ENDURE: Efficacy and Safety of Alogliptin Plus Metformin Compared to Glipizide Plus Metformin in Patients With Type 2 Diabetes Mellitus

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00856284
• Collaborator: (none)
• Enrollment: 2,639
• Locations: 262
• Arms: 3
• Duration (Months): 43
• Patients Per Site: 10.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety and effectiveness of adding alogliptin, once daily (QD), compared to glipizide with metformin in diabetic patients.

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

Detailed Description

For patients diagnosed with type 2 diabetes mellitus, metformin is the usual first-line therapy in addition to diet control and exercise. For those patients with inadequate glycemic control with metformin monotherapy or experiencing serious side effects of metformin, sulfonylurea is a popular choice as a second-line oral antidiabetic treatment.

Alogliptin is a dipeptidyl peptidase-4 inhibitor currently being developed by Takeda for use in patients with type 2 diabetes mellitus.

This study is designed to further explore the durability of efficacy and safety of alogliptin compared to glipizide in type 2 diabetes mellitus patients whose blood sugar level is inadequately controlled with metformin therapy.

The duration of this study will be approximately 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2639 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Active-Controlled Study to Evaluate the Durability of the Efficacy and Safety of Alogliptin Compared to Glipizide When Used in Combination With Metformin in Subjects With Type 2 Diabetes
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin + Alogliptin 12.5 mg Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Drug: Alogliptin; Alogliptin tablets; Other Names: SYR-322 Nesina ; Drug: Metformin; Metformin tablets; Other Names: Glucophage
Experimental: Metformin + Alogliptin 25 mg Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Drug: Alogliptin; Alogliptin tablets; Other Names: SYR-322 Nesina ; Drug: Metformin; Metformin tablets; Other Names: Glucophage
Active Comparator: Metformin + Glipizide Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.	Drug: Metformin; Metformin tablets; Other Names: Glucophage ; Drug: Glipizide; Glipizide tablets; Other Names: Glucotrol

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 52 [Baseline and Week 52]

   The change from Baseline to Week 52 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). The least squares (LS) means are from an analysis of covariance (ANCOVA) model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates.

2. Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 104 [Baseline and Week 104]

   The change from Baseline to Week 104 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). The least squares (LS) means are from an analysis of covariance (ANCOVA) model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates.

Secondary Outcome Measures

1. Change From Baseline in Glycosylated Hemoglobin at Other Time Points [Baseline and Weeks 4, 8, 12, 16, 20, 26, 39, 65, 78, and 91.]

   The change from Baseline over time in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). LS means are from an ANCOVA model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates.

2. Change From Baseline in Fasting Plasma Glucose Over Time [Baseline and Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104.]

   The change from Baseline in fasting plasma glucose (FPG) was assessed at Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104. LS means are from an ANCOVA model with treatment, study schedule, and geographic region as class variables, and Baseline FPG and Baseline metformin dose as covariates.

3. Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% [Weeks 26, 52, 78, and 104.]

   The percentage of participants with HbA1c less than or equal to 6.5% at Weeks 26, 52, 78, and 104. Participants who did not complete the scheduled Week 104 visit were assessed based on their response at the time of discontinuation.

4. Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% [Weeks 26, 52, 78, and 104.]

   Percentage of participants with HbA1c ≤ 7.0% at Weeks 26, 52, 78, and 104. Participants who did not complete the scheduled Week 104 visit were assessed based on their response at the time of discontinuation.

5. Change From Baseline in Body Weight Over Time [Baseline and Weeks 12, 26, 39, 52, 65, 78, 91, and 104.]

   LS Means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and Baseline weight and Baseline metformin dose as covariates.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Has a diagnosis of type 2 diabetes mellitus.

• Must meet one of the following:

• Has been inadequately controlled on a stable daily dose of ≥1500 mg (or documented maximum tolerated dose) of metformin for at least 2 months prior to Screening.

• Has been inadequately controlled (as defined by a glycosylated hemoglobin 7.5 - 10%, inclusive) on metformin <1500 mg without documented maximum tolerated dose.

• No treatment with antidiabetic agents other than metformin within 2 months prior to Screening (for Schedule A)/Pre-Screening (for Schedule B).

• Has body mass index within 23 kg/m^{2 and 45 kg/m}2 unless the patient is Asian or of Asian descent, for whom the allowable body mass index will be ≥ 20 kg/m^{2 and ≤ 35 kg/m}2, inclusive.

• Has fasting C-peptide concentration at least 0.8 ng.

• If regularly using non-excluded medications, must be on a stable dose at least 4 weeks prior to Screening/Pre-screening.

• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant, lactating or intends to donate ova from Screening throughout the duration of the study.

• Must be able and willing to monitor their blood glucose concentrations with a home monitor, and comply with protocol requirements including scheduled clinic appointments.

Exclusion Criteria:

• Systolic blood pressure greater than or equal to 150 mmHg and/or diastolic pressure greater than or equal to 90.

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

• Alanine aminotransferase greater than or equal to 2.5 times the upper limit of normal at Screening Visit.

• Serum creatinine greater than or equal to 1.5 mg/dL for males and 1.4 for females, or calculated creatinine clearance less than 60 L/min.

• Males intending to impregnate others or donate sperm before, during or within 1 month after participating in the study.

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

• A history of laser treatment for diabetic retinopathy within 6 months of screening.

• Treated for diabetic gastric paresis, gastric banding, or gastric bypass.

• New York Heart Association Class III or IV heart failure.

• History of coronary angioplasty, coronary stent placement, coronary bypass surgery, myocardial infarction, stroke or transient ischemic attack within 3 months prior to screening.

• Known history of human immunodeficiency virus, hepatitis B or C.

• Alcohol or substance abuse within 2 years prior to screening.

• Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

• Any investigational drug within 30 days

• Any investigational diabetic drug within 3 months

• Any antidiabetic drug in the dipeptidyl peptidase-4 inhibitors or glucagon-like peptide-1 mimetics classes within 90 days prior to Screening other than metformin

• Prior treatment with alogliptin.

