Trial Outcomes & Findings for Efficacy and Safety of Alogliptin Compared to Glipizide in Elderly Diabetics (NCT NCT00707993)

Last Updated: 2013-05-24

Results Overview

The change in the percentage of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 52 or final visit and glycosylated hemoglobin collected at baseline.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

441 participants

Primary outcome timeframe

Baseline and Week 52.

Results posted on

2013-05-24

Participant Flow

Participants enrolled at 110 investigative sites in Hungary, India, Israel, Mexico, Peru, Poland, Romania, Russia, South Africa, the Ukraine and the United States from 25 June 2008 to 30 August 2010.

Participants with a historical diagnosis of type 2 diabetes mellitus were enrolled in one of two, once-daily (QD) treatment groups.

Participant milestones

Participant milestones
Measure	Alogliptin 25 mg QD Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Overall Study STARTED	222	219
Overall Study COMPLETED	133	125
Overall Study NOT COMPLETED	89	94

Reasons for withdrawal

Reasons for withdrawal
Measure	Alogliptin 25 mg QD Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Overall Study Adverse Event	16	20
Overall Study Protocol Violation	4	7
Overall Study Lost to Follow-up	0	4
Overall Study Withdrawal by Subject	12	16
Overall Study Hyperglycemic Rescue	55	47
Overall Study Other	2	0

Baseline Characteristics

Efficacy and Safety of Alogliptin Compared to Glipizide in Elderly Diabetics

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.	Total n=441 Participants Total of all reporting groups
Age Continuous	70.1 years STANDARD_DEVIATION 4.42 • n=5 Participants	69.8 years STANDARD_DEVIATION 4.07 • n=7 Participants	69.9 years STANDARD_DEVIATION 4.24 • n=5 Participants
Age, Customized <75 years	186 participants n=5 Participants	193 participants n=7 Participants	379 participants n=5 Participants
Age, Customized ≥75 years	36 participants n=5 Participants	26 participants n=7 Participants	62 participants n=5 Participants
Sex: Female, Male Female	120 Participants n=5 Participants	123 Participants n=7 Participants	243 Participants n=5 Participants
Sex: Female, Male Male	102 Participants n=5 Participants	96 Participants n=7 Participants	198 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	79 Participants n=5 Participants	70 Participants n=7 Participants	149 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	143 Participants n=5 Participants	149 Participants n=7 Participants	292 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	12 Participants n=5 Participants	13 Participants n=7 Participants	25 Participants n=5 Participants
Race (NIH/OMB) Asian	19 Participants n=5 Participants	26 Participants n=7 Participants	45 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	16 Participants n=5 Participants	20 Participants n=7 Participants	36 Participants n=5 Participants
Race (NIH/OMB) White	169 Participants n=5 Participants	154 Participants n=7 Participants	323 Participants n=5 Participants
Race (NIH/OMB) More than one race	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Weight	78.60 kg STANDARD_DEVIATION 14.842 • n=5 Participants	78.81 kg STANDARD_DEVIATION 15.239 • n=7 Participants	78.70 kg STANDARD_DEVIATION 15.024 • n=5 Participants
Body Mass Index (BMI)	29.58 kg/m2 STANDARD_DEVIATION 4.348 • n=5 Participants	30.02 kg/m2 STANDARD_DEVIATION 4.459 • n=7 Participants	29.79 kg/m2 STANDARD_DEVIATION 4.404 • n=5 Participants
Diabetes duration	6.25 years STANDARD_DEVIATION 6.285 • n=5 Participants	5.94 years STANDARD_DEVIATION 6.276 • n=7 Participants	6.10 years STANDARD_DEVIATION 6.275 • n=5 Participants
Glomerular Filtration Rate (GFR)	73.62 mL/min/1.73 m2 STANDARD_DEVIATION 14.762 • n=5 Participants	72.89 mL/min/1.73 m2 STANDARD_DEVIATION 15.524 • n=7 Participants	73.26 mL/min/1.73 m2 STANDARD_DEVIATION 15.133 • n=5 Participants
Smoking history Never smoked	160 participants n=5 Participants	168 participants n=7 Participants	328 participants n=5 Participants
Smoking history Current smoker	16 participants n=5 Participants	11 participants n=7 Participants	27 participants n=5 Participants
Smoking history Ex-smoker	46 participants n=5 Participants	40 participants n=7 Participants	86 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Week 52.

Population: Randomized participants who received at least 1 dose of study drug, had measurements at Baseline and at the visit, and who met pre-specified criteria (no major protocol violations) for inclusion in the Per Protocol Set. Missing data were imputed using last observation carried forward (LOCF).

