Trial Outcomes & Findings for Efficacy of Alogliptin and Pioglitazone in Subjects With Type 2 Diabetes Mellitus (NCT NCT00432276)

NCT ID: NCT00432276

Last Updated: 2013-04-04

Results Overview

The change from Baseline to Week 26 and Week 52 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 803 participants
• Primary outcome timeframe: Baseline and Weeks 26 and 52.
• Results posted on: 2013-04-04

Participant Flow

Participants took part in the study at 235 investigative sites in 16 countries worldwide from 30 January 2007 to 5 June 2009.

Participants with a diagnosis of type 2 diabetes who were experiencing inadequate glycemic control on their existing treatment regimen of metformin HCl plus pioglitazone were randomized in a 1:1 ratio to 1 of 2 treatment arms: addition of alogliptin 25 mg versus titration of pioglitazone 30 mg to 45 mg.

Participant milestones

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Overall Study STARTED	404	399
Overall Study Per Protocol Set	303	306
Overall Study COMPLETED	283	243
Overall Study NOT COMPLETED	121	156

Reasons for withdrawal

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Overall Study Hyperglycemic Rescue	44	87
Overall Study Adverse Event	13	16
Overall Study Protocol Violation	25	20
Overall Study Lost to Follow-up	6	2
Overall Study Withdrawal by Subject	25	20
Overall Study Physician Decision	6	8
Overall Study Other	2	3

Baseline Characteristics

Efficacy of Alogliptin and Pioglitazone in Subjects With Type 2 Diabetes Mellitus

Baseline characteristics by cohort

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Total n=803 Participants Total of all reporting groups
Age Continuous	54.3 years STANDARD_DEVIATION 9.86 • n=5 Participants	55.9 years STANDARD_DEVIATION 9.94 • n=7 Participants	55.1 years STANDARD_DEVIATION 9.93 • n=5 Participants
Age, Customized <65 years	339 participants n=5 Participants	320 participants n=7 Participants	659 participants n=5 Participants
Age, Customized ≥65 years	65 participants n=5 Participants	79 participants n=7 Participants	144 participants n=5 Participants
Sex: Female, Male Female	194 Participants n=5 Participants	195 Participants n=7 Participants	389 Participants n=5 Participants
Sex: Female, Male Male	210 Participants n=5 Participants	204 Participants n=7 Participants	414 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	30 Participants n=5 Participants	31 Participants n=7 Participants	61 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	374 Participants n=5 Participants	368 Participants n=7 Participants	742 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized Asian	79 participants n=5 Participants	78 participants n=7 Participants	157 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	41 participants n=5 Participants	36 participants n=7 Participants	77 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized White	242 participants n=5 Participants	256 participants n=7 Participants	498 participants n=5 Participants
Race/Ethnicity, Customized Other	38 participants n=5 Participants	29 participants n=7 Participants	67 participants n=5 Participants
Height	166.82 cm STANDARD_DEVIATION 9.884 • n=5 Participants	166.37 cm STANDARD_DEVIATION 10.856 • n=7 Participants	166.60 cm STANDARD_DEVIATION 10.375 • n=5 Participants
Weight	88.16 kg STANDARD_DEVIATION 18.898 • n=5 Participants	87.98 kg STANDARD_DEVIATION 19.283 • n=7 Participants	88.07 kg STANDARD_DEVIATION 19.078 • n=5 Participants
BMI	31.52 kg/m^2 STANDARD_DEVIATION 5.248 • n=5 Participants	31.58 kg/m^2 STANDARD_DEVIATION 5.177 • n=7 Participants	31.55 kg/m^2 STANDARD_DEVIATION 5.210 • n=5 Participants
Duration of diabetes	7.47 years STANDARD_DEVIATION 5.243 • n=5 Participants	6.85 years STANDARD_DEVIATION 4.611 • n=7 Participants	7.16 years STANDARD_DEVIATION 4.946 • n=5 Participants
Baseline daily metformin HCl use	1700.0 mg n=5 Participants	1700.0 mg n=7 Participants	1700.0 mg n=5 Participants
Current smoker Yes	100 participants n=5 Participants	99 participants n=7 Participants	199 participants n=5 Participants
Current smoker No	304 participants n=5 Participants	300 participants n=7 Participants	604 participants n=5 Participants
HbA1c <8.0%	161 participants n=5 Participants	163 participants n=7 Participants	324 participants n=5 Participants
HbA1c ≥8.0%	243 participants n=5 Participants	236 participants n=7 Participants	479 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Weeks 26 and 52.

Population: Per-protocol set included all randomized patients who received at least 1 dose of double-blind study medication and who had no major protocol violations. Last observation carried forward (LOCF) imputation was utilized.

The change from Baseline to Week 26 and Week 52 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound).

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=303 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=306 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Glycosylated Hemoglobin (HbA1c) Change from Baseline at Week 26	-0.89 percentage of glycosylated hemoglobin Standard Error 0.042	-0.42 percentage of glycosylated hemoglobin Standard Error 0.042
Change From Baseline in Glycosylated Hemoglobin (HbA1c) Change from Baseline at Week 52	-0.70 percentage of glycosylated hemoglobin Standard Error 0.048	-0.29 percentage of glycosylated hemoglobin Standard Error 0.048

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, 12, 16, 20, 34 and 42.

Population: Per-protocol set. Last observation carried forward (LOCF) imputation 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) during the study. Least Squares Means were 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.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=303 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=306 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in HbA1c Over Time Change from Baseline at Week 4 (n=276, 277)	-0.42 percentage of glycosylated hemoglobin Standard Error 0.025	-0.15 percentage of glycosylated hemoglobin Standard Error 0.025
Change From Baseline in HbA1c Over Time Change from Baseline at Week 8 (n=303, 306)	-0.71 percentage of glycosylated hemoglobin Standard Error 0.030	-0.27 percentage of glycosylated hemoglobin Standard Error 0.030
Change From Baseline in HbA1c Over Time Change from Baseline at Week 12 (n=303, 306)	-0.85 percentage of glycosylated hemoglobin Standard Error 0.037	-0.35 percentage of glycosylated hemoglobin Standard Error 0.037
Change From Baseline in HbA1c Over Time Change from Baseline at Week 16 (n=303, 306)	-0.91 percentage of glycosylated hemoglobin Standard Error 0.039	-0.43 percentage of glycosylated hemoglobin Standard Error 0.038
Change From Baseline in HbA1c Over Time Change from Baseline at Week 20 (n=303, 306)	-0.91 percentage of glycosylated hemoglobin Standard Error 0.039	-0.45 percentage of glycosylated hemoglobin Standard Error 0.039
Change From Baseline in HbA1c Over Time Change from Baseline at Week 34 (n=303, 306)	-0.82 percentage of glycosylated hemoglobin Standard Error 0.046	-0.37 percentage of glycosylated hemoglobin Standard Error 0.045
Change From Baseline in HbA1c Over Time Change from Baseline at Week 42 (n=303, 306)	-0.80 percentage of glycosylated hemoglobin Standard Error 0.048	-0.36 percentage of glycosylated hemoglobin Standard Error 0.048

SECONDARY outcome

Timeframe: Weeks 26 and 52.

