, 94, 102, 94, 101)	0.09 (0.058)	-0.34 (0.057)	-0.42 (0.060)	-0.37 (0.058)	-0.58 (0.056)	-0.70 (0.058)	-0.75 (0.056)
Week 8 (n=102, 104, 104, 103, 108, 102, 111)	0.08 (0.073)	-0.51 (0.073)	-0.58 (0.072)	-0.59 (0.073)	-0.86 (0.071)	-1.08 (0.073)	-1.17 (0.070)
Week 12 (n=102, 104, 104, 103, 108, 102, 111)	0.12 (0.081)	-0.53 (0.080)	-0.62 (0.080)	-0.68 (0.081)	-1.02 (0.079)	-1.22 (0.081)	-1.40 (0.078)
Week 16 (n=102, 104, 104, 103, 108, 102, 111)	0.13 (0.087)	-0.58 (0.087)	-0.63 (0.086)	-0.72 (0.087)	-1.09 (0.085)	-1.26 (0.087)	-1.50 (0.084)
Week 20 (n=102, 104, 104, 103, 108, 102, 111)	0.12 (0.092)	-0.57 (0.091)	-0.59 (0.091)	-0.68 (0.092)	-1.14 (0.089)	-1.25 (0.092)	-1.54 (0.088)

3. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose Over Time
Description	The change from Baseline in fasting plasma glucose was assessed at Weeks 1, 2, 4, 8, 12, 16, 20 and 26. Least Squares Means were from an ANCOVA model with treatment and geographic region as fixed effects, and baseline fasting plasma glucose as a covariate.
Time Frame	Baseline and Weeks 1, 2, 4, 8, 12, 16, 20 and 26.

Outcome Measure Data

Analysis Population Description

Full analysis set where a baseline assessment and at least 1 valid postbaseline assessment were available. Includes only data collected on or after baseline and within 1 day after the last dose of study medication or hyperglycemic rescue, whichever came first. Last observation carried forward was utilized.

Arm/Group Title	Placebo	Alogliptin 25 QD	Alogliptin 12.5 BID	Metformin 500 BID	Metformin 1000 BID	Alogliptin 12.5 BID + Metformin 500 BID	Alogliptin 12.5 BID + Metformin 1000 BID
Arm/Group Description	Alogliptin placebo-matching tablets, orally, twice daily and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin 25 mg, tablets, orally, once daily (QD) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice daily (BID) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, twice daily and Metformin 500 mg capsules, orally, twice daily for up to 26 weeks.	Alogliptin placebo-matching tablets, orally, twice daily and Metformin 1000 mg capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5mg, tablets, orally, twice daily and Metformin 500 mg, capsules, orally, twice daily for up to 26 weeks.	Alogliptin 12.5 mg, tablets, orally, twice daily and Metformin 1000 mg, capsules, orally, twice daily for up to 26 weeks.
Measure Participants	106	112	110	109	111	106	114
Week 1 (n=102, 103, 94, 95, 104, 101, 109)	5.7 (3.40)	-3.9 (3.38)	-11.9 (3.54)	-12.6 (3.52)	-23.1 (3.36)	-32.7 (3.41)	-36.3 (3.29)
Week 2 (n=105, 112, 105, 102, 108, 106, 111)	4.6 (3.58)	-7.4 (3.46)	-11.6 (3.58)	-14.5 (3.63)	-22.2 (3.53)	-34.5 (3.56)	-43.6 (3.48)
Week 4 (n=105, 112, 106, 106, 110, 106, 111)	7.2 (3.69)	-11.5 (3.57)	-16.6 (3.67)	-16.9 (3.67)	-29.0 (3.60)	-37.6 (3.67)	-44.1 (3.58)
Week 8 (n=105, 112, 106, 106, 110, 106, 112)	7.1 (4.00)	-10.9 (3.87)	-12.1 (3.98)	-11.8 (3.98)	-30.7 (3.91)	-32.9 (3.98)	-43.8 (3.87)
Week 12 (n=105, 112, 106, 106, 110, 106, 112)	11.6 (4.16)	-9.7 (4.03)	-14.7 (4.14)	-14.0 (4.14)	-30.7 (4.06)	-31.6 (4.14)	-44.7 (4.03)
Week 16 (n=105, 112, 106, 106, 110, 106, 112)	10.1 (4.17)	-7.1 (4.04)	-14.7 (4.15)	-13.3 (4.15)	-33.5 (4.07)	-35.9 (4.15)	-47.7 (4.04)
Week 20 (n=105, 112, 106, 106, 110, 106, 112)	8.7 (4.36)	-9.2 (4.22)	-12.3 (4.34)	-10.9 (4.34)	-35.1 (4.25)	-33.8 (4.34)	-44.6 (4.22)
Week 26 (n=105, 112, 106, 106, 110, 106, 112)	12.4 (4.52)	-6.1 (4.37)	-9.7 (4.49)	-11.5 (4.49)	-31.9 (4.41)	-31.7 (4.49)	-45.9 (4.37)