• Weight-loss drugs

• Oral or systemically injected glucocorticoids

• A hypersensitivity allergy or anaphylactic reaction to any dipeptidyl peptidase-4 drug, metformin or glipizide.

• Has a documented history or concurrent signs of significant thyroid disease (eg, autoimmune thyroid diseases such as Graves disease and Hashimoto thyroiditis or active thyroid nodules).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Montgomery	Alabama	United States
2		Muscle Shoals	Alabama	United States
3		Pell City	Alabama	United States
4		Mesa	Arizona	United States
5		Peoria	Arizona	United States
6		Phoenix	Arizona	United States
7		Sierra Vista	Arizona	United States
8		Tempe	Arizona	United States
9		Tucson	Arizona	United States
10		Anaheim	California	United States
11		Artesia	California	United States
12		Chico	California	United States
13		Los Alamitos	California	United States
14		Mission Viejo	California	United States
15		National City	California	United States
16		Northridge	California	United States
17		Pismo Beach	California	United States
18		Riverside	California	United States
19		Roseville	California	United States
20		Sacramento	California	United States
21		San Diego	California	United States
22		Santa Monica	California	United States
23		Tustin	California	United States
24		Arvada	Colorado	United States
25		Colorado Springs	Colorado	United States
26		Ridgefield	Connecticut	United States
27		Waterbury	Connecticut	United States
28		Brooksville	Florida	United States
29		New Port Richey	Florida	United States
30		North Miami Beach	Florida	United States
31		Ocala	Florida	United States
32		Opa Locka	Florida	United States
33		Orlando	Florida	United States
34		Augusta	Georgia	United States
35		Savannah	Georgia	United States
36		Addison	Illinois	United States
37		Chicago	Illinois	United States
38		Bloomington	Indiana	United States
39		Evansville	Indiana	United States
40		Indianapolis	Indiana	United States
41		Mishawaka	Indiana	United States
42		South Bend	Indiana	United States
43		Lexington	Kentucky	United States
44		Munfordville	Kentucky	United States
45		Marrero	Louisiana	United States
46		Bangor	Maine	United States
47		Elkridge	Maryland	United States
48		Oxon Hill	Maryland	United States
49		North Dartmouth	Massachusetts	United States
50		Ann Arbor	Michigan	United States
51		Flint	Michigan	United States
52		Picayune	Mississippi	United States
53		Springfield	Missouri	United States
54		St Peters	Missouri	United States
55		St. Louis	Missouri	United States
56		Omaha	Nebraska	United States
57		Las Vegas	Nevada	United States
58		Albuquerque	New Mexico	United States
59		New Windsor	New York	United States
60		New York	New York	United States
61		Rochester	New York	United States
62		Fargo	North Dakota	United States
63		Beachwood	Ohio	United States
64		Cincinnati	Ohio	United States
65		Dayton	Ohio	United States
66		Willoughby Hills	Ohio	United States
67		Zanesville	Ohio	United States
68		Norman	Oklahoma	United States
69		Oklahoma City	Oklahoma	United States
70		Medford	Oregon	United States
71		Havertown	Pennsylvania	United States
72		Norristown	Pennsylvania	United States
73		Philadelphia	Pennsylvania	United States
74		Pittsburgh	Pennsylvania	United States
75		Tipton	Pennsylvania	United States
76		Anderson	South Carolina	United States
77		Charleston	South Carolina	United States
78		Greer	South Carolina	United States
79		Rapid City	South Dakota	United States
80		New Tazewell	Tennessee	United States
81		Arlington	Texas	United States
82		Carrollton	Texas	United States
83		Dallas	Texas	United States
84		Fort Worth	Texas	United States
85		Houston	Texas	United States
86		Hurst	Texas	United States
87		Katy	Texas	United States
88		San Antonio	Texas	United States
89		Spring	Texas	United States
90		Temple	Texas	United States
91		Midvale	Utah	United States
92		Hampton	Virginia	United States
93		Lewisburg	West Virginia	United States
94		Milwaukee	Wisconsin	United States
95		Mar del Plata		Argentina
96		Garran	Australian Capital Territory	Australia
97		Wollongong	New South Wales	Australia
98		Herston	Queensland	Australia
99		Nedlands	Western Australia	Australia
100		Graz		Austria
101		Salzburg		Austria
102		Recife	Pernambuco	Brazil
103		Brasília - DF	Planalto Central	Brazil
104		Mogi das Cruzes	São Paulo	Brazil
105		Fortaleza		Brazil
106		São Paulo		Brazil
107		St. John's	Newfoundland and Labrador	Canada
108		Brampton	Ontario	Canada
109		Collingwood	Ontario	Canada
110		Corunna	Ontario	Canada
