Trial Outcomes & Findings for Efficacy and Safety Study of Alogliptin and Insulin in the Treatment of Type 2 Diabetes. (NCT NCT00286429)

Results Overview

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 week 26 or final visit and glycosylated hemoglobin collected at baseline.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

390 participants

Primary outcome timeframe

Baseline and Week 26.

Results posted on

2012-02-03

Participant Flow

Participants enrolled at 110 investigative sites in Australia, Brazil, Chile, Guatemala, Germany, Hungary, India, Mexico, New Zealand, the Netherlands, Poland, South Africa, and the United States from 16 March 2006 to 18 September 2006

Participants with a historical diagnosis of type 2 diabetes mellitus who were inadequately controlled while being treated with insulin with or without metformin were enrolled in one of three, once-daily (QD) treatment groups.

Participant milestones

Participant milestones
Measure	Placebo Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Overall Study STARTED	130	131	129
Overall Study COMPLETED	55	83	77
Overall Study NOT COMPLETED	75	48	52

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Overall Study Adverse Event	4	1	6
Overall Study Lack of Efficacy	52	27	25
Overall Study Lost to Follow-up	2	4	3
Overall Study Physician Decision	10	7	7
Overall Study Protocol Violation	3	5	4
Overall Study Withdrawal by Subject	3	2	6
Overall Study Administrative Error	1	1	1
Overall Study Administrative Decision	0	1	0

Baseline Characteristics

Efficacy and Safety Study of Alogliptin and Insulin in the Treatment of Type 2 Diabetes.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=130 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=129 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Total n=390 Participants Total of all reporting groups
Age, Customized <65 years	109 participants n=5 Participants	112 participants n=7 Participants	106 participants n=5 Participants	327 participants n=4 Participants
Age, Customized ≥65 years	21 participants n=5 Participants	19 participants n=7 Participants	23 participants n=5 Participants	63 participants n=4 Participants
Sex: Female, Male Female	68 Participants n=5 Participants	76 Participants n=7 Participants	85 Participants n=5 Participants	229 Participants n=4 Participants
Sex: Female, Male Male	62 Participants n=5 Participants	55 Participants n=7 Participants	44 Participants n=5 Participants	161 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and Week 26.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 26. Missing data are imputed using last observation carried forward (LOCF). ANCOVA = Analysis of covariance.

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 week 26 or final visit and glycosylated hemoglobin collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=126 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=130 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=126 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26.	-0.13 percentage of Glycosylated Hemoglobin Standard Error 0.077	-0.63 percentage of Glycosylated Hemoglobin Standard Error 0.076	-0.71 percentage of Glycosylated Hemoglobin Standard Error 0.078

SECONDARY outcome

Timeframe: Baseline and Week 4.

Population: Randomized participants who received at least 1 dose of study drug and who had an HbA1c measurement at baseline and at Week 4. Missing data are imputed using last observation carried forward (LOCF).

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 week 4 and Glycosylated Hemoglobin collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=114 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=116 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=116 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Glycosylated Hemoglobin (Week 4).	-0.26 percentage of Glycosylated Hemoglobin Standard Error 0.045	-0.47 percentage of Glycosylated Hemoglobin Standard Error 0.045	-0.58 percentage of Glycosylated Hemoglobin Standard Error 0.045

SECONDARY outcome

Timeframe: Baseline and Week 8.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 8. Missing data are imputed using last observation carried forward (LOCF).

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 week 8 and Glycosylated Hemoglobin collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=126 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=130 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=126 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Glycosylated Hemoglobin (Week 8).	-0.27 percentage of Glycosylated Hemoglobin Standard Error 0.061	-0.76 percentage of Glycosylated Hemoglobin Standard Error 0.060	-0.84 percentage of Glycosylated Hemoglobin Standard Error 0.062

SECONDARY outcome

Timeframe: Baseline and Week 12.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 12. Missing data are imputed using last observation carried forward (LOCF).

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 week 12 and Glycosylated Hemoglobin collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=126 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=130 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=126 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Glycosylated Hemoglobin (Week 12).	-0.27 percentage of Glycosylated Hemoglobin Standard Error 0.073	-0.84 percentage of Glycosylated Hemoglobin Standard Error 0.072	-0.81 percentage of Glycosylated Hemoglobin Standard Error 0.073

SECONDARY outcome

Timeframe: Baseline and Week 16.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 16. Missing data are imputed using last observation carried forward (LOCF).

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 week 16 and Glycosylated Hemoglobin collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=126 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=130 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=126 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Glycosylated Hemoglobin (Week 16).	-0.22 percentage of Glycosylated Hemoglobin Standard Error 0.076	-0.80 percentage of Glycosylated Hemoglobin Standard Error 0.074	-0.76 percentage of Glycosylated Hemoglobin Standard Error 0.076

SECONDARY outcome

Timeframe: Baseline and Week 20.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 20. Missing data are imputed using last observation carried forward (LOCF).

