Trial Outcomes & Findings for Efficacy and Safety of Alogliptin in Participants With Type 2 Diabetes (NCT NCT01289119)

NCT ID: NCT01289119

Last Updated: 2013-03-22

Results Overview

The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Week 16. Least squares means are derived from an analysis of covariance (ANCOVA) model with treatment as a fixed effect, and baseline HbA1c as a covariate for the monotherapy, baseline HbA1c with baseline metformin dose as covariates for the metformin therapy, baseline HbA1c with baseline metformin therapy status and baseline pioglitazone dose as covariates for the pioglitazone therapy.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 506 participants
• Primary outcome timeframe: Baseline and Week 16.
• Results posted on: 2013-03-22

Participant Flow

Participants took part in the study at 30 investigative sites in China, Taiwan province and Hong Kong from 23 December 2010 to 19 December 2011.

Participants with a historical diagnosis of Type 2 diabetes mellitus who were experiencing inadequate glycemic control were stratified into 1 of the 3 therapy groups based upon their background antidiabetic therapy before being randomized 1:1 to receive either alogliptin 25 mg once daily or matching placebo once daily.

Participant milestones

Measure	Placebo Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Overall Study STARTED	93	92	98	99	63	61
Overall Study Treated	92	92	98	99	63	61
Overall Study COMPLETED	84	83	89	93	58	57
Overall Study NOT COMPLETED	9	9	9	6	5	4

Reasons for withdrawal

Measure	Placebo Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Overall Study Adverse Event	2	1	0	2	1	0
Overall Study Major Protocol Deviation	2	1	3	0	2	1
Overall Study Lost to Follow-up	0	3	0	0	0	1
Overall Study Withdrawal by Subject	4	2	4	3	1	1
Overall Study Pregnancy	0	1	0	0	0	0
Overall Study Lack of Efficacy	0	1	1	1	1	1
Overall Study Other	1	0	1	0	0	0