Adverse Events

Time Frame	Adverse events that occurred after the first dose of double-blind study medication and within 14 days after the last dose of double-blind study medication.
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	Placebo		Alogliptin 25 QD		Alogliptin 12.5 BID		Metformin 500 BID		Metformin 1000 BID		Alogliptin 12.5 BID + Metformin 500 BID		Alogliptin 12.5 BID + Metformin 1000 BID
Arm/Group Description	Alogliptin placebo-matching tablets, orally, twice daily and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.		Alogliptin 25 mg, tablets, orally, once daily (QD) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.		Alogliptin 12.5 mg, tablets, orally, twice daily (BID) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks.		Alogliptin placebo-matching tablets, orally, twice daily and Metformin 500 mg capsules, orally, twice daily for up to 26 weeks.		Alogliptin placebo-matching tablets, orally, twice daily and Metformin 1000 mg capsules, orally, twice daily for up to 26 weeks.		Alogliptin 12.5mg, tablets, orally, twice daily and Metformin 500 mg, capsules, orally, twice daily for up to 26 weeks.		Alogliptin 12.5 mg, tablets, orally, twice daily and Metformin 1000 mg, capsules, orally, twice daily for up to 26 weeks.
All Cause Mortality
	Placebo		Alogliptin 25 QD		Alogliptin 12.5 BID		Metformin 500 BID		Metformin 1000 BID		Alogliptin 12.5 BID + Metformin 500 BID		Alogliptin 12.5 BID + Metformin 1000 BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Alogliptin 25 QD		Alogliptin 12.5 BID		Metformin 500 BID		Metformin 1000 BID		Alogliptin 12.5 BID + Metformin 500 BID		Alogliptin 12.5 BID + Metformin 1000 BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/106 (2.8%)		1/112 (0.9%)		4/110 (3.6%)		3/109 (2.8%)		2/111 (1.8%)		2/106 (1.9%)		2/114 (1.8%)
Cardiac disorders
Angina pectoris	0/106 (0%)		0/112 (0%)		0/110 (0%)		1/109 (0.9%)		0/111 (0%)		0/106 (0%)		0/114 (0%)
Myocardial ischaemia	1/106 (0.9%)		0/112 (0%)		0/110 (0%)		0/109 (0%)		0/111 (0%)		0/106 (0%)		0/114 (0%)
Wandering pacemaker	0/106 (0%)		0/112 (0%)		0/110 (0%)		0/109 (0%)		1/111 (0.9%)		0/106 (0%)		0/114 (0%)
General disorders
Non-cardiac chest pain	0/106 (0%)		0/112 (0%)		0/110 (0%)		0/109 (0%)		0/111 (0%)		1/106 (0.9%)		0/114 (0%)
Hepatobiliary disorders
Cholecystitis	0/106 (0%)		0/112 (0%)		0/110 (0%)		0/109 (0%)		0/111 (0%)		0/106 (0%)		1/114 (0.9%)
Infections and infestations
Gallbladder empyema	0/106 (0%)		0/112 (0%)		0/110 (0%)		0/109 (0%)		0/111 (0%)		0/106 (0%)		1/114 (0.9%)
Pneumonia	0/106 (0%)		0/112 (0%)		1/110 (0.9%)		0/109 (0%)		0/111 (0%)		0/106 (0%)		0/114 (0%)
Urinary tract infection	0/106 (0%)		1/112 (0.9%)		0/110 (0%)		0/109 (0%)		0/111 (0%)		0/106 (0%)		0/114 (0%)
Injury, poisoning and procedural complications
Ankle fracture	0/106 (0%)		0/112 (0%)		0/110 (0%)		1/109 (0.9%)		0/111 (0%)		0/106 (0%)		0/114 (0%)
Multiple drug overdose intentional	0/106 (0%)		0/112 (0%)		1/110 (0.9%)		0/109 (0%)		0/111 (0%)		0/106 (0%)		0/114 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	1/106 (0.9%)		0/112 (0%)		0/110 (0%)		0/109 (0%)		0/111 (0%)		0/106 (0%)		0/114 (0%)