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 week 20 and Glycosylated Hemoglobin collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=126 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=130 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=126 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Glycosylated Hemoglobin (Week 20).	-0.17 percentage of Glycosylated Hemoglobin Standard Error 0.078	-0.76 percentage of Glycosylated Hemoglobin Standard Error 0.076	-0.74 percentage of Glycosylated Hemoglobin Standard Error 0.078

SECONDARY outcome

Timeframe: Baseline and Week 1.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 1. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of fasting plasma glucose collected at final visit or week 1 and fasting plasma glucose collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=107 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=121 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=111 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Fasting Plasma Glucose (Week 1).	6.3 mg/dL Standard Error 5.40	-5.0 mg/dL Standard Error 5.07	-9.9 mg/dL Standard Error 5.33

SECONDARY outcome

Timeframe: Baseline and Week 2.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 2. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of fasting plasma glucose collected at week 2 and fasting plasma glucose collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=115 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=127 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=119 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Fasting Plasma Glucose (Week 2).	1.0 mg/dL Standard Error 5.09	-3.1 mg/dL Standard Error 4.84	-11.4 mg/dL Standard Error 5.03

SECONDARY outcome

Timeframe: Baseline and Week 4.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 4. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of fasting plasma glucose collected at week 4 and fasting plasma glucose collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=119 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=128 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=120 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Fasting Plasma Glucose (Week 4).	5.3 mg/dL Standard Error 5.28	-5.0 mg/dL Standard Error 5.08	-12.1 mg/dL Standard Error 5.28

SECONDARY outcome

Timeframe: Baseline and Week 8.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 8. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of fasting plasma glucose collected at week 8 and fasting plasma glucose collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=124 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=126 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Fasting Plasma Glucose (Week 8).	5.4 mg/dL Standard Error 5.42	-13.5 mg/dL Standard Error 5.26	-14.1 mg/dL Standard Error 5.39

SECONDARY outcome

Timeframe: Baseline and Week 12.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 12. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of fasting plasma glucose collected at week 12 and fasting plasma glucose collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=127 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=128 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Fasting Plasma Glucose (Week 12).	-1.4 mg/dL Standard Error 5.47	-5.2 mg/dL Standard Error 5.38	-2.9 mg/dL Standard Error 5.47

SECONDARY outcome

Timeframe: Baseline and Week 16.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 16. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of fasting plasma glucose collected at week 16 and fasting plasma glucose collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=127 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=128 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Fasting Plasma Glucose (Week 16).	4.6 mg/dL Standard Error 5.38	-5.3 mg/dL Standard Error 5.29	-6.3 mg/dL Standard Error 5.38

SECONDARY outcome

Timeframe: Baseline and Week 20.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 20. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of fasting plasma glucose collected at week 20 and fasting plasma glucose collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=127 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=128 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Fasting Plasma Glucose (Week 20).	8.6 mg/dL Standard Error 5.45	-4.2 mg/dL Standard Error 5.36	-11.3 mg/dL Standard Error 5.46

SECONDARY outcome

Timeframe: Baseline and Week 26.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 26. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of fasting plasma glucose collected at week 26 or final visit and fasting plasma glucose collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=127 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=128 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Fasting Plasma Glucose (Week 26).	5.8 mg/dL Standard Error 5.69	2.3 mg/dL Standard Error 5.59	-11.7 mg/dL Standard Error 5.69

SECONDARY outcome

Timeframe: 26 Weeks.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had at least 1 fasting plasma glucose measurement after baseline.

The number of participants with a fasting plasma glucose value greater than or equal to 200 mg per dL during the 26 week study.

Outcome measures

Outcome measures
Measure	Placebo n=128 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=128 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Number of Participants With Marked Hyperglycemia (Fasting Plasma Glucose ≥ 200 mg Per dL).	105 participants	99 participants	86 participants

SECONDARY outcome

Timeframe: 26 Weeks.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who completed at least 1 study visit after baseline.

The number of participants requiring rescue for failing to achieve pre-specified glycemic targets during the 26 week study.

Outcome measures

Outcome measures
Measure	Placebo n=129 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=128 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Number of Participants Requiring Rescue.	52 participants	27 participants	25 participants

SECONDARY outcome

Timeframe: Baseline and Week 4.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 4. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of C-peptide collected at week 4 and C-peptide collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=99 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=111 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=109 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in C-peptide (Week 4).	-0.023 ng/mL Standard Error 0.1062	0.132 ng/mL Standard Error 0.1001	0.453 ng/mL Standard Error 0.1014

SECONDARY outcome

Timeframe: Baseline and Week 8.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 8. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of C-peptide collected at week 8 and C-peptide collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=121 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=130 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=123 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in C-peptide (Week 8).	-0.024 ng/mL Standard Error 0.1224	0.178 ng/mL Standard Error 0.1180	0.348 ng/mL Standard Error 0.1220

SECONDARY outcome

Timeframe: Baseline and Week 12.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 12. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of C-peptide collected at week 12 and C-peptide collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=124 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=130 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=126 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in C-peptide (Week 12).	0.207 ng/mL Standard Error 0.1558	0.333 ng/mL Standard Error 0.1521	0.390 ng/mL Standard Error 0.1553

SECONDARY outcome

Timeframe: Baseline and Week 16.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 16. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of C-peptide collected at week 16 and C-peptide collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=124 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=130 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=126 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in C-peptide (Week 16).	0.241 ng/mL Standard Error 0.1536	0.319 ng/mL Standard Error 0.1500	0.396 ng/mL Standard Error 0.1532

SECONDARY outcome

Timeframe: Baseline and Week 20.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 20. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of C-peptide collected at week 20 and C-peptide collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=124 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=130 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=126 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in C-peptide (Week 20).	0.239 ng/mL Standard Error 0.1467	0.318 ng/mL Standard Error 0.1432	0.281 ng/mL Standard Error 0.1463

SECONDARY outcome

Timeframe: Baseline and Week 26.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 26. Missing data are imputed using last observation carried forward (LOCF).

The change between the value of C-peptide collected at week 26 or final visit and C-peptide collected at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=124 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=130 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=126 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in C-peptide (Week 26).	-0.083 ng/mL Standard Error 0.1192	0.199 ng/mL Standard Error 0.1164	0.042 ng/mL Standard Error 0.1189

SECONDARY outcome

Timeframe: Baseline and Week 26.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who completed at least 1 HbA1c measurement after baseline. Due to no participants in the placebo arm achieved HbA1c ≤ 6.5%, the odds ratio of alogliptin to placebo and 95% CI were not estimable from the logistic regression.

The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 6.5% during the 26 week study.

Outcome measures

Outcome measures
Measure	Placebo n=129 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=129 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Number of Participants With Glycosylated Hemoglobin ≤ 6.5%.	0 participants	3 participants	3 participants

SECONDARY outcome

Timeframe: Baseline and Week 26.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had at least 1 HbA1c measurement after baseline.

The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 7.0% during the 26 week study.

Outcome measures

Outcome measures
Measure	Placebo n=129 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=129 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Number of Participants With Glycosylated Hemoglobin ≤ 7.0%.	1 participants	11 participants	10 participants

SECONDARY outcome

Timeframe: Baseline and Week 26.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had at least 1 HbA1c measurement after baseline.

The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 7.5% during the 26 week study.

Outcome measures

Outcome measures
Measure	Placebo n=129 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=129 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Number of Participants With Glycosylated Hemoglobin ≤ 7.5%.	5 participants	22 participants	33 participants

SECONDARY outcome

Timeframe: Baseline and Week 26.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had at least 1 HbA1c measurement after baseline.

The number 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% during the 26 week study.

Outcome measures

Outcome measures
Measure	Placebo n=129 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=129 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 0.5%.	40 participants	70 participants	70 participants

SECONDARY outcome

Timeframe: Baseline and Week 26.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had at least 1 HbA1c measurement after baseline.

The number 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 1.0% during the 26 week study.

Outcome measures

Outcome measures
Measure	Placebo n=129 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=129 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 1.0%.	17 participants	41 participants	47 participants

SECONDARY outcome

Timeframe: Baseline and Week 26.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had at least 1 HbA1c measurement after baseline.

The number 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 1.5% during the 26 week study.

Outcome measures

Outcome measures
Measure	Placebo n=129 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=129 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 1.5%.	6 participants	22 participants	23 participants

SECONDARY outcome

Timeframe: Baseline and Week 26.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had at least 1 HbA1c measurement after baseline. Due to no participants in the placebo arm achieved HbA1c decrease from baseline ≥2.0%, the odds ratio of alogliptin to placebo and 95% CI were not estimable from the logistic regression.

The number 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 2.0% during the 26 week study.

Outcome measures

Outcome measures
Measure	Placebo n=129 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=129 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 2.0%.	0 participants	11 participants	11 participants

SECONDARY outcome

Timeframe: Baseline and Week 8.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 8. Missing data are imputed using last observation carried forward (LOCF).

The change between Body Weight measured at week 8 and Body Weight measured at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=118 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=125 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=121 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Body Weight (Week 8).	0.39 kg Standard Error 0.191	0.10 kg Standard Error 0.185	0.18 kg Standard Error 0.189

SECONDARY outcome

Timeframe: Baseline and Week 12.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 12. Missing data are imputed using last observation carried forward (LOCF).