Population: The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with HbA1c less than or equal to 6.5%.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Percentage of Participants With Glycosylated Hemoglobin ≤ 6.5% Week 26	13.9 percentage of participants	7.8 percentage of participants
Percentage of Participants With Glycosylated Hemoglobin ≤ 6.5% Week 52	8.7 percentage of participants	4.3 percentage of participants

SECONDARY outcome

Timeframe: Weeks 26 and 52.

Population: The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with HbA1c less than or equal to 7%.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Percentage of Participants With Glycosylated Hemoglobin ≤ 7.0% Week 26	39.1 percentage of participants	25.8 percentage of participants
Percentage of Participants With Glycosylated Hemoglobin ≤ 7.0% Week 52	33.2 percentage of participants	21.3 percentage of participants

SECONDARY outcome

Timeframe: Weeks 26 and 52.

Population: The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with HbA1c less than or equal to 7.5%.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Percentage of Participants With Glycosylated Hemoglobin ≤ 7.5% Week 26	64.9 percentage of participants	47.1 percentage of participants
Percentage of Participants With Glycosylated Hemoglobin ≤ 7.5% Week 52	59.9 percentage of participants	44.1 percentage of participants

SECONDARY outcome

Timeframe: Weeks 26 and 52.

Population: The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 0.5%.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 0.5% Week 26	72.0 percentage of participants	42.1 percentage of participants
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 0.5% Week 52	60.9 percentage of participants	37.6 percentage of participants

SECONDARY outcome

Timeframe: Weeks 26 and 52.

Population: The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1.0%.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.0% Week 26	42.3 percentage of participants	20.3 percentage of participants
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.0% Week 52	35.6 percentage of participants	17.3 percentage of participants

SECONDARY outcome

Timeframe: Weeks 26 and 52.

Population: The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 1.5%.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.5% Week 26	18.6 percentage of participants	7.5 percentage of participants
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 1.5% Week 52	17.1 percentage of participants	8.0 percentage of participants

SECONDARY outcome

Timeframe: Weeks 26 and 52.

Population: The full analysis set. Patients who did not complete the scheduled Week 26 or Week 52 visit were assessed based on their response at the time of discontinuation.

Clinical response at Weeks 26 and 52 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of greater than or equal to 2.0%.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 2.0% Week 52	7.9 percentage of participants	3.3 percentage of participants
Percentage of Participants With a Decrease in Glycosylated Hemoglobin ≥ 2.0% Week 26	8.2 percentage of participants	3.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Population: The full analysis set, which included all randomized patients who received at least 1 dose of double-blind study drug and where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

The change from Baseline in fasting plasma glucose (FPG) was assessed at Weeks 2, 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least Squares Means were from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline FPG as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Fasting Plasma Glucose Week 12 (n=399, 396)	-19.6 mg/dL Standard Error 1.60	-4.8 mg/dL Standard Error 1.61
Change From Baseline in Fasting Plasma Glucose Week 2 (n=360, 345)	-15.5 mg/dL Standard Error 1.56	-0.5 mg/dL Standard Error 1.59
Change From Baseline in Fasting Plasma Glucose Week 4 (n=397, 394)	-17.7 mg/dL Standard Error 1.48	-1.4 mg/dL Standard Error 1.49
Change From Baseline in Fasting Plasma Glucose Week 8 (n=399, 396)	-19.1 mg/dL Standard Error 1.56	-5.7 mg/dL Standard Error 1.57
Change From Baseline in Fasting Plasma Glucose Week 16 (n=399, 396)	-18.0 mg/dL Standard Error 1.60	-4.5 mg/dL Standard Error 1.60
Change From Baseline in Fasting Plasma Glucose Week 20 (n=399, 396)	-16.4 mg/dL Standard Error 1.65	-5.8 mg/dL Standard Error 1.66
Change From Baseline in Fasting Plasma Glucose Week 26 (n=399, 396)	-17.1 mg/dL Standard Error 1.79	-4.9 mg/dL Standard Error 1.79
Change From Baseline in Fasting Plasma Glucose Week 34 (n=399, 396)	-13.6 mg/dL Standard Error 1.88	-6.2 mg/dL Standard Error 1.88
Change From Baseline in Fasting Plasma Glucose Week 42 (n=399, 396)	-15.9 mg/dL Standard Error 1.87	-4.9 mg/dL Standard Error 1.88
Change From Baseline in Fasting Plasma Glucose Week 52 (n=399, 396)	-14.6 mg/dL Standard Error 1.89	-3.7 mg/dL Standard Error 1.89

SECONDARY outcome

Timeframe: Baseline to Week 52

Population: Full Analysis Set including patients with at least one non-missing fasting plasma glucose result in each treatment group.

Marked Hyperglycemia is defined as fasting plasma glucose greater than or equal to 200 mg/dL (11.10 mmol/L).

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=399 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=396 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Percentage of Participants With Marked Hyperglycemia	27.3 percentage of participants	36.1 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Week 52

Population: Full Analysis Set including patients with a postbaseline visit.

Rescue was defined as meeting 1 of the following criteria, confirmed by a 2nd sample drawn within 7 days after the first sample and analyzed by the central laboratory:

1. After more than 2 weeks of treatment but prior to the Week 4 Visit: A single fasting plasma glucose (FPG) ≥275 mg/dL;

2. From the Week 4 Visit but prior to the Week 8 Visit: A single FPG ≥250 mg/dL;

3. From the Week 8 Visit but prior to the Week 12 Visit: A single FPG ≥225 mg/dL;

4. From the Week 12 Visit through the End-of-Treatment Visit: HbA1c ≥8.5% AND ≤0.5% reduction in HbA1c as compared with the baseline HbA1c.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=402 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=397 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Percentage of Participants Meeting Hyperglycemic Rescue Criteria	10.9 percentage of participants	21.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Proinsulin is a precursor to insulin, and was measured as an indicator of pancreatic function. The change from Baseline in fasting proinsulin was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least Squares Means were from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline fasting proinsulin as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Fasting Proinsulin Week 4 (n=342, 325)	-2.0 pmol/L Standard Error 0.67	-0.8 pmol/L Standard Error 0.69
Change From Baseline in Fasting Proinsulin Week 8 (n=380, 376)	-2.3 pmol/L Standard Error 0.77	-0.5 pmol/L Standard Error 0.77
Change From Baseline in Fasting Proinsulin Week 12 (n=380, 376)	-1.3 pmol/L Standard Error 0.89	1.6 pmol/L Standard Error 0.89
Change From Baseline in Fasting Proinsulin Week 16 (n=381, 376)	-0.2 pmol/L Standard Error 1.01	0.6 pmol/L Standard Error 1.02
Change From Baseline in Fasting Proinsulin Week 20 (n=381, 376)	-0.5 pmol/L Standard Error 0.67	0.3 pmol/L Standard Error 0.68
Change From Baseline in Fasting Proinsulin Week 26 (n=381, 376)	0.6 pmol/L Standard Error 0.82	0.7 pmol/L Standard Error 0.83
Change From Baseline in Fasting Proinsulin Week 34 (n=381, 376)	0.9 pmol/L Standard Error 0.86	0.3 pmol/L Standard Error 0.86
Change From Baseline in Fasting Proinsulin Week 42 (n=381, 376)	-0.1 pmol/L Standard Error 0.80	1.1 pmol/L Standard Error 0.81
Change From Baseline in Fasting Proinsulin Week 52 (n=381, 376)	-0.5 pmol/L Standard Error 0.74	1.2 pmol/L Standard Error 0.74

