Trial Outcomes & Findings for Efficacy and Safety of Alogliptin Plus Metformin Compared to Glipizide Plus Metformin in Patients With Type 2 Diabetes Mellitus (NCT NCT00856284)

Last Updated: 2013-12-03

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2639 participants

Primary outcome timeframe

Baseline and Week 52

Results posted on

2013-12-03

Participant Flow

Participants took part in the study at 310 study sites worldwide from 05 March 2009 to 17 October 2012.

Participants with type 2 diabetes mellitus experiencing inadequate glycemic control while on metformin therapy were enrolled equally in 1 of 3 treatment groups: alogliptin 12.5 mg once daily (QD), alogliptin 25 mg QD, and glipizide 5 mg QD.

Participant milestones

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

Reasons for withdrawal

Reasons for withdrawal
Measure	Metformin + Alogliptin 12.5 mg Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Alogliptin 25 mg Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Glipizide Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Overall Study Hyperglycemic rescue	231	201	235
Overall Study Adverse Event	60	74	82
Overall Study Major protocol deviation	24	16	15
Overall Study Lost to Follow-up	20	22	28
Overall Study Voluntary withdrawal	48	52	62
Overall Study Pregnancy	1	2	0
Overall Study Investigator discretion	9	8	10
Overall Study Other	15	17	14
Overall Study Randomized in error	0	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Metformin + Alogliptin 12.5 mg n=880 Participants Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Alogliptin 25 mg n=885 Participants Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Glipizide n=874 Participants Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.	Total n=2639 Participants Total of all reporting groups
Age Continuous	55.2 years STANDARD_DEVIATION 9.60 • n=5 Participants	55.5 years STANDARD_DEVIATION 9.81 • n=7 Participants	55.4 years STANDARD_DEVIATION 9.60 • n=5 Participants	55.4 years STANDARD_DEVIATION 9.67 • n=4 Participants
Age, Customized <65 years	734 participants n=5 Participants	710 participants n=7 Participants	723 participants n=5 Participants	2167 participants n=4 Participants
Age, Customized ≥65 years	146 participants n=5 Participants	175 participants n=7 Participants	151 participants n=5 Participants	472 participants n=4 Participants
Age, Customized ≥75 years	13 participants n=5 Participants	17 participants n=7 Participants	15 participants n=5 Participants	45 participants n=4 Participants
Sex: Female, Male Female	461 Participants n=5 Participants	433 Participants n=7 Participants	433 Participants n=5 Participants	1327 Participants n=4 Participants
Sex: Female, Male Male	419 Participants n=5 Participants	452 Participants n=7 Participants	441 Participants n=5 Participants	1312 Participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	40 participants n=5 Participants	42 participants n=7 Participants	36 participants n=5 Participants	118 participants n=4 Participants
Race/Ethnicity, Customized Asian	191 participants n=5 Participants	207 participants n=7 Participants	203 participants n=5 Participants	601 participants n=4 Participants
Race/Ethnicity, Customized Black or African American	74 participants n=5 Participants	66 participants n=7 Participants	81 participants n=5 Participants	221 participants n=4 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	7 participants n=5 Participants	1 participants n=7 Participants	4 participants n=5 Participants	12 participants n=4 Participants
Race/Ethnicity, Customized White	557 participants n=5 Participants	555 participants n=7 Participants	533 participants n=5 Participants	1645 participants n=4 Participants
Race/Ethnicity, Customized Multiracial	11 participants n=5 Participants	14 participants n=7 Participants	17 participants n=5 Participants	42 participants n=4 Participants
Race/Ethnicity, Customized Hispanic or Latino	192 participants n=5 Participants	204 participants n=7 Participants	192 participants n=5 Participants	588 participants n=4 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	688 participants n=5 Participants	681 participants n=7 Participants	682 participants n=5 Participants	2051 participants n=4 Participants
Body Mass Index (BMI)	31.27 kg/m^2 STANDARD_DEVIATION 5.417 • n=5 Participants	31.27 kg/m^2 STANDARD_DEVIATION 5.341 • n=7 Participants	31.11 kg/m^2 STANDARD_DEVIATION 5.320 • n=5 Participants	31.22 kg/m^2 STANDARD_DEVIATION 5.358 • n=4 Participants
Glycosylated hemoglobin (HbA1c)	7.59 percentage STANDARD_DEVIATION 0.599 • n=5 Participants	7.61 percentage STANDARD_DEVIATION 0.606 • n=7 Participants	7.60 percentage STANDARD_DEVIATION 0.617 • n=5 Participants	7.60 percentage STANDARD_DEVIATION 0.607 • n=4 Participants
Baseline HbA1c Category <8.0%	615 participants n=5 Participants	620 participants n=7 Participants	613 participants n=5 Participants	1848 participants n=4 Participants
Baseline HbA1c Category ≥8.0%	265 participants n=5 Participants	265 participants n=7 Participants	261 participants n=5 Participants	791 participants n=4 Participants
Diabetes duration	5.65 years STANDARD_DEVIATION 5.324 • n=5 Participants	5.42 years STANDARD_DEVIATION 4.730 • n=7 Participants	5.48 years STANDARD_DEVIATION 4.884 • n=5 Participants	5.52 years STANDARD_DEVIATION 4.985 • n=4 Participants
Metformin dose	1825.2 mg STANDARD_DEVIATION 405.59 • n=5 Participants	1837.2 mg STANDARD_DEVIATION 373.06 • n=7 Participants	1823.4 mg STANDARD_DEVIATION 390.63 • n=5 Participants	1828.6 mg STANDARD_DEVIATION 389.85 • n=4 Participants
Glomerular filtration rate MDRD	83.04 mL/min/1.73m^2 STANDARD_DEVIATION 16.586 • n=5 Participants	82.35 mL/min/1.73m^2 STANDARD_DEVIATION 16.199 • n=7 Participants	82.28 mL/min/1.73m^2 STANDARD_DEVIATION 16.994 • n=5 Participants	82.56 mL/min/1.73m^2 STANDARD_DEVIATION 16.591 • n=4 Participants
Glomerular filtration rate Cockcroft-Gault	109.3 mL/min/1.73m^2 STANDARD_DEVIATION 33.40 • n=5 Participants	109.3 mL/min/1.73m^2 STANDARD_DEVIATION 32.85 • n=7 Participants	108.0 mL/min/1.73m^2 STANDARD_DEVIATION 32.64 • n=5 Participants	108.9 mL/min/1.73m^2 STANDARD_DEVIATION 32.96 • n=4 Participants
Smoking history Never smoked	543 participants n=5 Participants	586 participants n=7 Participants	578 participants n=5 Participants	1707 participants n=4 Participants
Smoking history Current smoker	135 participants n=5 Participants	122 participants n=7 Participants	111 participants n=5 Participants	368 participants n=4 Participants
Smoking history Ex-smoker	202 participants n=5 Participants	177 participants n=7 Participants	185 participants n=5 Participants	564 participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and Week 52