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=180 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=162 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in Glycosylated Hemoglobin at Week 52.	-0.14 percentage of Glycosylated Hemoglobin Standard Error 0.063	-0.09 percentage of Glycosylated Hemoglobin Standard Error 0.067

SECONDARY outcome

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

The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at each week indicated including final visit relative to baseline.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=180 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=162 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in Glycosylated Hemoglobin Week 4 (n=175; n=148)	-0.14 percentage of Glycosylated Hemoglobin Standard Error 0.047	-0.11 percentage of Glycosylated Hemoglobin Standard Error 0.051
Change From Baseline in Glycosylated Hemoglobin Week 8 (n=180; n=161)	-0.27 percentage of Glycosylated Hemoglobin Standard Error 0.051	-0.23 percentage of Glycosylated Hemoglobin Standard Error 0.054
Change From Baseline in Glycosylated Hemoglobin Week 12 (n=180; n=162)	-0.34 percentage of Glycosylated Hemoglobin Standard Error 0.053	-0.25 percentage of Glycosylated Hemoglobin Standard Error 0.055
Change From Baseline in Glycosylated Hemoglobin Week 16 (n=180; n=162)	-0.31 percentage of Glycosylated Hemoglobin Standard Error 0.050	-0.32 percentage of Glycosylated Hemoglobin Standard Error 0.052
Change From Baseline in Glycosylated Hemoglobin Week 20 (n=180; n=162)	-0.31 percentage of Glycosylated Hemoglobin Standard Error 0.051	-0.27 percentage of Glycosylated Hemoglobin Standard Error 0.054
Change From Baseline in Glycosylated Hemoglobin Week 26 (n=180; n=162)	-0.28 percentage of Glycosylated Hemoglobin Standard Error 0.052	-0.25 percentage of Glycosylated Hemoglobin Standard Error 0.055
Change From Baseline in Glycosylated Hemoglobin Week 34 (n=180; n=162)	-0.21 percentage of Glycosylated Hemoglobin Standard Error 0.056	-0.21 percentage of Glycosylated Hemoglobin Standard Error 0.059
Change From Baseline in Glycosylated Hemoglobin Week 42 (n=180; n=162)	-0.17 percentage of Glycosylated Hemoglobin Standard Error 0.062	-0.17 percentage of Glycosylated Hemoglobin Standard Error 0.065

SECONDARY outcome

Timeframe: On occurrence (up to 52 weeks).

Population: Percentages based on the number of Safety Set participants in each treatment group.

Percentage of participants with at least one hypoglycemic episode during 52 week study.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Incidence of Hypoglycemia	5.4 percentage of participants	26.0 percentage of participants

SECONDARY outcome

Timeframe: On Occurrence (up to 52 weeks).

Population: All randomized participants who had at least 1 dose of study medication (full analysis set).

The number of participants with a fasting plasma glucose value ≥ to 200 mg per dL during the 52 week study.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Incidence of Marked Hyperglycemia (Fasting Plasma Glucose ≥200 mg Per dL). Baseline to <Week 4	30 participants	17 participants
Incidence of Marked Hyperglycemia (Fasting Plasma Glucose ≥200 mg Per dL). Week 4 to <Week 8	11 participants	5 participants
Incidence of Marked Hyperglycemia (Fasting Plasma Glucose ≥200 mg Per dL). Week 8 to <Week 12	12 participants	8 participants
Incidence of Marked Hyperglycemia (Fasting Plasma Glucose ≥200 mg Per dL). Week 12 to <Week 16	11 participants	8 participants
Incidence of Marked Hyperglycemia (Fasting Plasma Glucose ≥200 mg Per dL). Week 16 to <Week 20	5 participants	4 participants
Incidence of Marked Hyperglycemia (Fasting Plasma Glucose ≥200 mg Per dL). Week 20 to <Week 26	2 participants	3 participants
Incidence of Marked Hyperglycemia (Fasting Plasma Glucose ≥200 mg Per dL). Week 26 to <Week 34	3 participants	8 participants
Incidence of Marked Hyperglycemia (Fasting Plasma Glucose ≥200 mg Per dL). Week 34 to <Week 42	2 participants	4 participants
Incidence of Marked Hyperglycemia (Fasting Plasma Glucose ≥200 mg Per dL). Week 42 to Week 52	9 participants	6 participants
Incidence of Marked Hyperglycemia (Fasting Plasma Glucose ≥200 mg Per dL). Overall	50 participants	37 participants

SECONDARY outcome

Timeframe: On Occurrence (up to 52 weeks).