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

The change from Baseline in fasting insulin was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least Squares Means were from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline fasting insulin as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Fasting Insulin Week 4 (n=344, 328)	0.53 μIU/mL Standard Error 0.346	-0.54 μIU/mL Standard Error 0.355
Change From Baseline in Fasting Insulin Week 8 (n=382, 378)	0.72 μIU/mL Standard Error 0.393	0.05 μIU/mL Standard Error 0.395
Change From Baseline in Fasting Insulin Week 16 (n=383, 378)	1.19 μIU/mL Standard Error 0.414	0.56 μIU/mL Standard Error 0.416
Change From Baseline in Fasting Insulin Week 12 (n=382, 378)	1.21 μIU/mL Standard Error 0.505	1.22 μIU/mL Standard Error 0.507
Change From Baseline in Fasting Insulin Week 20 (n=383, 378)	1.60 μIU/mL Standard Error 0.414	0.38 μIU/mL Standard Error 0.417
Change From Baseline in Fasting Insulin Week 26 (n=383, 378)	1.94 μIU/mL Standard Error 0.479	0.88 μIU/mL Standard Error 0.482
Change From Baseline in Fasting Insulin Week 34 (n=383, 378)	1.41 μIU/mL Standard Error 0.430	0.83 μIU/mL Standard Error 0.433
Change From Baseline in Fasting Insulin Week 42 (n=383, 378)	1.79 μIU/mL Standard Error 0.441	1.10 μIU/mL Standard Error 0.443
Change From Baseline in Fasting Insulin Week 52 (n=383, 378)	1.91 μIU/mL Standard Error 0.470	1.18 μIU/mL Standard Error 0.473

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

The ratio of proinsulin to insulin was calculated as proinsulin (pmol/L) / insulin (μIU/mL) at weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52 relative to the Baseline value. Least squares means were from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline fasting proinsulin/insulin ratio as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Proinsulin/Insulin Ratio Week 4 (n=341, 325)	-0.046 ratio Standard Error 0.0095	-0.005 ratio Standard Error 0.0097
Change From Baseline in Proinsulin/Insulin Ratio Week 8 (n=380, 375)	-0.049 ratio Standard Error 0.0148	-0.001 ratio Standard Error 0.0149
Change From Baseline in Proinsulin/Insulin Ratio Week 12 (n=380, 375)	-0.053 ratio Standard Error 0.0105	0.004 ratio Standard Error 0.0106
Change From Baseline in Proinsulin/Insulin Ratio Week 16 (n=381, 375)	-0.044 ratio Standard Error 0.0100	0.002 ratio Standard Error 0.0101
Change From Baseline in Proinsulin/Insulin Ratio Week 20 (n=381, 375)	-0.037 ratio Standard Error 0.0085	-0.004 ratio Standard Error 0.0085
Change From Baseline in Proinsulin/Insulin Ratio Week 26 (n=381, 375)	-0.036 ratio Standard Error 0.0081	-0.015 ratio Standard Error 0.0081
Change From Baseline in Proinsulin/Insulin Ratio Week 34 (n=381, 375)	-0.038 ratio Standard Error 0.0084	-0.004 ratio Standard Error 0.0085
Change From Baseline in Proinsulin/Insulin Ratio Week 42 (n=381, 375)	-0.047 ratio Standard Error 0.0083	-0.010 ratio Standard Error 0.0083
Change From Baseline in Proinsulin/Insulin Ratio Week 52 (n=381, 375)	-0.048 ratio Standard Error 0.0080	-0.007 ratio Standard Error 0.0081

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

C-peptide is a byproduct created when the hormone insulin is produced and is measured by a blood test. Change from Baseline was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline fasting C-peptide as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in C-peptide Week 42 (n=395, 390)	0.140 ng/mL Standard Error 0.0413	0.037 ng/mL Standard Error 0.0415
Change From Baseline in C-peptide Week 4 (n=349, 333)	0.110 ng/mL Standard Error 0.0350	-0.033 ng/mL Standard Error 0.0358
Change From Baseline in C-peptide Week 8 (n=393, 389)	0.074 ng/mL Standard Error 0.0387	-0.038 ng/mL Standard Error 0.0389
Change From Baseline in C-peptide Week 12 (n=394, 390)	0.070 ng/mL Standard Error 0.0459	0.030 ng/mL Standard Error 0.0462
Change From Baseline in C-peptide Week 16 (n=395, 390)	0.064 ng/mL Standard Error 0.0380	0.010 ng/mL Standard Error 0.0382
Change From Baseline in C-peptide Week 20 (n=395, 390)	0.104 ng/mL Standard Error 0.0384	-0.001 ng/mL Standard Error 0.0386
Change From Baseline in C-peptide Week 26 (n=395, 390)	0.102 ng/mL Standard Error 0.0407	-0.013 ng/mL Standard Error 0.0409
Change From Baseline in C-peptide Week 34 (n=395, 390)	0.118 ng/mL Standard Error 0.0403	0.003 ng/mL Standard Error 0.0406
Change From Baseline in C-peptide Week 52 (n=395, 390)	0.182 ng/mL Standard Error 0.0430	0.108 ng/mL Standard Error 0.0433

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

The Homeostasis Model Assessment of insulin resistance (HOMA IR) measures insulin resistance based on fasting glucose and insulin measurements:

HOMA IR = fasting plasma insulin (µIU/mL) * fasting plasma glucose (mmol/L) / 22.5

A higher number indicates a greater degree of insulin resistance. The change from Baseline in HOMA IR was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline HOMA insulin resistance as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Calculated HOMA Insulin Resistance Week 12 (n=380, 378)	0.007 insulin resistance Standard Error 0.2339	0.350 insulin resistance Standard Error 0.2345
Change From Baseline in Calculated HOMA Insulin Resistance Week 26 (n=381, 378)	0.336 insulin resistance Standard Error 0.2446	0.312 insulin resistance Standard Error 0.2455
Change From Baseline in Calculated HOMA Insulin Resistance Week 42 (n=381, 378)	0.200 insulin resistance Standard Error 0.2103	0.431 insulin resistance Standard Error 0.2111
Change From Baseline in Calculated HOMA Insulin Resistance Week 52 (n=381, 378)	0.353 insulin resistance Standard Error 0.2310	0.541 insulin resistance Standard Error 0.2319

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

The Homeostasis Model Assessment (HOMA) estimates steady state beta cell function (%B) as a percentage of a normal reference population.