111		Etobichoke	Ontario	Canada
112		Etobicoke	Ontario	Canada
113		Mississauga	Ontario	Canada
114		Smith Falls	Ontario	Canada
115		Smiths Falls	Ontario	Canada
116		Toronto	Ontario	Canada
117		Granby	Quebec	Canada
118		Montreal	Quebec	Canada
119		Providencia	Santiago	Chile
120		Santiago		Chile
121		Potsdam	Brandenburg	Germany
122		Kelkheim	Hesse	Germany
123		Offenbach	Hesse	Germany
124		Münster	North Rhine-Westphalia	Germany
125		Mainz	Rhineland-Palatinate	Germany
126		Neuwied	Rhineland-Palatinate	Germany
127		Rhaunen	Rhineland-Palatinate	Germany
128		Guatemala City		Guatemala
129		Wong Tai Sin	Kowloon	Hong Kong
130		Pok Fu Lam	Southern District	Hong Kong
131		Kowloon		Hong Kong
132		Pécs	Baranya	Hungary
133		Miskolc	Borsod-Abaúj-Zemplén	Hungary
134		Kalocsa	Bács-Kiskun	Hungary
135		Gyula	Békés	Hungary
136		Makó	Csongrád	Hungary
137		Szentes	Csongrád	Hungary
138		Nyíregyháza	Szabolcs-Szatmár-Bereg	Hungary
139		Zalaegerszeg	Zala	Hungary
140		Budapest		Hungary
141		Hyderabad	Andhra Pradesh	India
142		Patna	Bihar	India
143		Karnal	Haryana	India
144		Bangalore	Karnataka	India
145		Belgaum	Karnataka	India
146		Bhopal	Madhya Pradesh	India
147		Mumbai	Maharashtra	India
148		Trichy	Tamil Nadu	India
149		Kfar-Saba	Center District	Israel
150		Kfar Saba	Central District	Israel
151		Matan	Central District	Israel
152		Petach Tikva	Central District	Israel
153		Hadera	Haifa District	Israel
154		Haifa	Haifa District	Israel
155		Nahariya	Northern District	Israel
156		Safed	Northern District	Israel
157		Ashkelon	Southern District	Israel
158		Be'er Sheva	Southern District	Israel
159		Holon	Tel Aviv	Israel
160		Tel- Aviv	Tel Aviv	Israel
161		Jerusalem		Israel
162		Zefat		Israel
163		Milano	Milan	Italy
164		Perugia		Italy
165		Pistoia		Italy
166		Gwangju	Honam	Korea, Republic of
167		Daejeon	Hoseo	Korea, Republic of
168		Daegu	Yeongnam	Korea, Republic of
169		Daugavpils		Latvia
170		Liepaja		Latvia
171		Limbazi		Latvia
172		Ogre		Latvia
173		Riga		Latvia
174		Talsi		Latvia
175		Tukums		Latvia
176		Valmiera		Latvia
177		Alytus		Lithuania
178		Kaunas		Lithuania
179		Kedainiai		Lithuania
180		Klaipeda		Lithuania
181		Palanga		Lithuania
182		Panevezys		Lithuania
183		Vilnius		Lithuania
184		Ipoh		Malaysia
185		Kajang		Malaysia
186		Kota Bahru		Malaysia
187		Kota Bharu		Malaysia
188		Kuala Terengganu		Malaysia
189		Kuantan		Malaysia
190		Melaka		Malaysia
191		Taiping		Malaysia
192		Mexico	Distrito Federal	Mexico
193		Tlalnepantla	Edo de Mexico	Mexico
194		Guadalajara	Jalisco	Mexico
195		Monterrey	Nuevo Leon	Mexico
196		Huixquilucan Edo. de Mexico		Mexico
197		Mexico City		Mexico
198		Auckland		New Zealand
199		Christchurch		New Zealand
200		Hamilton		New Zealand
201		Otahuhu		New Zealand
202		Palmerston North		New Zealand
203		Takapuna		New Zealand
204		Tauranga		New Zealand
205		Wellington		New Zealand
206		Chiclayo	Lambayeque	Peru
207		Lima	San Juan de Miraflores	Peru
208		Ica		Peru
209		Manila		Philippines
210		Bytom		Poland
211		Gniewkowo		Poland
212		Krakow		Poland
213		Radom		Poland
214		Rzeszow		Poland
215		Tychy		Poland
216		Warszawa		Poland
217		Ponce		Puerto Rico
218		San Juan		Puerto Rico
219		Bacau		Romania
220		Bucharest		Romania
221		Galati		Romania
222		Oradea		Romania
223		Sibiu		Romania
224		Targu Mures		Romania
225		Arkhangelsk		Russian Federation
226		Irkutsk		Russian Federation
227		Moscow		Russian Federation
228		Samara		Russian Federation
229		Smolensk		Russian Federation
230		St Petersburg		Russian Federation
231		Yaroslavl		Russian Federation
232		Singapore		Singapore
233		Port Elizabeth	Eastern Cape	South Africa
234		Johannesburg	Gauteng	South Africa
235		Pretoria	Gauteng	South Africa
236		Durban	Kwazulu-Natal	South Africa
237		Tongaat	Kwazulu-Natal	South Africa
238		Cape Town	Western Cape	South Africa
239		Barcelona	Cataluña	Spain
240		Santiago de Compostela	Galicia	Spain
241		Alicante		Spain
242		Amphure Muang		Thailand
243		Bangkok		Thailand
244		Chiangmai		Thailand
245		Khon Kaen		Thailand
246		Dnepropertovsk		Ukraine
247		Dnipropetrovsk		Ukraine
248		Donetsk		Ukraine
249		Kharkiv		Ukraine
250		Kyiv		Ukraine
251		Lviv		Ukraine
252		Vinnytsa		Ukraine
253		Vinnytsya		Ukraine
254		Zaporizhye		Ukraine
255		Zaporizhzhya		Ukraine
256		Aintree-Liverpool		United Kingdom
257		Bath		United Kingdom
258		Bournemouth		United Kingdom
259		Dundee		United Kingdom
260		London		United Kingdom
261		Stevenage		United Kingdom
262		Swansea		United Kingdom