Population: All randomized participants who had at least 1 dose of study medication (full analysis set). Participants who discontinued prior to Week 2 were excluded from analysis.

The number of participants requiring rescue for failing to achieve pre-specified glycemic targets during the 52 week study.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Incidence of Hyperglycemic Rescue Week 2 to <Week 4	1 participants	0 participants
Incidence of Hyperglycemic Rescue Week 4 to <Week 8	2 participants	1 participants
Incidence of Hyperglycemic Rescue Week 8 to <Week 12	1 participants	0 participants
Incidence of Hyperglycemic Rescue Week 12 to <Week 16	14 participants	14 participants
Incidence of Hyperglycemic Rescue Week 16 to <Week 20	6 participants	9 participants
Incidence of Hyperglycemic Rescue Week 20 to <Week 26	5 participants	8 participants
Incidence of Hyperglycemic Rescue Week 26 to <Week 34	10 participants	2 participants
Incidence of Hyperglycemic Rescue Week 34 to <Week 42	6 participants	7 participants
Incidence of Hyperglycemic Rescue Week 42 to Week 52	10 participants	6 participants
Incidence of Hyperglycemic Rescue Overall	50 participants	37 participants

SECONDARY outcome

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

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The change in the value of fasting plasma glucose collected at each week indicated including final visit relative to baseline.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in Fasting Plasma Glucose Week 2 (n=196; n=199)	-3.8 mg/dL Standard Error 1.93	-5.0 mg/dL Standard Error 1.91
Change From Baseline in Fasting Plasma Glucose Week 4 (n=217; n=213)	-7.7 mg/dL Standard Error 1.93	-7.6 mg/dL Standard Error 1.95
Change From Baseline in Fasting Plasma Glucose Week 8 (n=217; n=214)	-8.9 mg/dL Standard Error 1.76	-8.7 mg/dL Standard Error 1.77
Change From Baseline in Fasting Plasma Glucose Week 12 (n=217; n=214)	-10.2 mg/dL Standard Error 1.84	-9.9 mg/dL Standard Error 1.86
Change From Baseline in Fasting Plasma Glucose Week 16 (n=217; n=214)	-7.9 mg/dL Standard Error 1.85	-11.4 mg/dL Standard Error 1.86
Change From Baseline in Fasting Plasma Glucose Week 20 (n=217; n=214)	-9.8 mg/dL Standard Error 1.78	-8.7 mg/dL Standard Error 1.79
Change From Baseline in Fasting Plasma Glucose Week 26 (n=217; n=214)	-7.9 mg/dL Standard Error 1.97	-6.2 mg/dL Standard Error 1.99
Change From Baseline in Fasting Plasma Glucose Week 34 (n=217; n=214)	-5.4 mg/dL Standard Error 1.98	-5.7 mg/dL Standard Error 1.99
Change From Baseline in Fasting Plasma Glucose Week 42 (n=217; n=214)	-3.6 mg/dL Standard Error 2.13	-7.4 mg/dL Standard Error 2.14
Change From Baseline in Fasting Plasma Glucose Week 52 (n=217; n=214)	-2.4 mg/dL Standard Error 2.24	-4.2 mg/dL Standard Error 2.26

SECONDARY outcome

Timeframe: Baseline and Week 52.

Population: All randomized participants who had at least 1 dose of study medication (full analysis set).

The change in postprandial (after eating a meal) glucose levels at week 52 relative to baseline. Standard 2-hour postprandial glucose (PPG) tests performed following an overnight fast and evaluated right before and after a 120-minute (2-hour) timeframe relative to ingestion of a standard oral glucose drink.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in 2-hour Postprandial Glucose Week 52 PPG level (n=109; n=93)	-5.80 mg/dL Standard Error 5.530	6.30 mg/dL Standard Error 5.989
Change From Baseline in 2-hour Postprandial Glucose Week 52 PPG excursion (n=109; n=93)	1.82 mg/dL Standard Error 4.434	7.17 mg/dL Standard Error 4.804

SECONDARY outcome

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

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The change between the value of fasting proinsulin collected at each week indicated including final visit relative to baseline.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in Fasting Proinsulin Week 12 (n=207; n=186)	-6.0 pmol/L Standard Error 0.99	1.0 pmol/L Standard Error 1.05
Change From Baseline in Fasting Proinsulin Week 26 (n=211; n=194)	-4.6 pmol/L Standard Error 1.49	3.0 pmol/L Standard Error 1.56
Change From Baseline in Fasting Proinsulin Week 42 (n=211; n=194)	-4.6 pmol/L Standard Error 1.48	3.1 pmol/L Standard Error 1.54
Change From Baseline in Fasting Proinsulin Week 52 (n=211; n=194)	-4.9 pmol/L Standard Error 1.42	3.0 pmol/L Standard Error 1.48

SECONDARY outcome

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

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The change between the value of insulin collected at each week indicated including final visit relative to baseline.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in Insulin Week 12 (n=207; n=188)	-2.36 mcIU/mL Standard Error 0.673	0.84 mcIU/mL Standard Error 0.707
Change From Baseline in Insulin Week 26 (n=210; n=194)	-0.41 mcIU/mL Standard Error 1.548	3.03 mcIU/mL Standard Error 1.611
Change From Baseline in Insulin Week 42 (n=210; n=194)	-0.58 mcIU/mL Standard Error 1.254	1.53 mcIU/mL Standard Error 1.305
Change From Baseline in Insulin Week 52 (n=210; n=194)	-1.72 mcIU/mL Standard Error 1.731	3.15 mcIU/mL Standard Error 1.801

SECONDARY outcome

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

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The change between the ratio value of proinsulin and insulin collected at each week indicated including final visit relative to baseline.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in Proinsulin/Insulin Ratio Week 52 (n=210; n=193)	-0.155 ratio Standard Error 0.0899	-0.057 ratio Standard Error 0.0938
Change From Baseline in Proinsulin/Insulin Ratio Week 12 (n=206; n=185)	-0.288 ratio Standard Error 0.1035	0.053 ratio Standard Error 0.1092
Change From Baseline in Proinsulin/Insulin Ratio Week 26 (n=210; n=193)	-0.253 ratio Standard Error 0.4333	0.562 ratio Standard Error 0.4520
Change From Baseline in Proinsulin/Insulin Ratio Week 42 (n=210; n=193)	-0.289 ratio Standard Error 0.1500	0.183 ratio Standard Error 0.1565

SECONDARY outcome

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

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The change between homeostasis model assessment of beta cell function collected at each week indicated including final visit relative to baseline. Homeostasis model assessment of beta cell function measures beta cell function, calculated by a constant (20) times insulin, divided by fasting plasma glucose minus a constant (3.5).

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Homeostasis Model Assessment of Beta Cell Function Week 12 (n=203; n=184)	-6.104 percent score of beta cell function Standard Error 8.3062	30.081 percent score of beta cell function Standard Error 8.7264
Homeostasis Model Assessment of Beta Cell Function Week 26 (n=207; n=193)	-0.136 percent score of beta cell function Standard Error 9.7088	31.669 percent score of beta cell function Standard Error 10.0562
Homeostasis Model Assessment of Beta Cell Function Week 42 (n=207; n=193)	-5.571 percent score of beta cell function Standard Error 7.1395	16.004 percent score of beta cell function Standard Error 7.3950
Homeostasis Model Assessment of Beta Cell Function Week 52 (n=207; n=193)	-9.755 percent score of beta cell function Standard Error 13.8868	35.281 percent score of beta cell function Standard Error 14.3836

SECONDARY outcome

Timeframe: Baseline, Week 8, Week 12, Week 26, Week 42 and Week 52.

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The change in body weight measured at each week indicated including final visit from baseline.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in Body Weight Week 8 (n=213; n=200)	-0.42 kg Standard Error 0.118	0.55 kg Standard Error 0.122
Change From Baseline in Body Weight Week 12 (n=215; n=203)	-0.52 kg Standard Error 0.142	0.42 kg Standard Error 0.146
Change From Baseline in Body Weight Week 26 (n=215; n=204)	-0.68 kg Standard Error 0.188	0.66 kg Standard Error 0.193
Change From Baseline in Body Weight Week 42 (n=215; n=204)	-0.72 kg Standard Error 0.211	0.57 kg Standard Error 0.216
Change From Baseline in Body Weight Week 52 (n=215; n=204)	-0.62 kg Standard Error 0.227	0.60 kg Standard Error 0.233

SECONDARY outcome

Timeframe: Baseline, Week 8, Week 12, Week 26, Week 42 and Week 52.

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The change in total cholesterol measured at each week indicated including final visit from baseline.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in Serum Lipids (Total Cholesterol) Week 8 (n=208; n=195)	-5.6 mg/dL Standard Error 2.01	-1.6 mg/dL Standard Error 2.08
Change From Baseline in Serum Lipids (Total Cholesterol) Week 12 (n=213; n=201)	-4.2 mg/dL Standard Error 2.06	-0.7 mg/dL Standard Error 2.12
Change From Baseline in Serum Lipids (Total Cholesterol) Week 26 (n=213; n=201)	1.6 mg/dL Standard Error 2.03	0.1 mg/dL Standard Error 2.09
Change From Baseline in Serum Lipids (Total Cholesterol) Week 42 (n=213; n=201)	0.2 mg/dL Standard Error 2.07	0.1 mg/dL Standard Error 2.13
Change From Baseline in Serum Lipids (Total Cholesterol) Week 52 (n=213; n=201)	-0.8 mg/dL Standard Error 2.28	-0.5 mg/dL Standard Error 2.35

SECONDARY outcome

Timeframe: Baseline, Week 8, Week 12, Week 26, Week 42 and Week 52.

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The change in high-density lipoprotein cholesterol measured at each week indicated including final visit from baseline.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in Serum Lipids (High-Density Lipoprotein Cholesterol) Week 8 (n=206; n=193)	-0.1 mg/dL Standard Error 0.59	1.2 mg/dL Standard Error 0.61
Change From Baseline in Serum Lipids (High-Density Lipoprotein Cholesterol) Week 12 (n=212; n=201)	0.4 mg/dL Standard Error 0.47	0.5 mg/dL Standard Error 0.48
Change From Baseline in Serum Lipids (High-Density Lipoprotein Cholesterol) Week 26 (n=212; n=201)	1.7 mg/dL Standard Error 0.50	0.2 mg/dL Standard Error 0.52
Change From Baseline in Serum Lipids (High-Density Lipoprotein Cholesterol) Week 42 (n=212; n=201)	1.4 mg/dL Standard Error 0.59	0.1 mg/dL Standard Error 0.61
Change From Baseline in Serum Lipids (High-Density Lipoprotein Cholesterol) Week 52 (n=212; n=201)	0.8 mg/dL Standard Error 0.50	0.3 mg/dL Standard Error 0.51

SECONDARY outcome

Timeframe: Baseline, Week 8, Week 12, Week 26, Week 42 and Week 52.

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The change in low-density lipoprotein cholesterol measured at each week indicated including final visit from baseline.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in Serum Lipids (Low-Density Lipoprotein Cholesterol) Week 8 (n=200; n=185)	-3.2 mg/dL Standard Error 1.70	-2.8 mg/dL Standard Error 1.76
Change From Baseline in Serum Lipids (Low-Density Lipoprotein Cholesterol) Week 12 (n=208; n=195)	-2.0 mg/dL Standard Error 1.75	-2.4 mg/dL Standard Error 1.81
Change From Baseline in Serum Lipids (Low-Density Lipoprotein Cholesterol) Week 26 (n=208; n=196)	3.1 mg/dL Standard Error 1.67	-1.1 mg/dL Standard Error 1.72
Change From Baseline in Serum Lipids (Low-Density Lipoprotein Cholesterol) Week 42 (n=208; n=197)	1.2 mg/dL Standard Error 1.79	-0.8 mg/dL Standard Error 1.84
Change From Baseline in Serum Lipids (Low-Density Lipoprotein Cholesterol) Week 52 (n=209; n=197)	0.9 mg/dL Standard Error 1.83	-1.4 mg/dL Standard Error 1.88

SECONDARY outcome

Timeframe: Baseline, Week 8, Week 12, Week 26, Week 42 and Week 52.

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The change in triglycerides measured at each week indicated including final visit from baseline.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in Serum Lipids (Triglycerides) Week 8 (n=208; n=195)	-12.8 mg/dL Standard Error 5.04	2.7 mg/dL Standard Error 5.20
Change From Baseline in Serum Lipids (Triglycerides) Week 12 (n=213; n=201)	-15.5 mg/dL Standard Error 5.72	7.5 mg/dL Standard Error 5.89
Change From Baseline in Serum Lipids (Triglycerides) Week 26 (n=213; n=201)	-16.3 mg/dL Standard Error 4.74	3.9 mg/dL Standard Error 4.88
Change From Baseline in Serum Lipids (Triglycerides) Week 42 (n=213; n=201)	-12.6 mg/dL Standard Error 5.01	5.5 mg/dL Standard Error 5.16
Change From Baseline in Serum Lipids (Triglycerides) Week 52 (n=213; n=201)	-13.2 mg/dL Standard Error 5.27	1.9 mg/dL Standard Error 5.42

SECONDARY outcome

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

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The change between the high sensitivity C-reactive protein value collected at each week indicated including final visit from baseline.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Change From Baseline in High Sensitivity C-reactive Protein Week 12 (n=209; n=192)	0.45 mg/L Standard Error 0.699	0.10 mg/L Standard Error 0.730
Change From Baseline in High Sensitivity C-reactive Protein Week 26 (n=212; n=198)	-0.02 mg/L Standard Error 0.682	0.47 mg/L Standard Error 0.706
Change From Baseline in High Sensitivity C-reactive Protein Week 42 (n=212; n=198)	0.33 mg/L Standard Error 0.736	0.53 mg/L Standard Error 0.762
Change From Baseline in High Sensitivity C-reactive Protein Week 52 (n=212; n=198)	0.01 mg/L Standard Error 0.656	0.21 mg/L Standard Error 0.679

SECONDARY outcome

Timeframe: Baseline and Week 52.

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The percentage of participants with a value for the percentage of glycosylated hemoglobin (HbA1c; the percentage of hemoglobin that is bound to glucose) less than or equal to 6.5 and 7.0% during the 52 week study.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Incidence of Subjects Achieving Glycosylated Hemoglobin <=7% HbA1c ≤6.5%	22.3 percentage of participants	18.2 percentage of participants
Incidence of Subjects Achieving Glycosylated Hemoglobin <=7% HbA1c ≤7.0%	48.8 percentage of participants	45.3 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Week 52.

Population: All randomized participants who had at least 1 dose of study medication (full analysis set) with last observation carried forward.

The percentage of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 0.5, 1.0, 1.5 and 2.0% during the 52 week study.

Outcome measures

Outcome measures
Measure	Alogliptin 25 mg QD n=222 Participants Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 Participants Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Incidence of Glycosylated Hemoglobin Decrease From Baseline. Decrease from Baseline in HbA1c ≥0.5%	32.1 percentage of participants	29.0 percentage of participants
Incidence of Glycosylated Hemoglobin Decrease From Baseline. Decrease from Baseline in HbA1c ≥1.0%	12.6 percentage of participants	10.3 percentage of participants
Incidence of Glycosylated Hemoglobin Decrease From Baseline. Decrease from Baseline in HbA1c ≥1.5%	5.1 percentage of participants	2.3 percentage of participants
Incidence of Glycosylated Hemoglobin Decrease From Baseline. Decrease from Baseline in HbA1c ≥2.0%	2.8 percentage of participants	1.4 percentage of participants

Adverse Events

Alogliptin 25 mg QD

Serious events: 16 serious events

Other events: 103 other events

Deaths: 0 deaths

Glipizide 5 mg QD

Serious events: 13 serious events

Other events: 105 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Sr. VP, Clinical Science

Takeda Global Research and Development Center, Inc.

Phone: 800-778-2860

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee No publication related to study results will be published prior to publication of a multi-center report submitted for publication within 18 months after conclusion or termination of a study at all study sites. Results publications will be submitted to sponsor for review 60 days in advance of publication. Sponsor can require removal of confidential information unrelated to study results. Sponsor can embargo a proposed publication for another 60 days to preserve intellectual property.
Publication restrictions are in place

Restriction type: OTHER

Measure	Alogliptin 25 mg QD n=222 participants at risk Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.	Glipizide 5 mg QD n=219 participants at risk Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.
Musculoskeletal and connective tissue disorders Arthralgia	4.5% 10/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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.	5.5% 12/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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	4.1% 9/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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.	5.0% 11/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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	2.7% 6/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 9/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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 C-reactive protein increased	4.1% 9/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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.	1.4% 3/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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 Diarrhoea	4.1% 9/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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.	6.4% 14/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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	5.9% 13/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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.	8.2% 18/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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	2.3% 5/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 10/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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 Dyspepsia	3.2% 7/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 1/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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	7.2% 16/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 15/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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	5.4% 12/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 10/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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	0.00% 0/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 8/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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	5.9% 13/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 10/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 7/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 8/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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 Osteoarthritis	1.4% 3/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 8/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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	2.7% 6/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 7/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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 Pharyngitis	2.3% 5/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 7/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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 Pyrexia	0.90% 2/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 7/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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	5.4% 12/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 5/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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	11.7% 26/222 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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% 23/219 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days after the last dose of double-blind study drug. At each visit the investigator was 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.