Baseline Characteristics

Efficacy and Safety of Alogliptin in Participants With Type 2 Diabetes

Baseline characteristics by cohort

Measure	Placebo n=93 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=92 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=98 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=99 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=61 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.	Total n=506 Participants Total of all reporting groups
Age Continuous	53.1 years STANDARD_DEVIATION 8.88 • n=5 Participants	51.6 years STANDARD_DEVIATION 10.41 • n=7 Participants	53.2 years STANDARD_DEVIATION 9.46 • n=5 Participants	53.0 years STANDARD_DEVIATION 9.88 • n=4 Participants	51.8 years STANDARD_DEVIATION 10.37 • n=21 Participants	52.6 years STANDARD_DEVIATION 9.44 • n=8 Participants	52.6 years STANDARD_DEVIATION 9.71 • n=8 Participants
Age, Customized <65 Years	81 participants n=5 Participants	80 participants n=7 Participants	86 participants n=5 Participants	85 participants n=4 Participants	56 participants n=21 Participants	52 participants n=8 Participants	440 participants n=8 Participants
Age, Customized ≥65 years	12 participants n=5 Participants	12 participants n=7 Participants	12 participants n=5 Participants	14 participants n=4 Participants	7 participants n=21 Participants	9 participants n=8 Participants	66 participants n=8 Participants
Sex: Female, Male Female	39 Participants n=5 Participants	37 Participants n=7 Participants	50 Participants n=5 Participants	48 Participants n=4 Participants	24 Participants n=21 Participants	33 Participants n=8 Participants	231 Participants n=8 Participants
Sex: Female, Male Male	54 Participants n=5 Participants	55 Participants n=7 Participants	48 Participants n=5 Participants	51 Participants n=4 Participants	39 Participants n=21 Participants	28 Participants n=8 Participants	275 Participants n=8 Participants
Race/Ethnicity, Customized	93 participants n=5 Participants	92 participants n=7 Participants	98 participants n=5 Participants	99 participants n=4 Participants	63 participants n=21 Participants	61 participants n=8 Participants	506 participants n=8 Participants
Region of Enrollment Taiwan	1 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants	3 participants n=4 Participants	0 participants n=21 Participants	0 participants n=8 Participants	6 participants n=8 Participants
Region of Enrollment Hong Kong	1 participants n=5 Participants	2 participants n=7 Participants	2 participants n=5 Participants	4 participants n=4 Participants	0 participants n=21 Participants	0 participants n=8 Participants	9 participants n=8 Participants
Region of Enrollment China	91 participants n=5 Participants	90 participants n=7 Participants	94 participants n=5 Participants	92 participants n=4 Participants	63 participants n=21 Participants	61 participants n=8 Participants	491 participants n=8 Participants
Height	165.4 cm STANDARD_DEVIATION 7.19 • n=5 Participants	165.9 cm STANDARD_DEVIATION 8.61 • n=7 Participants	164.8 cm STANDARD_DEVIATION 8.47 • n=5 Participants	165.7 cm STANDARD_DEVIATION 9.06 • n=4 Participants	166.2 cm STANDARD_DEVIATION 8.87 • n=21 Participants	163.0 cm STANDARD_DEVIATION 7.06 • n=8 Participants	165.2 cm STANDARD_DEVIATION 8.31 • n=8 Participants
Weight	70.86 kg STANDARD_DEVIATION 10.464 • n=5 Participants	71.16 kg STANDARD_DEVIATION 11.065 • n=7 Participants	69.67 kg STANDARD_DEVIATION 11.792 • n=5 Participants	71.20 kg STANDARD_DEVIATION 13.473 • n=4 Participants	72.44 kg STANDARD_DEVIATION 11.989 • n=21 Participants	67.59 kg STANDARD_DEVIATION 11.989 • n=8 Participants	70.55 kg STANDARD_DEVIATION 11.856 • n=8 Participants
Body Mass Index (BMI)	25.86 kg/m^2 STANDARD_DEVIATION 3.002 • n=5 Participants	25.79 kg/m^2 STANDARD_DEVIATION 3.086 • n=7 Participants	25.54 kg/m^2 STANDARD_DEVIATION 2.876 • n=5 Participants	25.75 kg/m^2 STANDARD_DEVIATION 3.122 • n=4 Participants	26.13 kg/m^2 STANDARD_DEVIATION 3.031 • n=21 Participants	25.32 kg/m^2 STANDARD_DEVIATION 3.223 • n=8 Participants	25.73 kg/m^2 STANDARD_DEVIATION 3.042 • n=8 Participants
Diabetes duration	2.12 years STANDARD_DEVIATION 2.845 • n=5 Participants	1.86 years STANDARD_DEVIATION 2.369 • n=7 Participants	5.33 years STANDARD_DEVIATION 3.873 • n=5 Participants	5.38 years STANDARD_DEVIATION 4.335 • n=4 Participants	4.85 years STANDARD_DEVIATION 4.724 • n=21 Participants	5.80 years STANDARD_DEVIATION 5.300 • n=8 Participants	4.11 years STANDARD_DEVIATION 4.215 • n=8 Participants
HbA1c <8.0%	47 participants n=5 Participants	48 participants n=7 Participants	54 participants n=5 Participants	55 participants n=4 Participants	34 participants n=21 Participants	32 participants n=8 Participants	270 participants n=8 Participants
HbA1c ≥8.0%	46 participants n=5 Participants	44 participants n=7 Participants	44 participants n=5 Participants	44 participants n=4 Participants	29 participants n=21 Participants	29 participants n=8 Participants	236 participants n=8 Participants
Stable Daily Dose of Metformin	NA mg STANDARD_DEVIATION NA • n=5 Participants	NA mg STANDARD_DEVIATION NA • n=7 Participants	1484.2 mg STANDARD_DEVIATION 451.09 • n=5 Participants	1472.2 mg STANDARD_DEVIATION 417.31 • n=4 Participants	1355.0 mg STANDARD_DEVIATION 431.80 • n=21 Participants	1295.0 mg STANDARD_DEVIATION 506.82 • n=8 Participants	1426.6 mg STANDARD_DEVIATION 450.90 • n=8 Participants
Stable Daily Dose of Pioglitazone	NA mg STANDARD_DEVIATION NA • n=5 Participants	NA mg STANDARD_DEVIATION NA • n=7 Participants	NA mg STANDARD_DEVIATION NA • n=5 Participants	NA mg STANDARD_DEVIATION NA • n=4 Participants	21.9 mg STANDARD_DEVIATION 11.37 • n=21 Participants	20.2 mg STANDARD_DEVIATION 7.19 • n=8 Participants	21.0 mg STANDARD_DEVIATION 9.55 • n=8 Participants

PRIMARY outcome

Timeframe: Baseline and Week 16.

Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.