The change between Body Weight measured at week 12 and Body Weight measured at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=121 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=127 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=123 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Body Weight (Week 12).	0.50 kg Standard Error 0.221	0.44 kg Standard Error 0.215	0.31 kg Standard Error 0.219

SECONDARY outcome

Timeframe: Baseline and Week 20.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 20. Missing data are imputed using last observation carried forward (LOCF).

The change between Body Weight measured at week 20 and Body Weight measured at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=121 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=127 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=124 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Body Weight (Week 20).	0.73 kg Standard Error 0.231	0.55 kg Standard Error 0.225	0.45 kg Standard Error 0.229

SECONDARY outcome

Timeframe: Baseline and Week 26.

Population: Randomized subjects who received at least 1 dose of study drug (Full Analysis Set), and who had measurements at baseline and at Week 26. Missing data are imputed using last observation carried forward (LOCF).

The change between Body Weight measured at week 26 or final visit and Body Weight measured at baseline.

Outcome measures

Outcome measures
Measure	Placebo n=121 Participants Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=127 Participants Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=124 Participants Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Change From Baseline in Body Weight (Week 26).	0.63 kg Standard Error 0.244	0.68 kg Standard Error 0.237	0.60 kg Standard Error 0.241

Adverse Events

Placebo

Serious events: 6 serious events

Other events: 54 other events

Deaths: 0 deaths

Alogliptin 12.5 mg QD

Serious events: 8 serious events

Other events: 58 other events

Deaths: 0 deaths

Alogliptin 25 mg QD

Serious events: 7 serious events

Other events: 50 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

Serious adverse events
Measure	Placebo n=129 participants at risk Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 participants at risk Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=129 participants at risk Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Cardiac disorders Angina unstable	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrial fibrillation	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	1.5% 2/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cervix carcinoma	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Hepatobiliary disorders Cholecystitis	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	1.5% 2/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Cardiac disorders Coronary artery disease	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.76% 1/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Nervous system disorders Demyelination	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Diverticulitis intestinal haemorrhagic	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Immune system disorders Hypersensitivity	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Nervous system disorders Hypoglycaemic coma	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Incisional hernia	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Nervous system disorders Ischaemic stroke	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Pancreatitis	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.76% 1/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Infections and infestations Pyelonephritis	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Nervous system disorders Sciatica	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.76% 1/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Infections and infestations Scrotal abscess	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.76% 1/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Infections and infestations Staphylococcal infection	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
General disorders Sudden death	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.76% 1/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.

Other adverse events
Measure	Placebo n=129 participants at risk Alogliptin placebo-matching tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 12.5 mg QD n=131 participants at risk Alogliptin 12.5 mg, tablets, orally, once daily and insulin for up to 26 weeks.	Alogliptin 25 mg QD n=129 participants at risk Alogliptin 25 mg, tablets, orally, once daily and insulin for up to 26 weeks.
Gastrointestinal disorders Abdominal pain	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.76% 1/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	4.7% 6/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Arthralgia	2.3% 3/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	6.9% 9/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	2.3% 3/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Back pain	1.6% 2/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	1.5% 2/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	4.7% 6/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Infections and infestations Bronchitis	3.1% 4/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	2.3% 3/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Cough	3.1% 4/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	1.5% 2/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	1.6% 2/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Diarrhoea	5.4% 7/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.76% 1/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	6.2% 8/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Nervous system disorders Dizziness	1.6% 2/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	3.8% 5/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Nervous system disorders Headache	4.7% 6/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	5.3% 7/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	3.1% 4/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Vascular disorders Hypertension	4.7% 6/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	3.8% 5/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	1.6% 2/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Metabolism and nutrition disorders Hypertriglyceridaemia	2.3% 3/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	3.8% 5/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	1.6% 2/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Infections and infestations Influenza	2.3% 3/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	3.1% 4/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	2.3% 3/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Insomnia	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	3.1% 4/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.78% 1/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Infections and infestations Nasopharyngitis	4.7% 6/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	3.8% 5/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	6.2% 8/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Nausea	2.3% 3/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	3.1% 4/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	4.7% 6/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
General disorders Oedema peripheral	3.1% 4/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	3.1% 4/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	5.4% 7/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	3.1% 4/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Infections and infestations Upper respiratory tract	3.1% 4/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	4.6% 6/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	3.1% 4/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Infections and infestations Urinary tract infection	7.8% 10/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	6.1% 8/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	7.0% 9/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Vomiting	3.1% 4/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	0.00% 0/131 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.	2.3% 3/129 • Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious event) after the last dose of double-blind drug. 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 was recorded, irrespective of the relation to study treatment.