HOMA %B = 20 * insulin (µIU/mL) / fasting plasma glucose (mmol/L) - 3.5

The change from Baseline in the homeostasis model assessment of beta cell function was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline HOMA beta cell function as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Calculated HOMA Beta-cell Function Week 12 (n=380, 377)	14.770 percentage beta cell function Standard Error 3.6543	4.580 percentage beta cell function Standard Error 3.6689
Change From Baseline in Calculated HOMA Beta-cell Function Week 26 (n=381, 377)	30.012 percentage beta cell function Standard Error 8.6151	3.242 percentage beta cell function Standard Error 8.6608
Change From Baseline in Calculated HOMA Beta-cell Function Week 42 (n=381, 377)	15.397 percentage beta cell function Standard Error 2.7628	2.400 percentage beta cell function Standard Error 2.7774
Change From Baseline in Calculated HOMA Beta-cell Function Week 52 (n=381, 377)	15.020 percentage beta cell function Standard Error 2.7396	2.057 percentage beta cell function Standard Error 2.7541

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in body weight was assessed at Weeks 4, 8, 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline body weight as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Body Weight Week 4 (n=354, 344)	0.18 kg Standard Error 0.094	0.32 kg Standard Error 0.095
Change From Baseline in Body Weight Week 8 (n=394, 394	0.31 kg Standard Error 0.107	0.51 kg Standard Error 0.107
Change From Baseline in Body Weight Week 12 (n=395, 394)	0.35 kg Standard Error 0.124	0.64 kg Standard Error 0.124
Change From Baseline in Body Weight Week 26 (n=395, 394)	0.73 kg Standard Error 0.150	0.97 kg Standard Error 0.150
Change From Baseline in Body Weight Week 42 (n=395, 394)	1.09 kg Standard Error 0.179	1.52 kg Standard Error 0.179
Change From Baseline in Body Weight Week 52 (n=395, 394)	1.10 kg Standard Error 0.194	1.60 kg Standard Error 0.194

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in total cholesterol was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline total cholesterol as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Total Cholesterol Week 4 (n=397, 393)	-5.2 mg/dL Standard Error 1.28	-1.9 mg/dL Standard Error 1.29
Change From Baseline in Total Cholesterol Week 8 (n=399, 395)	-4.0 mg/dL Standard Error 1.40	0.3 mg/dL Standard Error 1.40
Change From Baseline in Total Cholesterol Week 12 (n=399, 395)	-3.6 mg/dL Standard Error 1.44	1.1 mg/dL Standard Error 1.45
Change From Baseline in Total Cholesterol Week 16 (n=399, 395)	-4.3 mg/dL Standard Error 1.56	-0.4 mg/dL Standard Error 1.57
Change From Baseline in Total Cholesterol Week 20 (n=399, 395)	-3.9 mg/dL Standard Error 1.55	-0.5 mg/dL Standard Error 1.56
Change From Baseline in Total Cholesterol Week 26 (n=399, 395)	-2.1 mg/dL Standard Error 1.62	1.0 mg/dL Standard Error 1.63
Change From Baseline in Total Cholesterol Week 34 (n=399, 395)	-3.5 mg/dL Standard Error 1.61	-0.7 mg/dL Standard Error 1.62
Change From Baseline in Total Cholesterol Week 42 (n=399, 395)	-3.8 mg/dL Standard Error 1.62	0.0 mg/dL Standard Error 1.62
Change From Baseline in Total Cholesterol Week 52 (n=399, 395)	-4.4 mg/dL Standard Error 1.58	-0.1 mg/dL Standard Error 1.59

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in high-density lipoprotein cholesterol (HDL-C) was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline HDL cholesterol as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in High-Density Lipoprotein Cholesterol Week 4 (n=397, 392)	-0.7 mg/dL Standard Error 0.33	0.4 mg/dL Standard Error 0.34
Change From Baseline in High-Density Lipoprotein Cholesterol Week 8 (n=399, 395)	-0.8 mg/dL Standard Error 0.35	0.6 mg/dL Standard Error 0.35
Change From Baseline in High-Density Lipoprotein Cholesterol Week 12 (n=399, 395)	-0.2 mg/dL Standard Error 0.42	1.1 mg/dL Standard Error 0.42
Change From Baseline in High-Density Lipoprotein Cholesterol Week 16 (n=399, 395)	-0.5 mg/dL Standard Error 0.37	0.9 mg/dL Standard Error 0.38
Change From Baseline in High-Density Lipoprotein Cholesterol Week 20 (n=399, 395)	-0.2 mg/dL Standard Error 0.37	0.7 mg/dL Standard Error 0.37
Change From Baseline in High-Density Lipoprotein Cholesterol Week 26 (n=399, 395)	0.0 mg/dL Standard Error 0.37	0.6 mg/dL Standard Error 0.37
Change From Baseline in High-Density Lipoprotein Cholesterol Week 34 (n=399, 395)	-0.6 mg/dL Standard Error 0.38	0.3 mg/dL Standard Error 0.38
Change From Baseline in High-Density Lipoprotein Cholesterol Week 42 (n=399, 395)	-0.3 mg/dL Standard Error 0.38	0.6 mg/dL Standard Error 0.38
Change From Baseline in High-Density Lipoprotein Cholesterol Week 52 (n=395, 395)	-0.3 mg/dL Standard Error 0.37	0.3 mg/dL Standard Error 0.37

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in low-density lipoprotein cholesterol (LDL-C) was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline LDL cholesterol as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Low-Density Lipoprotein Cholesterol Week 4 (n=388, 383)	-2.4 mg/dL Standard Error 1.11	0.0 mg/dL Standard Error 1.12
Change From Baseline in Low-Density Lipoprotein Cholesterol Week 8 (n=390, 386)	-0.6 mg/dL Standard Error 1.18	2.1 mg/dL Standard Error 1.19
Change From Baseline in Low-Density Lipoprotein Cholesterol Week 12 (n=390, 386)	-1.2 mg/dL Standard Error 1.21	1.4 mg/dL Standard Error 1.22
Change From Baseline in Low-Density Lipoprotein Cholesterol Week 16 (n=390, 386)	-1.7 mg/dL Standard Error 1.31	-0.1 mg/dL Standard Error 1.32
Change From Baseline in Low-Density Lipoprotein Cholesterol Week 20 (n=390, 386)	-2.0 mg/dL Standard Error 1.24	0.1 mg/dL Standard Error 1.25
Change From Baseline in Low-Density Lipoprotein Cholesterol Week 26 (n=390, 386)	-0.6 mg/dL Standard Error 1.36	1.6 mg/dL Standard Error 1.37
Change From Baseline in Low-Density Lipoprotein Cholesterol Week 34 (n=390, 386)	-1.9 mg/dL Standard Error 1.33	1.2 mg/dL Standard Error 1.33
Change From Baseline in Low-Density Lipoprotein Cholesterol Week 42 (n=390, 386)	-1.6 mg/dL Standard Error 1.35	0.7 mg/dL Standard Error 1.36
Change From Baseline in Low-Density Lipoprotein Cholesterol Week 52 (n=390, 386)	-1.9 mg/dL Standard Error 1.32	1.0 mg/dL Standard Error 1.33