Nervous system disorders
Cerebrovascular accident	0/106 (0%)		0/112 (0%)		1/110 (0.9%)		0/109 (0%)		0/111 (0%)		0/106 (0%)		0/114 (0%)
Ischaemic stroke	0/106 (0%)		0/112 (0%)		1/110 (0.9%)		0/109 (0%)		0/111 (0%)		0/106 (0%)		0/114 (0%)
Tremor	1/106 (0.9%)		0/112 (0%)		0/110 (0%)		0/109 (0%)		0/111 (0%)		0/106 (0%)		0/114 (0%)
Psychiatric disorders
Delusion	0/106 (0%)		0/112 (0%)		0/110 (0%)		0/109 (0%)		0/111 (0%)		1/106 (0.9%)		0/114 (0%)
Renal and urinary disorders
Urinary retention	0/106 (0%)		0/112 (0%)		0/110 (0%)		0/109 (0%)		1/111 (0.9%)		0/106 (0%)		0/114 (0%)
Respiratory, thoracic and mediastinal disorders
Alveolitis allergic	0/106 (0%)		0/112 (0%)		0/110 (0%)		1/109 (0.9%)		0/111 (0%)		0/106 (0%)		0/114 (0%)
Pulmonary fibrosis	0/106 (0%)		0/112 (0%)		0/110 (0%)		1/109 (0.9%)		0/111 (0%)		0/106 (0%)		0/114 (0%)
Vascular disorders
Hypotension	0/106 (0%)		0/112 (0%)		0/110 (0%)		0/109 (0%)		0/111 (0%)		0/106 (0%)		1/114 (0.9%)
Other (Not Including Serious) Adverse Events
	Placebo		Alogliptin 25 QD		Alogliptin 12.5 BID		Metformin 500 BID		Metformin 1000 BID		Alogliptin 12.5 BID + Metformin 500 BID		Alogliptin 12.5 BID + Metformin 1000 BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	50/106 (47.2%)		38/112 (33.9%)		34/110 (30.9%)		44/109 (40.4%)		43/111 (38.7%)		40/106 (37.7%)		37/114 (32.5%)
Gastrointestinal disorders
Diarrhoea	3/106 (2.8%)		1/112 (0.9%)		3/110 (2.7%)		4/109 (3.7%)		10/111 (9%)		6/106 (5.7%)		8/114 (7%)
Nausea	2/106 (1.9%)		0/112 (0%)		3/110 (2.7%)		4/109 (3.7%)		6/111 (5.4%)		3/106 (2.8%)		6/114 (5.3%)
Dyspepsia	3/106 (2.8%)		0/112 (0%)		1/110 (0.9%)		0/109 (0%)		2/111 (1.8%)		0/106 (0%)		8/114 (7%)
Infections and infestations
Upper respiratory tract infection	3/106 (2.8%)		3/112 (2.7%)		3/110 (2.7%)		4/109 (3.7%)		3/111 (2.7%)		8/106 (7.5%)		2/114 (1.8%)
Nasopharyngitis	2/106 (1.9%)		7/112 (6.3%)		1/110 (0.9%)		2/109 (1.8%)		4/111 (3.6%)		3/106 (2.8%)		2/114 (1.8%)
Investigations
Creatinine renal clearance decreased	4/106 (3.8%)		1/112 (0.9%)		4/110 (3.6%)		0/109 (0%)		6/111 (5.4%)		5/106 (4.7%)		9/114 (7.9%)
Metabolism and nutrition disorders
Hyperglycaemia	28/106 (26.4%)		19/112 (17%)		13/110 (11.8%)		19/109 (17.4%)		9/111 (8.1%)		8/106 (7.5%)		1/114 (0.9%)
Dyslipidaemia	6/106 (5.7%)		1/112 (0.9%)		2/110 (1.8%)		7/109 (6.4%)		6/111 (5.4%)		6/106 (5.7%)		2/114 (1.8%)
Hypertriglyceridaemia	3/106 (2.8%)		3/112 (2.7%)		1/110 (0.9%)		3/109 (2.8%)		6/111 (5.4%)		6/106 (5.7%)		1/114 (0.9%)
Musculoskeletal and connective tissue disorders
Back pain	1/106 (0.9%)		0/112 (0%)		1/110 (0.9%)		6/109 (5.5%)		1/111 (0.9%)		4/106 (3.8%)		0/114 (0%)
Nervous system disorders
Headache	3/106 (2.8%)		6/112 (5.4%)		5/110 (4.5%)		8/109 (7.3%)		4/111 (3.6%)		7/106 (6.6%)		6/114 (5.3%)
Vascular disorders
Hypertension	5/106 (4.7%)		3/112 (2.7%)		2/110 (1.8%)		6/109 (5.5%)		1/111 (0.9%)		5/106 (4.7%)		8/114 (7%)

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.