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT00856284
• Other Study ID Numbers: SYR-322_305; 2008-007444-34; U1111-1111-7397; HKCTR-862; DOH-27-0709-2825; 09/H0703/66; NMRR-09-203-3590
• First Posted: Mar 5, 2009
• Last Update Posted: Dec 3, 2013
• Last Verified: Sep 1, 2013

• Keywords provided by Takeda: Diabetes Mellitus; Drug Therapy; Hyperinsulinism; Hyperglycemia; Glucose Intolerance
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Alogliptin; Glipizide

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 310 study sites worldwide from 05 March 2009 to 17 October 2012.
Pre-assignment Detail	Participants with type 2 diabetes mellitus experiencing inadequate glycemic control while on metformin therapy were enrolled equally in 1 of 3 treatment groups: alogliptin 12.5 mg once daily (QD), alogliptin 25 mg QD, and glipizide 5 mg QD.

Arm/Group Title	Metformin + Alogliptin 12.5 mg	Metformin + Alogliptin 25 mg	Metformin + Glipizide
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Period Title: Overall Study
STARTED	880	885	874
Received Study Drug	873	878	869
COMPLETED	472	493	427
NOT COMPLETED	408	392	447

Baseline Characteristics

Arm/Group Title	Metformin + Alogliptin 12.5 mg	Metformin + Alogliptin 25 mg	Metformin + Glipizide	Total
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.	Total of all reporting groups
Overall Participants	880	885	874	2639
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.2 (9.60)	55.5 (9.81)	55.4 (9.60)	55.4 (9.67)
Age, Customized (participants) [Number]
<65 years	734 83.4%	710 80.2%	723 82.7%	2167 82.1%
≥65 years	146 16.6%	175 19.8%	151 17.3%	472 17.9%
≥75 years	13 1.5%	17 1.9%	15 1.7%	45 1.7%
Sex: Female, Male (Count of Participants)
Female	461 52.4%	433 48.9%	433 49.5%	1327 50.3%
Male	419 47.6%	452 51.1%	441 50.5%	1312 49.7%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	40 4.5%	42 4.7%	36 4.1%	118 4.5%
Asian	191 21.7%	207 23.4%	203 23.2%	601 22.8%
Black or African American	74 8.4%	66 7.5%	81 9.3%	221 8.4%
Native Hawaiian or Other Pacific Islander	7 0.8%	1 0.1%	4 0.5%	12 0.5%
White	557 63.3%	555 62.7%	533 61%	1645 62.3%
Multiracial	11 1.3%	14 1.6%	17 1.9%	42 1.6%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	192 21.8%	204 23.1%	192 22%	588 22.3%
Not Hispanic or Latino	688 78.2%	681 76.9%	682 78%	2051 77.7%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	31.27 (5.417)	31.27 (5.341)	31.11 (5.320)	31.22 (5.358)
Glycosylated hemoglobin (HbA1c) (percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage]	7.59 (0.599)	7.61 (0.606)	7.60 (0.617)	7.60 (0.607)
Baseline HbA1c Category (participants) [Number]
<8.0%	615 69.9%	620 70.1%	613 70.1%	1848 70%
≥8.0%	265 30.1%	265 29.9%	261 29.9%	791 30%
Diabetes duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	5.65 (5.324)	5.42 (4.730)	5.48 (4.884)	5.52 (4.985)
Metformin dose (mg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg]	1825.2 (405.59)	1837.2 (373.06)	1823.4 (390.63)	1828.6 (389.85)
Glomerular filtration rate (mL/min/1.73m^2) [Mean (Standard Deviation) ]
MDRD	83.04 (16.586)	82.35 (16.199)	82.28 (16.994)	82.56 (16.591)
Cockcroft-Gault	109.3 (33.40)	109.3 (32.85)	108.0 (32.64)	108.9 (32.96)
Smoking history (participants) [Number]
Never smoked	543 61.7%	586 66.2%	578 66.1%	1707 64.7%
Current smoker	135 15.3%	122 13.8%	111 12.7%	368 13.9%
Ex-smoker	202 23%	177 20%	185 21.2%	564 21.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 52
Description	The change from Baseline to Week 52 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). The least squares (LS) means are from an analysis of covariance (ANCOVA) model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

The Per-protocol set included all randomized patients who took at least 1 dose of double-blind study drug, with a Baseline assessment and at least 1 post-baseline assessment for that variable and who had no major protocol violations. Last observation carried forward (LOCF) was used.

Arm/Group Title	Metformin + Alogliptin 12.5 mg	Metformin + Alogliptin 25 mg	Metformin + Glipizide
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Measure Participants	371	382	336
Least Squares Mean (Standard Error) [percentage glycosylated hemoglobin]	-0.81 (0.027)	-0.76 (0.027)	-0.73 (0.029)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metformin + Alogliptin 25 mg, Metformin + Glipizide
	Comments	The null hypotheses were tested in a fixed order at the 1-sided 0.0125 significance level at Weeks 52 and 104, independently: H01: Alogliptin 25 mg was inferior in HbA1c change from Baseline vs glipizide. H02: Alogliptin 12.5 mg was inferior vs glipizide. H03: Alogliptin 25 mg was not superior vs glipizide. H04: Alogliptin 12.5 mg was not superior vs glipizide. Each subsequent null hypothesis was tested only if all previously tested null hypotheses were rejected with respect to Weeks 52 and 104.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was met if the upper limit of the 1-sided 98.75% CI for the difference between alogliptin 25 mg and glipizide in HbA1c change from Baseline was less than 0.3%. If the null hypothesis H01 was rejected, then H02 was tested to show noninferiority of alogliptin 12.5 mg versus glipizide with a margin of 0.3%. Non-inferiority was met if the upper limit of the 1-sided 98.75% CI for the difference between alogliptin 12.5 mg and glipizide in HbA1c change from Baseline was less than 0.3%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.03
	Confidence Interval	(1-Sided) 98.75%; to 0.059
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Metformin + Alogliptin 12.5 mg, Metformin + Glipizide
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was met if the upper limit of the 1-sided 98.75% CI for the difference between alogliptin 25 mg and glipizide in HbA1c change from Baseline was less than 0.3%. If the null hypothesis H01 was rejected, then H02 was tested to show noninferiority of alogliptin 12.5 mg versus glipizide with a margin of 0.3%. Non-inferiority was met if the upper limit of the 1-sided 98.75% CI for the difference between alogliptin 12.5 mg and glipizide in HbA1c change from Baseline was less than 0.3%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.09
	Confidence Interval	(1-Sided) 98.75%; to 0.003
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin at Other Time Points
Description	The change from Baseline over time in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). LS means are from an ANCOVA model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates.
Time Frame	Baseline and Weeks 4, 8, 12, 16, 20, 26, 39, 65, 78, and 91.