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in triglycerides was assessed at Weeks 4, 8, 12, 16, 20, 26, 34, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline triglycerides as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Triglycerides Week 42 (n=399, 395)	-14.6 mg/dL Standard Error 3.67	-7.0 mg/dL Standard Error 3.69
Change From Baseline in Triglycerides Week 52 (n=399, 395)	-16.4 mg/dL Standard Error 3.47	-7.8 mg/dL Standard Error 3.49
Change From Baseline in Triglycerides Week 4 (n=397, 393)	-16.4 mg/dL Standard Error 2.98	-12.2 mg/dL Standard Error 3.00
Change From Baseline in Triglycerides Week 8 (n=399, 395)	-17.9 mg/dL Standard Error 3.61	-12.3 mg/dL Standard Error 3.63
Change From Baseline in Triglycerides Week 12 (n=399, 395)	-16.1 mg/dL Standard Error 3.69	-4.5 mg/dL Standard Error 3.71
Change From Baseline in Triglycerides Week 16 (n=399, 395)	-16.3 mg/dL Standard Error 3.36	-9.4 mg/dL Standard Error 3.38
Change From Baseline in Triglycerides Week 20 (n=399, 395)	-12.7 mg/dL Standard Error 3.68	-8.5 mg/dL Standard Error 3.70
Change From Baseline in Triglycerides Week 26 (n=399, 395)	-11.9 mg/dL Standard Error 3.98	-6.3 mg/dL Standard Error 4.00
Change From Baseline in Triglycerides Week 34 (n=399, 395)	-7.4 mg/dL Standard Error 3.98	-8.1 mg/dL Standard Error 4.00

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42, and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in free fatty acids was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline free fatty acids as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Free Fatty Acids Week 12 (n=355, 360)	-0.0526 mmol/L Standard Error 0.01037	-0.0332 mmol/L Standard Error 0.01031
Change From Baseline in Free Fatty Acids Week 26 (n=366, 368)	-0.0364 mmol/L Standard Error 0.01231	-0.0162 mmol/L Standard Error 0.01228
Change From Baseline in Free Fatty Acids Week 42 (n=367, 368)	-0.0243 mmol/L Standard Error 0.01083	-0.0222 mmol/L Standard Error 0.01081
Change From Baseline in Free Fatty Acids Week 52 (n=367, 368)	-0.0294 mmol/L Standard Error 0.01173	0.0019 mmol/L Standard Error 0.01171

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in Apolipoprotein A1 was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein A1 as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Apolipoprotein A1 Week 12 (n=348, 355)	0.5 mg/dL Standard Error 0.99	0.0 mg/dL Standard Error 0.98
Change From Baseline in Apolipoprotein A1 Week 26 (n=359, 363)	0.1 mg/dL Standard Error 0.95	-0.9 mg/dL Standard Error 0.95
Change From Baseline in Apolipoprotein A1 Week 42 (n=360, 363)	-2.1 mg/dL Standard Error 0.95	-2.2 mg/dL Standard Error 0.95
Change From Baseline in Apolipoprotein A1 Week 52 (n=360, 363)	-4.5 mg/dL Standard Error 0.99	-4.4 mg/dL Standard Error 0.98

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in Apolipoprotein A2 was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein A2 as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Apolipoprotein A2 Week 12 (n=348, 355)	-0.4 mg/dL Standard Error 0.22	0.6 mg/dL Standard Error 0.22
Change From Baseline in Apolipoprotein A2 Week 26 (n=359, 363)	0.4 mg/dL Standard Error 0.23	0.7 mg/dL Standard Error 0.22
Change From Baseline in Apolipoprotein A2 Week 42 (n=360, 363)	0.8 mg/dL Standard Error 0.25	1.1 mg/dL Standard Error 0.25
Change From Baseline in Apolipoprotein A2 Week 52 (n=360, 363)	0.3 mg/dL Standard Error 0.24	1.0 mg/dL Standard Error 0.24

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: Full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in Apolipoprotein B was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein B as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Apolipoprotein B Week 12 [N=348, 355]	-3.1 mg/dL Standard Error 1.02	0.1 mg/dL Standard Error 1.01
Change From Baseline in Apolipoprotein B Week 26 [N=359, 363]	-0.6 mg/dL Standard Error 1.09	1.1 mg/dL Standard Error 1.08
Change From Baseline in Apolipoprotein B Week 42 [N=360, 363]	-0.4 mg/dL Standard Error 1.15	1.8 mg/dL Standard Error 1.15
Change From Baseline in Apolipoprotein B Week 52 [N=360, 363]	-1.2 mg/dL Standard Error 1.10	1.7 mg/dL Standard Error 1.10

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: Full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in Apolipoprotein C-III was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline apolipoprotein C-III as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Apolipoprotein C-III Week 12 (n=352, 361)	-0.6 mg/dL Standard Error 0.15	0.1 mg/dL Standard Error 0.15
Change From Baseline in Apolipoprotein C-III Week 26 (n=365, 369)	-0.1 mg/dL Standard Error 0.17	0.2 mg/dL Standard Error 0.17
Change From Baseline in Apolipoprotein C-III Week 42 (n=366, 369)	-0.3 mg/dL Standard Error 0.17	0.2 mg/dL Standard Error 0.17
Change From Baseline in Apolipoprotein C-III Week 52 (n=366, 369)	-0.5 mg/dL Standard Error 0.16	0.0 mg/dL Standard Error 0.16

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in plasminogen activator inhibitor-1 (PAI-1) was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline PAI-1 as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Plasminogen Activator Inhibitor-1 Week 12 (n=322, 330)	-3.23 ng/ml Standard Error 1.483	-3.59 ng/ml Standard Error 1.464
Change From Baseline in Plasminogen Activator Inhibitor-1 Week 26 (n=342, 343)	-2.83 ng/ml Standard Error 1.523	-3.63 ng/ml Standard Error 1.520
Change From Baseline in Plasminogen Activator Inhibitor-1 Week 42 (n=346, 344)	-2.08 ng/ml Standard Error 1.429	-4.89 ng/ml Standard Error 1.434
Change From Baseline in Plasminogen Activator Inhibitor-1 Week 52 (n=346, 344)	-2.92 ng/ml Standard Error 1.234	-4.70 ng/ml Standard Error 1.237

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in high-sensitivity C-Reactive Protein (hsCRP) was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline hsCRP as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in High-sensitivity C-Reactive Protein Week 12 (n=357, 366)	0.2989 mg/L Standard Error 0.53213	0.7049 mg/L Standard Error 0.52569
Change From Baseline in High-sensitivity C-Reactive Protein Week 26 (n=366, 373)	-0.0632 mg/L Standard Error 0.49229	0.9706 mg/L Standard Error 0.48763
Change From Baseline in High-sensitivity C-Reactive Protein Week 42 (n=367, 373)	0.7251 mg/L Standard Error 0.48203	0.6443 mg/L Standard Error 0.47813
Change From Baseline in High-sensitivity C-Reactive Protein Week 52 (n=367, 373)	0.5875 mg/L Standard Error 0.54194	1.4085 mg/L Standard Error 0.53755

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in adiponectin was assessed at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline adiponectin as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Adiponectin Week 12 (n=355, 361)	1.15 μg/mL Standard Error 0.453	2.97 μg/mL Standard Error 0.449
Change From Baseline in Adiponectin Week 26 (n=366, 371)	1.17 μg/mL Standard Error 0.599	4.19 μg/mL Standard Error 0.595
Change From Baseline in Adiponectin Week 42 (n=367, 371)	-0.41 μg/mL Standard Error 0.529	3.04 μg/mL Standard Error 0.526
Change From Baseline in Adiponectin Week 52 (n=367, 371)	-0.70 μg/mL Standard Error 0.595	2.21 μg/mL Standard Error 0.591

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Nuclear Magnetic Resonance (NMR) lipid fractionation was used to assess the change from Baseline in total triglyceride levels at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline NMR triglycerides as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides Week 12 (n=357, 361)	-8.7 mg/dL Standard Error 3.24	0.2 mg/dL Standard Error 3.23
Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides Week 26 (n=367, 368)	-1.7 mg/dL Standard Error 3.58	0.8 mg/dL Standard Error 3.58
Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides Week 42 (n=367, 369)	-6.4 mg/dL Standard Error 3.60	0.7 mg/dL Standard Error 3.59
Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides Week 52 (n=367, 369)	-6.9 mg/dL Standard Error 3.35	-0.7 mg/dL Standard Error 3.34

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

The change from Baseline in levels of total VLDL/chylomicron particles and large VLDL/chylomicron particles was assessed by NMR lipid fractionation at Weeks 12, 26, 42 and 52.

Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline VLDL/chylomicron particles as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles Total Particles - Week 12 (n=357, 361)	-0.59 nmol/L Standard Error 1.814	2.39 nmol/L Standard Error 1.805
Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles Total Particles - Week 26 (n=367, 368)	1.27 nmol/L Standard Error 1.940	3.09 nmol/L Standard Error 1.937
Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles Total Particles - Week 42 (n=367, 369)	-1.35 nmol/L Standard Error 1.916	1.64 nmol/L Standard Error 1.911
Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles Total Particles - Week 52 (n=367, 369)	-1.20 nmol/L Standard Error 1.890	3.03 nmol/L Standard Error 1.885
Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles Large Particles - Week 12 (n=357, 361)	-0.83 nmol/L Standard Error 0.247	-0.27 nmol/L Standard Error 0.246
Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles Large Particles - Week 26 (n=367, 368)	-0.39 nmol/L Standard Error 0.282	-0.32 nmol/L Standard Error 0.281
Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles Large Particles - Week 42 (n=367, 369)	-0.72 nmol/L Standard Error 0.277	-0.38 nmol/L Standard Error 0.277
Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles Large Particles - Week 52 (n=367, 369)	-0.66 nmol/L Standard Error 0.260	-0.46 nmol/L Standard Error 0.260

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

The change from Baseline in levels of VLDL/chylomicron triglycerides was assessed by NMR lipid fractionation at Weeks 12, 26, 42 and 52.

Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline VLDL/chylomicron triglycerides as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in VLDL / Chylomicron Triglycerides Week 12 (n=357, 361)	-7.6 mg/dL Standard Error 3.22	-0.2 mg/dL Standard Error 3.20
Change From Baseline in VLDL / Chylomicron Triglycerides Week 26 (n=367, 368)	-1.3 mg/dL Standard Error 3.54	0.2 mg/dL Standard Error 3.54
Change From Baseline in VLDL / Chylomicron Triglycerides Week 42 (n=367, 369)	-5.4 mg/dL Standard Error 3.60	0.2 mg/dL Standard Error 3.59
Change From Baseline in VLDL / Chylomicron Triglycerides Week 52 (n=367, 369)	-6.1 mg/dL Standard Error 3.30	-1.5 mg/dL Standard Error 3.29

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

The change from Baseline in levels of medium VLDL particles and small VLDL particles was assessed by NMR fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline VLDL particles as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in VLDL Particles Medium Particles - Week 12 (n=357, 361)	-0.09 nmol/L Standard Error 1.152	1.74 nmol/L Standard Error 1.146
Change From Baseline in VLDL Particles Medium Particles - Week 26 (n=367, 368)	1.30 nmol/L Standard Error 1.208	2.23 nmol/L Standard Error 1.207
Change From Baseline in VLDL Particles Medium Particles - Week 42 (n=367, 369)	1.03 nmol/L Standard Error 1.307	2.43 nmol/L Standard Error 1.303
Change From Baseline in VLDL Particles Medium Particles - Week 52 (n=367, 369)	0.26 nmol/L Standard Error 1.166	2.12 nmol/L Standard Error 1.163
Change From Baseline in VLDL Particles Small Particles - Week 12 (n=357, 361)	-0.04 nmol/L Standard Error 1.077	1.30 nmol/L Standard Error 1.072
Change From Baseline in VLDL Particles Small Particles - Week 26 (n=367, 368)	0.07 nmol/L Standard Error 1.121	1.47 nmol/L Standard Error 1.119
Change From Baseline in VLDL Particles Small Particles - Week 42 (n=367, 369)	-1.86 nmol/L Standard Error 1.120	-0.21 nmol/L Standard Error 1.117
Change From Baseline in VLDL Particles Small Particles - Week 52 (n=367, 369)	-1.02 nmol/L Standard Error 1.192	1.58 nmol/L Standard Error 1.189

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in mean VLDL particle size was assessed by NMR lipid fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline mean VLDL particle size as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Mean VLDL Particle Size Week 12 (n=355, 361)	-0.67 nm Standard Error 0.369	-0.79 nm Standard Error 0.366
Change From Baseline in Mean VLDL Particle Size Week 26 (n=365, 368)	0.11 nm Standard Error 0.391	-0.87 nm Standard Error 0.389
Change From Baseline in Mean VLDL Particle Size Week 42 (n=365, 369)	0.44 nm Standard Error 0.445	-0.79 nm Standard Error 0.442
Change From Baseline in Mean VLDL Particle Size Week 52 (n=365, 369)	-0.12 nm Standard Error 0.395	-1.04 nm Standard Error 0.393