The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Week 16. Least squares means are derived from an analysis of covariance (ANCOVA) model with treatment as a fixed effect, and baseline HbA1c as a covariate for the monotherapy, baseline HbA1c with baseline metformin dose as covariates for the metformin therapy, baseline HbA1c with baseline metformin therapy status and baseline pioglitazone dose as covariates for the pioglitazone therapy.

Outcome measures

Measure	Placebo n=90 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=90 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=97 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=98 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=60 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Change From Baseline in Glycosylated Hemoglobin (HbA1c)	-0.42 percentage glycosylated hemoglobin Standard Error 0.074	-0.99 percentage glycosylated hemoglobin Standard Error 0.074	-0.22 percentage glycosylated hemoglobin Standard Error 0.065	-0.91 percentage glycosylated hemoglobin Standard Error 0.065	-0.25 percentage glycosylated hemoglobin Standard Error 0.097	-0.76 percentage glycosylated hemoglobin Standard Error 0.101

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8 and 12.

Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.

The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) at Weeks 4, 8 and 12. Least squares means are derived from an analysis of covariance (ANCOVA) model with treatment as a fixed effect, and baseline HbA1c as a covariate for the monotherapy, baseline HbA1c with baseline metformin dose as covariates for the metformin therapy, baseline HbA1c with baseline metformin therapy status and baseline pioglitazone dose as covariates for the pioglitazone therapy.

Outcome measures

Measure	Placebo n=92 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=92 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=98 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=99 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=61 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Change From Baseline in HbA1c Over Time Week 12 (n=90, 90, 97, 98, 63, 60)	-0.41 percentage glycosylated hemoglobin Standard Error 0.078	-0.99 percentage glycosylated hemoglobin Standard Error 0.078	-0.24 percentage glycosylated hemoglobin Standard Error 0.069	-0.86 percentage glycosylated hemoglobin Standard Error 0.068	-0.25 percentage glycosylated hemoglobin Standard Error 0.102	-0.77 percentage glycosylated hemoglobin Standard Error 0.106
Change From Baseline in HbA1c Over Time Week 4 (n=90, 88, 97, 98, 63, 60)	-0.24 percentage glycosylated hemoglobin Standard Error 0.059	-0.56 percentage glycosylated hemoglobin Standard Error 0.059	-0.15 percentage glycosylated hemoglobin Standard Error 0.036	-0.43 percentage glycosylated hemoglobin Standard Error 0.036	-0.09 percentage glycosylated hemoglobin Standard Error 0.064	-0.44 percentage glycosylated hemoglobin Standard Error 0.066
Change From Baseline in HbA1c Over Time Week 8 (n=90, 90, 97, 98, 63, 60)	-0.39 percentage glycosylated hemoglobin Standard Error 0.068	-0.86 percentage glycosylated hemoglobin Standard Error 0.068	-0.15 percentage glycosylated hemoglobin Standard Error 0.057	-0.66 percentage glycosylated hemoglobin Standard Error 0.057	-0.31 percentage glycosylated hemoglobin Standard Error 0.094	-0.70 percentage glycosylated hemoglobin Standard Error 0.098

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, 12 and 16.

Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline FPG assessment. Last observation carried forward was utilized.

The change from Baseline in fasting plasma glucose (FPG) at Weeks 4, 8, 12 and 16. Least squares means are derived from an ANCOVA model with treatment as a fixed effect, and baseline FPG as a covariate for the monotherapy, baseline FPG with baseline metformin dose as covariates for the metformin therapy, baseline FPG with baseline metformin therapy status and baseline pioglitazone dose as covariates for the pioglitazone therapy.