Outcome Measure Data

Analysis Population Description

Per-protocol set; LOCF was used.

Arm/Group Title	Metformin + Alogliptin 12.5 mg	Metformin + Alogliptin 25 mg	Metformin + Glipizide
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Measure Participants	371	382	336
Week 4 (n=341, 354, 318)	-0.37 (0.020)	-0.40 (0.020)	-0.41 (0.021)
Week 8 (n=370, 382, 336)	-0.56 (0.024)	-0.60 (0.024)	-0.66 (0.025)
Week 12 (n=371, 382, 336)	-0.69 (0.025)	-0.71 (0.025)	-0.78 (0.026)
Week 16 (n=371, 382, 336)	-0.74 (0.026)	-0.76 (0.025)	-0.78 (0.027)
Week 20 (n=371, 382, 336)	-0.76 (0.026)	-0.78 (0.025)	-0.79 (0.027)
Week 26 (n=371, 382, 336)	-0.80 (0.027)	-0.79 (0.026)	-0.80 (0.028)
Week 39 (n=371, 382, 336)	-0.81 (0.026)	-0.81 (0.025)	-0.74 (0.027)
Week 65 (n=371, 382, 336)	-0.81 (0.029)	-0.83 (0.028)	-0.76 (0.030)
Week 78 (n=371, 382, 336)	-0.82 (0.030)	-0.80 (0.030)	-0.73 (0.032)
Week 91 (n=371, 382, 336)	-0.76 (0.033)	-0.77 (0.033)	-0.68 (0.035)

3. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose Over Time
Description	The change from Baseline in fasting plasma glucose (FPG) was assessed at Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104. LS means are from an ANCOVA model with treatment, study schedule, and geographic region as class variables, and Baseline FPG and Baseline metformin dose as covariates.
Time Frame	Baseline and Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104.

Outcome Measure Data

Analysis Population Description

Full analysis set, which included all randomized patients who received at least 1 dose of double-blind study drug who had a Baseline assessment and at least 1 post-baseline assessment for FPG. LOCF was used.

Arm/Group Title	Metformin + Alogliptin 12.5 mg	Metformin + Alogliptin 25 mg	Metformin + Glipizide
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Measure Participants	867	867	859
Week 2 (n=781, 803, 777)	-10.2 (0.89)	-11.4 (0.87)	-7.7 (0.89)
Week 4 (n=863, 865, 855)	-10.6 (0.85)	-11.6 (0.85)	-10.2 (0.85)
Week 8 (n=867, 867, 859)	-9.2 (0.91)	-11.6 (0.91)	-9.3 (0.92)
Week 12 (n=867, 867, 859)	-10.7 (0.94)	-11.2 (0.94)	-9.4 (0.95)
Week 16 (n=867, 867, 859)	-8.6 (0.98)	-9.9 (0.98)	-7.1 (0.98)
Week 20 (n=867, 867, 859)	-7.6 (1.02)	-10.1 (1.02)	-5.5 (1.02)
Week 26 (n=867, 867, 859)	-7.5 (1.06)	-10.1 (1.06)	-4.3 (1.06)
Week 39 (n=867, 867, 859)	-6.9 (1.14)	-8.4 (1.14)	-0.6 (1.15)
Week 52 (n=867, 867, 859)	-5.0 (1.22)	-7.0 (1.22)	0.9 (1.23)
Week 65 (n=867, 867, 859)	-3.4 (1.21)	-5.9 (1.21)	1.4 (1.21)
Week 78 (n=867, 867, 859)	-2.8 (1.47)	-5.1 (1.47)	5.1 (1.48)
Week 91 (n=867, 867, 859)	-0.9 (1.27)	-3.4 (1.27)	4.9 (1.28)
Week 104 (n=867, 867, 859)	-0.9 (1.28)	-3.2 (1.28)	5.4 (1.29)

4. Secondary Outcome

Title	Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5%
Description	The percentage of participants with HbA1c less than or equal to 6.5% at Weeks 26, 52, 78, and 104. Participants who did not complete the scheduled Week 104 visit were assessed based on their response at the time of discontinuation.
Time Frame	Weeks 26, 52, 78, and 104.

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants who did not complete the scheduled Week 26, Week 52, Week 78 or Week 104 visit were assessed based on their response at the time of discontinuation.

Arm/Group Title	Metformin + Alogliptin 12.5 mg	Metformin + Alogliptin 25 mg	Metformin + Glipizide
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Measure Participants	873	878	869
Week 26	25.6 2.9%	26.2 3%	24.8 2.8%
Week 52	24.5 2.8%	24.8 2.8%	20.8 2.4%
Week 78	24.2 2.8%	26.4 3%	21.8 2.5%
Week 104	23.5 2.7%	24.1 2.7%	19.0 2.2%

5. Secondary Outcome

Title	Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0%
Description	Percentage of participants with HbA1c ≤ 7.0% at Weeks 26, 52, 78, and 104. Participants who did not complete the scheduled Week 104 visit were assessed based on their response at the time of discontinuation.
Time Frame	Weeks 26, 52, 78, and 104.

Outcome Measure Data

Analysis Population Description

Full analysis set. Participants who did not complete the scheduled Week 26, Week 52, Week 78 or Week 104 visit were assessed based on their response at the time of discontinuation.

Arm/Group Title	Metformin + Alogliptin 12.5 mg	Metformin + Alogliptin 25 mg	Metformin + Glipizide
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Measure Participants	873	878	869
Week 26	56.4 6.4%	59.2 6.7%	56.1 6.4%
Week 52	51.7 5.9%	55.5 6.3%	47.4 5.4%
Week 78	48.8 5.5%	52.4 5.9%	46.6 5.3%
Week 104	45.6 5.2%	48.5 5.5%	42.8 4.9%

6. Secondary Outcome

Title	Change From Baseline in Body Weight Over Time
Description	LS Means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and Baseline weight and Baseline metformin dose as covariates.
Time Frame	Baseline and Weeks 12, 26, 39, 52, 65, 78, 91, and 104.

Outcome Measure Data

Analysis Population Description

Full analysis set, LOCF was used.

Arm/Group Title	Metformin + Alogliptin 12.5 mg	Metformin + Alogliptin 25 mg	Metformin + Glipizide
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Measure Participants	867	868	861
Week 12	-0.51 (0.076)	-0.53 (0.076)	0.71 (0.077)
Week 26	-0.65 (0.101)	-0.71 (0.101)	0.86 (0.101)
Week 39	-0.60 (0.109)	-0.86 (0.109)	0.97 (0.110)
Week 52	-0.63 (0.117)	-0.90 (0.117)	0.89 (0.117)
Week 65	-0.70 (0.122)	-0.92 (0.122)	0.87 (0.123)
Week 78	-0.78 (0.124)	-0.94 (0.124)	0.88 (0.125)
Week 91	-0.67 (0.127)	-0.88 (0.127)	0.89 (0.127)
Week 104	-0.68 (0.127)	-0.89 (0.127)	0.95 (0.127)

7. Primary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 104
Description	The change from Baseline to Week 104 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). The least squares (LS) means are from an analysis of covariance (ANCOVA) model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates.
Time Frame	Baseline and Week 104

Outcome Measure Data

Analysis Population Description

The Per-protocol set included all randomized patients who took at least 1 dose of double-blind study drug, with a Baseline assessment and at least 1 post-baseline assessment for that variable and who had no major protocol violations. Last observation carried forward was used (LOCF).