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

Outcome measures

Outcome measures
Measure	Metformin + Alogliptin 12.5 mg n=371 Participants Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Alogliptin 25 mg n=382 Participants Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Glipizide n=336 Participants Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 52	-0.81 percentage glycosylated hemoglobin Standard Error 0.027	-0.76 percentage glycosylated hemoglobin Standard Error 0.027	-0.73 percentage glycosylated hemoglobin Standard Error 0.029

PRIMARY outcome

Timeframe: Baseline and Week 104

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

Outcome measures

Outcome measures
Measure	Metformin + Alogliptin 12.5 mg n=371 Participants Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Alogliptin 25 mg n=382 Participants Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Glipizide n=336 Participants Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 104	-0.68 percentage glycosylated hemoglobin Standard Error 0.037	-0.72 percentage glycosylated hemoglobin Standard Error 0.037	-0.59 percentage glycosylated hemoglobin Standard Error 0.039

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 8, 12, 16, 20, 26, 39, 65, 78, and 91.

Population: Per-protocol set; LOCF was used.

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

Outcome measures

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

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104.

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

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

Outcome measures

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

SECONDARY outcome

Timeframe: Weeks 26, 52, 78, and 104.

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

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

Outcome measures

Outcome measures
Measure	Metformin + Alogliptin 12.5 mg n=873 Participants Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Alogliptin 25 mg n=878 Participants Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Glipizide n=869 Participants Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% Week 104	23.5 percentage of participants	24.1 percentage of participants	19.0 percentage of participants
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% Week 26	25.6 percentage of participants	26.2 percentage of participants	24.8 percentage of participants
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% Week 52	24.5 percentage of participants	24.8 percentage of participants	20.8 percentage of participants
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% Week 78	24.2 percentage of participants	26.4 percentage of participants	21.8 percentage of participants

SECONDARY outcome

Timeframe: Weeks 26, 52, 78, and 104.

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

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

Outcome measures

Outcome measures
Measure	Metformin + Alogliptin 12.5 mg n=873 Participants Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Alogliptin 25 mg n=878 Participants Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Glipizide n=869 Participants Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% Week 26	56.4 percentage of participants	59.2 percentage of participants	56.1 percentage of participants
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% Week 78	48.8 percentage of participants	52.4 percentage of participants	46.6 percentage of participants
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% Week 52	51.7 percentage of participants	55.5 percentage of participants	47.4 percentage of participants
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% Week 104	45.6 percentage of participants	48.5 percentage of participants	42.8 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 26, 39, 52, 65, 78, 91, and 104.

Population: Full analysis set, LOCF was used.

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

Outcome measures

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

Adverse Events

Metformin + Alogliptin 12.5 mg

Serious events: 86 serious events

Other events: 688 other events

Deaths: 0 deaths

Metformin + Alogliptin 25 mg

Serious events: 97 serious events

Other events: 687 other events

Deaths: 0 deaths

Metformin + Glipizide

Serious events: 81 serious events

Other events: 668 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Director, Clinical Science

Takeda

Phone: 800-778-2860

Email: [email protected]

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

Serious adverse events
Measure	Metformin + Alogliptin 12.5 mg n=873 participants at risk Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Alogliptin 25 mg n=878 participants at risk Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Glipizide n=869 participants at risk Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Cardiac disorders Coronary artery disease	0.57% 5/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.34% 3/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.23% 2/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Angina unstable	0.11% 1/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.46% 4/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.46% 4/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Acute myocardial infarction	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.58% 5/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrial fibrillation	0.11% 1/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.34% 3/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.23% 2/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrial flutter	0.23% 2/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.23% 2/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac failure	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.34% 3/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac failure congestive	0.23% 2/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Myocardial infarction	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.35% 3/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Angina pectoris	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.23% 2/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Myocardial ischaemia	0.11% 1/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.23% 2/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrioventricular block complete	0.11% 1/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiomyopathy	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Silent myocardial infarction	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.23% 2/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Acute coronary syndrome	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Arteriosclerosis coronary artery	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrioventricular block	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrioventricular block second degree	0.11% 1/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Bradycardia	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Congestive cardiomyopathy	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Coronary artery occlusion	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Left ventricular failure	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Pericardial effusion	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Right ventricular failure	0.11% 1/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Tachyarrhythmia	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Cellulitis	0.34% 3/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.35% 3/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Pneumonia	0.11% 1/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.23% 2/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.23% 2/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Gastroenteritis	0.23% 2/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.23% 2/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Dengue fever	0.11% 1/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.23% 2/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Diverticulitis	0.11% 1/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Hepatitis viral	0.11% 1/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.23% 2/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Urinary tract infection	0.11% 1/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Urosepsis	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Abdominal abscess	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Abscess limb	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Acute sinusitis	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Amoebiasis	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Appendicitis	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Bronchitis	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Cystitis	0.11% 1/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Gangrene	0.00% 0/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 1/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Other adverse events
Measure	Metformin + Alogliptin 12.5 mg n=873 participants at risk Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Alogliptin 25 mg n=878 participants at risk Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.	Metformin + Glipizide n=869 participants at risk Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals.
Gastrointestinal disorders Diarrhoea	6.9% 60/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	6.8% 60/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	7.2% 63/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Upper respiratory tract infection	9.6% 84/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	10.3% 90/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.7% 76/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Nasopharyngitis	8.9% 78/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	7.6% 67/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	7.0% 61/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Blood and lymphatic system disorders Anaemia	1.8% 16/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.2% 37/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.7% 32/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Nausea	3.2% 28/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.6% 32/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.3% 20/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Fatigue	2.3% 20/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.2% 19/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.2% 28/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Asthenia	1.6% 14/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.7% 15/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.1% 27/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Influenza	4.1% 36/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.1% 36/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.8% 42/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Urinary tract infection	4.7% 41/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.8% 33/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.4% 38/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Bronchitis	4.5% 39/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.1% 36/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.1% 36/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Sinusitis	3.0% 26/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.3% 29/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.6% 23/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Investigations Creatinine renal clearance decreased	2.6% 23/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.9% 34/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.7% 32/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Metabolism and nutrition disorders Hypoglycaemia	2.1% 18/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.68% 6/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	10.5% 91/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Metabolism and nutrition disorders Dyslipidaemia	2.5% 22/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.3% 20/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.9% 34/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Back pain	6.2% 54/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.1% 45/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.6% 49/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Arthralgia	4.4% 38/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.8% 42/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.6% 40/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Pain in extremity	3.2% 28/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.2% 28/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.8% 33/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Headache	5.2% 45/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	6.8% 60/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.3% 46/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Dizziness	2.7% 24/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.7% 24/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.3% 29/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Tremor	0.57% 5/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.34% 3/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.3% 29/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Cough	4.0% 35/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.0% 26/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.8% 33/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Hypertension	5.2% 45/873 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	7.6% 67/878 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	7.5% 65/869 • Collection of adverse events commenced from the time the participant was first administered double-blind study medication until the end of the study and from spontaneous reporting for 30 days after the end of treatment (up to 108 weeks). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.