Outcome measures

Measure	Placebo n=92 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=92 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=98 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=99 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=61 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Change From Baseline in Fasting Plasma Glucose Over Time Week 8 (n=89, 89, 97, 97, 63, 60)	-0.330 mmol/L Standard Error 0.1224	-1.015 mmol/L Standard Error 0.1224	-0.235 mmol/L Standard Error 0.1397	-1.265 mmol/L Standard Error 0.1397	-0.038 mmol/L Standard Error 0.2503	-0.924 mmol/L Standard Error 0.2600
Change From Baseline in Fasting Plasma Glucose Over Time Week 4 (n=89, 87, 97, 97, 63, 60)	-0.331 mmol/L Standard Error 0.1221	-0.719 mmol/L Standard Error 0.1235	-0.251 mmol/L Standard Error 0.1454	-0.985 mmol/L Standard Error 0.1454	0.284 mmol/L Standard Error 0.2505	-0.985 mmol/L Standard Error 0.2603
Change From Baseline in Fasting Plasma Glucose Over Time Week 12 (n=89, 89, 97, 97, 63, 60)	-0.411 mmol/L Standard Error 0.1515	-1.123 mmol/L Standard Error 0.1515	-0.335 mmol/L Standard Error 0.1600	-1.270 mmol/L Standard Error 0.1600	-0.187 mmol/L Standard Error 0.2484	-1.177 mmol/L Standard Error 0.2581
Change From Baseline in Fasting Plasma Glucose Over Time Week 16 (n=89, 89, 97, 97, 63, 60)	-0.317 mmol/L Standard Error 0.1556	-1.243 mmol/L Standard Error 0.1556	-0.512 mmol/L Standard Error 0.1565	-1.240 mmol/L Standard Error 0.1565	-0.114 mmol/L Standard Error 0.2579	-1.070 mmol/L Standard Error 0.2679

SECONDARY outcome

Timeframe: Randomization to Week 16.

Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline assessment.

Marked Hyperglycemia was defined as fasting plasma glucose greater than or equal to 200 mg/dL (11.1 mmol/L).

Outcome measures

Measure	Placebo n=89 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=89 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=97 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=97 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=60 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Percentage of Participants With Marked Hyperglycemia	16.9 percentage of participants	4.5 percentage of participants	25.8 percentage of participants	13.4 percentage of participants	23.8 percentage of participants	8.3 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 8 and 16.

Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline weight assessment. Last observation carried forward was utilized.

The change between body weight measured at Baseline and body weight measured at Weeks 8 and 16. The least squares means are derived from an ANCOVA model with treatment as a fixed effect, and baseline body weight as a covariate for the monotherapy, baseline body weight with baseline metformin dose as covariates for the add-on to metformin therapy, baseline body weight with baseline metformin therapy status and baseline pioglitazone dose as covariates for the add-on to pioglitazone therapy.

Outcome measures

Measure	Placebo n=92 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=92 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=98 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=99 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=61 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Change From Baseline in Body Weight Week 8 (n=87, 86, 94, 96, 63, 59)	-1.04 kg Standard Error 0.210	-0.71 kg Standard Error 0.211	-0.82 kg Standard Error 0.170	-0.43 kg Standard Error 0.168	-0.74 kg Standard Error 0.286	-0.15 kg Standard Error 0.304
Change From Baseline in Body Weight Week 16 (n=88, 87, 94, 96, 63, 59)	-1.55 kg Standard Error 0.244	-0.89 kg Standard Error 0.245	-1.06 kg Standard Error 0.219	-0.76 kg Standard Error 0.217	-0.68 kg Standard Error 0.364	-0.10 kg Standard Error 0.388

SECONDARY outcome

Timeframe: Week 16

Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.

Clinical response was assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than or equal to 6.5% at Week 16.

Outcome measures

Measure	Placebo n=90 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=90 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=97 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=98 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=60 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Percentage of Participants With HbA1c ≤6.5% at Week 16	12.2 percentage of participants	36.7 percentage of participants	4.1 percentage of participants	21.4 percentage of participants	9.5 percentage of participants	30.0 percentage of participants

SECONDARY outcome

Timeframe: Week 16

Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.

Clinical response was assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than or equal to 7.0% at Week 16.

Outcome measures

Measure	Placebo n=90 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=90 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=97 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=98 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=60 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Percentage of Participants With HbA1c ≤7.0% at Week 16	30.0 percentage of participants	63.3 percentage of participants	25.8 percentage of participants	55.1 percentage of participants	31.7 percentage of participants	61.7 percentage of participants

SECONDARY outcome

Timeframe: Week 16

Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.

Clinical response was assessed by the percentage of participants with HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than or equal to 7.5% at Week 16.

Outcome measures

Measure	Placebo n=90 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=90 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=97 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=98 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=60 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Percentage of Participants With HbA1c ≤7.5% at Week 16	53.3 percentage of participants	81.1 percentage of participants	50.5 percentage of participants	80.6 percentage of participants	47.6 percentage of participants	85.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.

Clinical response was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 0.5% at Week 16.