Arm/Group Title	Metformin + Alogliptin 12.5 mg	Metformin + Alogliptin 25 mg	Metformin + Glipizide
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Measure Participants	371	382	336
Least Squares Mean (Standard Error) [percentage glycosylated hemoglobin]	-0.68 (0.037)	-0.72 (0.037)	-0.59 (0.039)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metformin + Alogliptin 25 mg, Metformin + Glipizide
	Comments	The null hypotheses were tested in a fixed order at the 1-sided 0.0125 significance level at Weeks 52 and 104, independently: H01: Alogliptin 25 mg was inferior in HbA1c change from Baseline vs glipizide. H02: Alogliptin 12.5 mg was inferior vs glipizide. H03: Alogliptin 25 mg was not superior vs glipizide. H04: Alogliptin 12.5 mg was not superior vs glipizide. Each subsequent null hypothesis was tested only if all previously tested null hypotheses were rejected with respect to Weeks 52 and 104.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was met if the upper limit of the 1-sided 98.75% CI for the difference between alogliptin 25 mg and glipizide in HbA1c change from Baseline was less than 0.3%. If the null hypothesis H01 was rejected, then H02 was tested to show noninferiority of alogliptin 12.5 mg versus glipizide with a margin of 0.3%. Non-inferiority was met if the upper limit of the 1-sided 98.75% CI for the difference between alogliptin 12.5 mg and glipizide in HbA1c change from Baseline was less than 0.3%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.13
	Confidence Interval	(1-Sided) 98.75%; to -0.006
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Metformin + Alogliptin 12.5 mg, Metformin + Glipizide
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was met if the upper limit of the 1-sided 98.75% CI for the difference between alogliptin 25 mg and glipizide in HbA1c change from Baseline was less than 0.3%. If the null hypothesis H01 was rejected, then H02 was tested to show noninferiority of alogliptin 12.5 mg versus glipizide with a margin of 0.3%. Non-inferiority was met if the upper limit of the 1-sided 98.75% CI for the difference between alogliptin 12.5 mg and glipizide in HbA1c change from Baseline was less than 0.3%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.09
	Confidence Interval	(1-Sided) 98.75%; to 0.035
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 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	Metformin + Alogliptin 12.5 mg		Metformin + Alogliptin 25 mg		Metformin + Glipizide
Arm/Group Description	Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.		Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.		Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
All Cause Mortality
	Metformin + Alogliptin 12.5 mg		Metformin + Alogliptin 25 mg		Metformin + Glipizide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Metformin + Alogliptin 12.5 mg		Metformin + Alogliptin 25 mg		Metformin + Glipizide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	86/873 (9.9%)		97/878 (11%)		81/869 (9.3%)
Blood and lymphatic system disorders
Anaemia	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Iron deficiency anaemia	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Cardiac disorders
Coronary artery disease	5/873 (0.6%)		3/878 (0.3%)		2/869 (0.2%)
Angina unstable	1/873 (0.1%)		4/878 (0.5%)		4/869 (0.5%)
Acute myocardial infarction	0/873 (0%)		1/878 (0.1%)		5/869 (0.6%)
Atrial fibrillation	1/873 (0.1%)		3/878 (0.3%)		2/869 (0.2%)
Atrial flutter	2/873 (0.2%)		2/878 (0.2%)		1/869 (0.1%)
Cardiac failure	0/873 (0%)		3/878 (0.3%)		1/869 (0.1%)
Cardiac failure congestive	2/873 (0.2%)		1/878 (0.1%)		1/869 (0.1%)
Myocardial infarction	0/873 (0%)		1/878 (0.1%)		3/869 (0.3%)
Angina pectoris	0/873 (0%)		2/878 (0.2%)		1/869 (0.1%)
Myocardial ischaemia	1/873 (0.1%)		0/878 (0%)		2/869 (0.2%)
Atrioventricular block complete	1/873 (0.1%)		0/878 (0%)		1/869 (0.1%)
Cardiomyopathy	0/873 (0%)		1/878 (0.1%)		1/869 (0.1%)
Silent myocardial infarction	0/873 (0%)		2/878 (0.2%)		0/869 (0%)
Acute coronary syndrome	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Arteriosclerosis coronary artery	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Atrioventricular block	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Atrioventricular block second degree	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Bradycardia	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Congestive cardiomyopathy	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Coronary artery occlusion	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Left ventricular failure	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Pericardial effusion	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Right ventricular failure	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Tachyarrhythmia	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Ear and labyrinth disorders
Acute vestibular syndrome	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Vertigo	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Vertigo positional	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Endocrine disorders
Primary hyperaldosteronism	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Eye disorders
Cataract	1/873 (0.1%)		1/878 (0.1%)		1/869 (0.1%)
Cataract nuclear	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Cataract subcapsular	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Iridocyclitis	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Retinal detachment	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Vision blurred	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Gastrointestinal disorders
Colitis	2/873 (0.2%)		2/878 (0.2%)		0/869 (0%)
Abdominal pain	1/873 (0.1%)		0/878 (0%)		2/869 (0.2%)
Inguinal hernia	1/873 (0.1%)		1/878 (0.1%)		1/869 (0.1%)
Nausea	0/873 (0%)		1/878 (0.1%)		1/869 (0.1%)
Pancreatitis acute	0/873 (0%)		1/878 (0.1%)		1/869 (0.1%)
Umbilical hernia	0/873 (0%)		1/878 (0.1%)		1/869 (0.1%)
Anal fistula	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Colitis ischaemic	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Diarrhoea	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Diverticulum	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Dyspepsia	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Enterocolitis	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Gastritis	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Gastrointestinal haemorrhage	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Haematemesis	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Haemorrhoids	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Intestinal ischaemia	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Mallory-Weiss syndrome	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Pancreatitis	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Umbilical hernia, obstructive	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Upper gastrointestinal haemorrhage	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Vomiting	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
General disorders
Non-cardiac chest pain	3/873 (0.3%)		4/878 (0.5%)		3/869 (0.3%)
Chest pain	0/873 (0%)		2/878 (0.2%)		0/869 (0%)
Hernia	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Sudden death	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Hepatobiliary disorders
Cholecystitis	1/873 (0.1%)		1/878 (0.1%)		1/869 (0.1%)
Cholecystitis acute	0/873 (0%)		3/878 (0.3%)		0/869 (0%)
Cholelithiasis	0/873 (0%)		1/878 (0.1%)		1/869 (0.1%)
Bile duct stone	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Drug-induced liver injury	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Immune system disorders
Anaphylactic reaction	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Infections and infestations
Cellulitis	3/873 (0.3%)		1/878 (0.1%)		3/869 (0.3%)
Pneumonia	1/873 (0.1%)		2/878 (0.2%)		2/869 (0.2%)
Gastroenteritis	2/873 (0.2%)		2/878 (0.2%)		0/869 (0%)
Dengue fever	1/873 (0.1%)		0/878 (0%)		2/869 (0.2%)
Diverticulitis	1/873 (0.1%)		1/878 (0.1%)		1/869 (0.1%)
Hepatitis viral	1/873 (0.1%)		0/878 (0%)		2/869 (0.2%)
Urinary tract infection	1/873 (0.1%)		1/878 (0.1%)		1/869 (0.1%)
Urosepsis	0/873 (0%)		1/878 (0.1%)		1/869 (0.1%)
Abdominal abscess	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Abscess limb	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Acute sinusitis	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Amoebiasis	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Appendicitis	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Bronchitis	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Cystitis	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Gangrene	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Gastroenteritis salmonella	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Lobar pneumonia	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Malaria	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Osteomyelitis	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Pneumocystis jiroveci pneumonia	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Scrotal abscess	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Sepsis	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Septic shock	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Staphylococcal infection	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Injury, poisoning and procedural complications
Ankle fracture	1/873 (0.1%)		2/878 (0.2%)		1/869 (0.1%)
Fall	2/873 (0.2%)		0/878 (0%)		0/869 (0%)
Joint injury	0/873 (0%)		0/878 (0%)		2/869 (0.2%)
Road traffic accident	1/873 (0.1%)		0/878 (0%)		1/869 (0.1%)
Comminuted fracture	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Craniocerebral injury	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Facial bones fracture	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Femur fracture	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Incisional hernia	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Joint dislocation	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Ligament rupture	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Lower limb fracture	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Patella fracture	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Peripheral nerve injury	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Tendon rupture	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Tibia fracture	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Metabolism and nutrition disorders
Dehydration	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Diabetic ketoacidosis	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Hypoglycaemia	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	2/873 (0.2%)		3/878 (0.3%)		4/869 (0.5%)
Musculoskeletal chest pain	1/873 (0.1%)		2/878 (0.2%)		1/869 (0.1%)
Intervertebral disc protrusion	1/873 (0.1%)		1/878 (0.1%)		0/869 (0%)
Muscle haemorrhage	2/873 (0.2%)		0/878 (0%)		0/869 (0%)
Spinal osteoarthritis	1/873 (0.1%)		1/878 (0.1%)		0/869 (0%)
Arthralgia	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Back pain	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Bursitis	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Haemarthrosis	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Myalgia intercostal	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Polymyositis	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Spinal column stenosis	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	2/873 (0.2%)		0/878 (0%)		1/869 (0.1%)
Basal cell carcinoma	1/873 (0.1%)		1/878 (0.1%)		0/869 (0%)
Uterine leiomyoma	2/873 (0.2%)		0/878 (0%)		0/869 (0%)
Adenocarcinoma	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Bladder transitional cell carcinoma	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Colon adenoma	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Colon cancer	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Colon cancer stage 0	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Endometrial cancer	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Gastrointestinal tract adenoma	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Lipoma	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Lung adenocarcinoma	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Non-Hodgkin's lymphoma	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Non-small cell lung cancer stage IIIB	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Ovarian adenoma	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Ovarian cancer	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Rectal cancer metastatic	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Renal oncocytoma	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Small cell lung cancer stage unspecified	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Squamous cell carcinoma of skin	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Nervous system disorders
Cerebrovascular accident	1/873 (0.1%)		1/878 (0.1%)		3/869 (0.3%)
Syncope	2/873 (0.2%)		0/878 (0%)		1/869 (0.1%)
Dizziness	1/873 (0.1%)		0/878 (0%)		1/869 (0.1%)
Epilepsy	1/873 (0.1%)		0/878 (0%)		1/869 (0.1%)
Headache	1/873 (0.1%)		1/878 (0.1%)		0/869 (0%)
Ischaemic stroke	1/873 (0.1%)		1/878 (0.1%)		0/869 (0%)
Transient ischaemic attack	0/873 (0%)		2/878 (0.2%)		0/869 (0%)
Carotid artery stenosis	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Cerebral infarction	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Haemorrhagic stroke	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Intercostal neuralgia	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Neuralgia	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Parkinsonism	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Presyncope	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Radiculopathy	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Tension headache	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
VIIth nerve paralysis	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
VIth nerve paralysis	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Vertebrobasilar insufficiency	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Psychiatric disorders
Bipolar disorder	1/873 (0.1%)		0/878 (0%)		1/869 (0.1%)
Alcohol withdrawal syndrome	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Depressed mood	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Depression	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Schizophrenia	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Renal and urinary disorders
Renal failure acute	1/873 (0.1%)		2/878 (0.2%)		3/869 (0.3%)
Nephrolithiasis	2/873 (0.2%)		2/878 (0.2%)		0/869 (0%)
Renal colic	1/873 (0.1%)		1/878 (0.1%)		1/869 (0.1%)
Calculus urinary	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Diabetic nephropathy	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Urinary retention	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/873 (0.1%)		1/878 (0.1%)		0/869 (0%)
Adenomyosis	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Cervical dysplasia	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Cervix disorder	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Cystocele	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Dysmenorrhoea	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Epididymitis	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Metrorrhagia	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Ovarian cyst	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Rectocele	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Uterine prolapse	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Uterovaginal prolapse	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	2/873 (0.2%)		0/878 (0%)		1/869 (0.1%)
Pulmonary embolism	1/873 (0.1%)		0/878 (0%)		1/869 (0.1%)
Acute pulmonary oedema	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Asthma	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Dyspnoea	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Emphysema	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Granulomatous pneumonitis	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Interstitial lung disease	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Pleuritic pain	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Pulmonary oedema	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Respiratory failure	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Vascular disorders
Hypertension	1/873 (0.1%)		3/878 (0.3%)		0/869 (0%)
Hypertensive crisis	0/873 (0%)		2/878 (0.2%)		1/869 (0.1%)
Deep vein thrombosis	1/873 (0.1%)		1/878 (0.1%)		0/869 (0%)
Aortic aneurysm	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Arterial thrombosis limb	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Embolism	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Femoral artery occlusion	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Iliac artery occlusion	0/873 (0%)		1/878 (0.1%)		0/869 (0%)
Orthostatic hypotension	0/873 (0%)		0/878 (0%)		1/869 (0.1%)
Peripheral arterial occlusive disease	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Thrombophlebitis	1/873 (0.1%)		0/878 (0%)		0/869 (0%)
Other (Not Including Serious) Adverse Events
	Metformin + Alogliptin 12.5 mg		Metformin + Alogliptin 25 mg		Metformin + Glipizide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	688/873 (78.8%)		687/878 (78.2%)		668/869 (76.9%)
Blood and lymphatic system disorders
Anaemia	16/873 (1.8%)		37/878 (4.2%)		32/869 (3.7%)
Gastrointestinal disorders
Diarrhoea	60/873 (6.9%)		60/878 (6.8%)		63/869 (7.2%)
Nausea	28/873 (3.2%)		32/878 (3.6%)		20/869 (2.3%)
General disorders
Fatigue	20/873 (2.3%)		19/878 (2.2%)		28/869 (3.2%)
Asthenia	14/873 (1.6%)		15/878 (1.7%)		27/869 (3.1%)
Infections and infestations
Upper respiratory tract infection	84/873 (9.6%)		90/878 (10.3%)		76/869 (8.7%)
Nasopharyngitis	78/873 (8.9%)		67/878 (7.6%)		61/869 (7%)
Influenza	36/873 (4.1%)		36/878 (4.1%)		42/869 (4.8%)
Urinary tract infection	41/873 (4.7%)		33/878 (3.8%)		38/869 (4.4%)
Bronchitis	39/873 (4.5%)		36/878 (4.1%)		36/869 (4.1%)
Sinusitis	26/873 (3%)		29/878 (3.3%)		23/869 (2.6%)
Investigations
Creatinine renal clearance decreased	23/873 (2.6%)		34/878 (3.9%)		32/869 (3.7%)
Metabolism and nutrition disorders
Hypoglycaemia	18/873 (2.1%)		6/878 (0.7%)		91/869 (10.5%)
Dyslipidaemia	22/873 (2.5%)		20/878 (2.3%)		34/869 (3.9%)
Musculoskeletal and connective tissue disorders
Back pain	54/873 (6.2%)		45/878 (5.1%)		49/869 (5.6%)
Arthralgia	38/873 (4.4%)		42/878 (4.8%)		40/869 (4.6%)
Pain in extremity	28/873 (3.2%)		28/878 (3.2%)		33/869 (3.8%)
Nervous system disorders
Headache	45/873 (5.2%)		60/878 (6.8%)		46/869 (5.3%)
Dizziness	24/873 (2.7%)		24/878 (2.7%)		29/869 (3.3%)
Tremor	5/873 (0.6%)		3/878 (0.3%)		29/869 (3.3%)
Respiratory, thoracic and mediastinal disorders
Cough	35/873 (4%)		26/878 (3%)		33/869 (3.8%)
Vascular disorders
Hypertension	45/873 (5.2%)		67/878 (7.6%)		65/869 (7.5%)

Limitations/Caveats

The Week 52 results summarized in herein differ from the Week 52 results summarized in an interim analysis, because the per protocol set (PPS) defined for the final analysis included fewer subjects than the PPS defined for the interim analysis.

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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.