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

The change from Baseline in levels of IDL particles was assessed by NMR lipid fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline IDL particles as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles Week 12 (n=357, 361)	-4.9 nmol/L Standard Error 2.24	3.2 nmol/L Standard Error 2.23
Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles Week 26 (n=367, 368)	-4.1 nmol/L Standard Error 2.39	1.0 nmol/L Standard Error 2.39
Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles Week 42 (n=367, 369)	-5.6 nmol/L Standard Error 2.26	2.0 nmol/L Standard Error 2.26
Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles Week 52 (n=367, 369)	-4.5 nmol/L Standard Error 2.22	3.2 nmol/L Standard Error 2.21

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

The change from Baseline in levels of total, large, medium-small, total small and very small LDL particles was assessed by NMR fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline LDL particles as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Low Density Lipoprotein (LDL) Particles Total Small Particles - Week 26 (n=367, 368)	-10.9 nmol/L Standard Error 17.80	-18.2 nmol/L Standard Error 17.77
Change From Baseline in Low Density Lipoprotein (LDL) Particles Total Particles - Week 12 (n=357, 361)	-46.9 nmol/L Standard Error 14.88	-22.3 nmol/L Standard Error 14.81
Change From Baseline in Low Density Lipoprotein (LDL) Particles Total Particles - Week 26 (n=367, 368)	-14.0 nmol/L Standard Error 15.83	-8.2 nmol/L Standard Error 15.81
Change From Baseline in Low Density Lipoprotein (LDL) Particles Total Particles - Week 42 (n=367, 369)	-11.7 nmol/L Standard Error 16.86	-10.7 nmol/L Standard Error 16.81
Change From Baseline in Low Density Lipoprotein (LDL) Particles Total Particles - Week 52 (n=367, 369)	-13.0 nmol/L Standard Error 15.98	-2.7 nmol/L Standard Error 15.94
Change From Baseline in Low Density Lipoprotein (LDL) Particles Large Particles - Week 12 (n=357, 361)	-4.4 nmol/L Standard Error 9.29	-5.0 nmol/L Standard Error 9.24
Change From Baseline in Low Density Lipoprotein (LDL) Particles Large Particles - Week 26 (n=367, 368)	1.1 nmol/L Standard Error 10.37	8.8 nmol/L Standard Error 10.36
Change From Baseline in Low Density Lipoprotein (LDL) Particles Large Particles - Week 42 (n=367, 369)	-20.8 nmol/L Standard Error 9.68	0.0 nmol/L Standard Error 9.65
Change From Baseline in Low Density Lipoprotein (LDL) Particles Large Particles - Week 52 (n=367, 369)	-19.2 nmol/L Standard Error 10.03	-2.4 nmol/L Standard Error 10.00
Change From Baseline in Low Density Lipoprotein (LDL) Particles Medium-small Particles - Week 12 (n=357, 361)	-7.0 nmol/L Standard Error 3.45	-0.3 nmol/L Standard Error 3.43
Change From Baseline in Low Density Lipoprotein (LDL) Particles Medium-small Particles - Week 26 (n=367, 368)	-0.7 nmol/L Standard Error 3.57	-0.7 nmol/L Standard Error 3.57
Change From Baseline in Low Density Lipoprotein (LDL) Particles Medium-small Particles - Week 42 (n=367, 369)	4.1 nmol/L Standard Error 3.82	1.8 nmol/L Standard Error 3.81
Change From Baseline in Low Density Lipoprotein (LDL) Particles Medium-small Particles - Week 52 (n=367, 369)	2.4 nmol/L Standard Error 3.54	1.2 nmol/L Standard Error 3.53
Change From Baseline in Low Density Lipoprotein (LDL) Particles Total Small Particles - Week 12 (n=357, 361)	-37.6 nmol/L Standard Error 16.93	-20.8 nmol/L Standard Error 16.84
Change From Baseline in Low Density Lipoprotein (LDL) Particles Total Small Particles - Week 42 (n=367, 369)	15.0 nmol/L Standard Error 18.63	-13.0 nmol/L Standard Error 18.58
Change From Baseline in Low Density Lipoprotein (LDL) Particles Total Small Particles - Week 52 (n=367, 369)	10.9 nmol/L Standard Error 17.84	-3.5 nmol/L Standard Error 17.79
Change From Baseline in Low Density Lipoprotein (LDL) Particles Very Small Particles - Week 12 (n=357, 361)	-30.6 nmol/L Standard Error 13.84	-20.6 nmol/L Standard Error 13.77
Change From Baseline in Low Density Lipoprotein (LDL) Particles Very Small Particles - Week 26 (n=367, 368)	-10.1 nmol/L Standard Error 14.49	-17.5 nmol/L Standard Error 14.47
Change From Baseline in Low Density Lipoprotein (LDL) Particles Very Small Particles - Week 42 (n=367, 369)	11.0 nmol/L Standard Error 15.13	-14.9 nmol/L Standard Error 15.09
Change From Baseline in Low Density Lipoprotein (LDL) Particles Very Small Particles - Week 52 (n=367, 369)	8.6 nmol/L Standard Error 14.56	-4.8 nmol/L Standard Error 14.52

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in mean LDL particle size was assessed by NMR lipid fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline mean LDL particle size as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Mean LDL Particle Size Week 12 (n=357, 361)	0.05 nm Standard Error 0.031	0.06 nm Standard Error 0.031
Change From Baseline in Mean LDL Particle Size Week 26 (n=367, 368)	0.03 nm Standard Error 0.032	0.07 nm Standard Error 0.032
Change From Baseline in Mean LDL Particle Size Week 42 (n=367, 369)	-0.02 nm Standard Error 0.032	0.05 nm Standard Error 0.032
Change From Baseline in Mean LDL Particle Size Week 52 (n=367, 369)	-0.04 nm Standard Error 0.032	0.03 nm Standard Error 0.032

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

The change from Baseline in levels of total, large, medium and small HDL particles was assessed by NMR fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline HDL particles as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in High Density Lipoprotein (HDL) Particles Total Particles - Week 12 (n=357, 361)	-0.18 μmol/L Standard Error 0.224	-0.14 μmol/L Standard Error 0.223
Change From Baseline in High Density Lipoprotein (HDL) Particles Total Particles - Week 26 (n=367, 368)	0.37 μmol/L Standard Error 0.228	0.03 μmol/L Standard Error 0.227
Change From Baseline in High Density Lipoprotein (HDL) Particles Total Particles - Week 42 (n=367, 369)	0.09 μmol/L Standard Error 0.227	-0.11 μmol/L Standard Error 0.227
Change From Baseline in High Density Lipoprotein (HDL) Particles Total Particles - Week 52 (n=367, 369)	0.38 μmol/L Standard Error 0.227	0.02 μmol/L Standard Error 0.226
Change From Baseline in High Density Lipoprotein (HDL) Particles Large Particles - Week 12 (n=357, 361)	0.08 μmol/L Standard Error 0.102	0.35 μmol/L Standard Error 0.101
Change From Baseline in High Density Lipoprotein (HDL) Particles Large Particles - Week 26 (n=367, 368)	0.19 μmol/L Standard Error 0.103	0.53 μmol/L Standard Error 0.103
Change From Baseline in High Density Lipoprotein (HDL) Particles Large Particles - Week 42 (n=367, 369)	0.06 μmol/L Standard Error 0.102	0.51 μmol/L Standard Error 0.101
Change From Baseline in High Density Lipoprotein (HDL) Particles Large Particles - Week 52 (n=367, 369)	0.19 μmol/L Standard Error 0.105	0.57 μmol/L Standard Error 0.105
Change From Baseline in High Density Lipoprotein (HDL) Particles Medium Particles - Week 12 (n=357, 361)	0.10 μmol/L Standard Error 0.165	0.43 μmol/L Standard Error 0.164
Change From Baseline in High Density Lipoprotein (HDL) Particles Medium Particles - Week 26 (n=367, 368)	0.71 μmol/L Standard Error 0.178	0.90 μmol/L Standard Error 0.178
Change From Baseline in High Density Lipoprotein (HDL) Particles Medium Particles - Week 42 (n=367, 369)	0.57 μmol/L Standard Error 0.172	0.70 μmol/L Standard Error 0.171
Change From Baseline in High Density Lipoprotein (HDL) Particles Medium Particles - Week 52 (n=367, 369)	0.66 μmol/L Standard Error 0.180	0.96 μmol/L Standard Error 0.179
Change From Baseline in High Density Lipoprotein (HDL) Particles Small Particles - Week 12 (n=357, 361)	-0.38 μmol/L Standard Error 0.243	-0.92 μmol/L Standard Error 0.242
Change From Baseline in High Density Lipoprotein (HDL) Particles Small Particles - Week 26 (n=367, 368)	-0.53 μmol/L Standard Error 0.250	-1.39 μmol/L Standard Error 0.250
Change From Baseline in High Density Lipoprotein (HDL) Particles Small Particles - Week 42 (n=367, 369)	-0.54 μmol/L Standard Error 0.247	-1.31 μmol/L Standard Error 0.246
Change From Baseline in High Density Lipoprotein (HDL) Particles Small Particles - Week 52 (n=367, 369)	-0.47 μmol/L Standard Error 0.251	-1.49 μmol/L Standard Error 0.250

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 42 and 52.

Population: The full analysis set where Baseline and at least 1 postbaseline value were available. Last observation carried forward (LOCF) imputation was utilized.

Change from Baseline in mean HDL particle size was assessed by NMR lipid fractionation at Weeks 12, 26, 42 and 52. Least squares means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and baseline metformin dose and baseline mean HDL particle size as covariates.

Outcome measures

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 Participants Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 Participants Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Change From Baseline in Mean HDL Particle Size Week 12 (n=357, 361)	0.04 nm Standard Error 0.012	0.05 nm Standard Error 0.012
Change From Baseline in Mean HDL Particle Size Week 26 (n=367, 368)	0.04 nm Standard Error 0.012	0.07 nm Standard Error 0.012
Change From Baseline in Mean HDL Particle Size Week 42 (n=367, 369)	0.02 nm Standard Error 0.012	0.07 nm Standard Error 0.012
Change From Baseline in Mean HDL Particle Size Week 52 (n=367, 369)	0.03 nm Standard Error 0.012	0.08 nm Standard Error 0.012

Adverse Events

Alogliptin 25 mg + Pioglitazone 30 mg + Metformin

Serious events: 20 serious events

Other events: 116 other events

Deaths: 0 deaths

Pioglitazone 45 mg + Metformin

Serious events: 20 serious events

Other events: 104 other events

Deaths: 0 deaths

Serious adverse events

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 participants at risk Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 participants at risk Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Cardiac disorders Acute myocardial infarction	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.50% 2/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Cardiac disorders Angina unstable	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Cardiac disorders Coronary artery disease	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Cardiac disorders Myocardial infarction	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Ear and labyrinth disorders Acute vestibular syndrome	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Eye disorders Cataract	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.50% 2/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Eye disorders Ocular myasthenia	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
General disorders Non-cardiac chest pain	0.50% 2/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Infections and infestations Abdominal abscess	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Infections and infestations Appendicitis	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Infections and infestations Gastroenteritis viral	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Infections and infestations Hepatitis B	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Infections and infestations Lobar pneumonia	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Infections and infestations Osteomyelitis	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Infections and infestations Pneumonia	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Infections and infestations Pneumonia primary atypical	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Infections and infestations Sepsis	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Injury, poisoning and procedural complications Fall	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.50% 2/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Injury, poisoning and procedural complications Frostbite	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Injury, poisoning and procedural complications Injury	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Injury, poisoning and procedural complications Road traffic accident	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Injury, poisoning and procedural complications Wound dehiscence	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.50% 2/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectosigmoid cancer	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Nervous system disorders Cerebrovascular accident	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Nervous system disorders Ischaemic stroke	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Nervous system disorders Migraine	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Psychiatric disorders Mania	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Renal and urinary disorders Calculus urinary	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Renal and urinary disorders Renal colic	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Vascular disorders Hypotension	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.50% 2/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Vascular disorders Arteriosclerosis obliterans	0.25% 1/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.00% 0/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Vascular disorders Hypertension	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Vascular disorders Peripheral vascular disorder	0.00% 0/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	0.25% 1/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.

Other adverse events

Measure	Alogliptin 25 mg + Pioglitazone 30 mg + Metformin n=404 participants at risk Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.	Pioglitazone 45 mg + Metformin n=399 participants at risk Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.
Infections and infestations Nasopharyngitis	6.9% 28/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	5.3% 21/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Vascular disorders Hypertension	5.9% 24/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	5.3% 21/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Infections and infestations Upper respiratory tract infection	7.2% 29/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	4.0% 16/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Infections and infestations Influenza	4.5% 18/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	5.8% 23/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Gastrointestinal disorders Diarrhoea	2.7% 11/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	6.0% 24/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.
Infections and infestations Urinary tract infection	5.4% 22/404 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug treatment.	3.3% 13/399 • Collection of AEs began from time of informed consent until the end of the study (Week 54 or End-of-Treatment/Early Termination) and from spontaneous reporting up to 30 days after the final dose of study drug. At each study visit, the investigator assessed whether any events had occurred. Patients could report events at any other time during the study. All events, whether reported by the patient or observed by the investigator, were documented, whether or not the investigator concluded the event to be related to the drug 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