Outcome measures

Measure	Placebo n=90 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=90 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=97 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=98 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=60 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Percentage of Participants With a Decrease in HbA1c ≥ 0.5%	41.1 percentage of participants	84.4 percentage of participants	37.1 percentage of participants	70.4 percentage of participants	42.9 percentage of participants	76.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.

Clinical response was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1.0% at Week 16.

Outcome measures

Measure	Placebo n=90 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=90 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=97 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=98 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=60 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Percentage of Participants With a Decrease in HbA1c ≥1.0%	20.0 percentage of participants	50.0 percentage of participants	9.3 percentage of participants	45.9 percentage of participants	19.0 percentage of participants	46.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Week 16.

Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.

Clinical response was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1.5% at Week 16.

Outcome measures

Measure	Placebo n=90 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=90 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=97 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=98 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=60 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Percentage of Participants With a Decrease in HbA1c ≥1.5%	7.8 percentage of participants	23.3 percentage of participants	1.0 percentage of participants	22.4 percentage of participants	7.9 percentage of participants	8.3 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Week 16.

Population: The full analysis set, consisting of all patients who received at least one dose of double-blind study drug and who had a baseline assessment and at least one post-baseline HbA1c assessment. Last observation carried forward was utilized.

Clinical response was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 2.0% at Week 16.

Outcome measures

Measure	Placebo n=90 Participants Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=90 Participants Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=97 Participants Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=98 Participants Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=60 Participants Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Percentage of Participants With a Decrease in HbA1c ≥2.0%	2.2 percentage of participants	8.9 percentage of participants	0.0 percentage of participants	9.2 percentage of participants	1.6 percentage of participants	3.3 percentage of participants

Adverse Events

Placebo

Serious events: 2 serious events

Other events: 11 other events

Deaths: 0 deaths

Alogliptin Monotherapy

Serious events: 2 serious events

Other events: 12 other events

Deaths: 0 deaths

Metformin

Serious events: 3 serious events

Other events: 8 other events

Deaths: 0 deaths

Metformin + Alogliptin Add-on Therapy

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Pioglitazone

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Pioglitazone + Alogliptin Add-on Therapy

Serious events: 1 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=92 participants at risk Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=92 participants at risk Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=98 participants at risk Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=99 participants at risk Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 participants at risk Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=61 participants at risk Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Cardiac disorders Atrial fibrillation	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.0% 1/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Coronary artery disease	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.0% 1/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Pancreatitis acute	1.1% 1/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Hepatobiliary disorders Cholangitis acute	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.1% 1/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Cellulitis	1.1% 1/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.0% 1/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Intraductal papilloma of breast	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.1% 1/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Lacunar infarction	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.6% 1/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Hypertension	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.0% 1/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Other adverse events

Measure	Placebo n=92 participants at risk Participants received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks	Alogliptin Monotherapy n=92 participants at risk Participants received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Metformin n=98 participants at risk Participants continued to receive their stable dose of Metformin (≥1000 mg/day) and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Metformin + Alogliptin Add-on Therapy n=99 participants at risk Participants continued to receive their stable dose of metformin (≥1000 mg/day) and also received alogliptin 25 mg tablets, orally, once daily for up to 16 weeks.	Pioglitazone n=63 participants at risk Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin placebo-matching tablets, orally once daily for up to 16 weeks.	Pioglitazone + Alogliptin Add-on Therapy n=61 participants at risk Participants continued to receive their stable dose of pioglitazone with or without metformin and also received alogliptin, 25 mg tablets orally once daily for up to 16 weeks.
Metabolism and nutrition disorders Hyperlipidaemia	1.1% 1/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	6.5% 6/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	6.3% 4/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	21.3% 13/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Upper respiratory tract infection	3.3% 3/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.4% 5/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.1% 5/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.0% 3/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	9.5% 6/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.3% 2/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Urinary tract infection	6.5% 6/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.2% 2/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 2/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 2/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.6% 1/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	6.6% 4/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Investigations Blood triglycerides increased	1.1% 1/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.2% 2/92 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 2/98 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 2/99 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	6.3% 4/63 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/61 • Treatment-emergent adverse events (TEAE) were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 days after the date of the last dose of double-blind study drug. The investigator had to document any occurrence of adverse events at each visit, and the occurrence of abnormal laboratory findings at applicable visits. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Additional Information

Sr. VP, Clinical Science

Takeda Global Research and Development Center, Inc.

Phone: 800-778-2860

Email: clinicaltrialregistry@tpna.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER