Trial Outcomes & Findings for Efficacy and Safety of TAK-875 Compared to Glimepiride When Used With Metformin in Participants With Type 2 Diabetes (NCT NCT01481116)

Last Updated: 2016-06-01

Results Overview

The change in the value of HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) to be collected at Weeks 78 and 104 relative to baseline.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

2454 participants

Primary outcome timeframe

Baseline and Weeks 78 and 104

Results posted on

2016-06-01

Participant Flow

Participants took part at 291 sites in Argentina, Australia, Bulgaria, Canada, Colombia, Czech Republic, Estonia, Hong Kong, Israel, Latvia, Lithuania, Malaysia, Mexico, New Zealand, Philippines, Poland, Romania, the Russian Federation, South Africa, Taiwan, Ukraine, the United Kingdom and the United States from 06 November 2011 to 24 April 2014.

Participants with a historical diagnosis of type 2 diabetes mellitus who were inadequately controlled while receiving metformin alone were enrolled in 1 of 3 treatment groups as follows: glimepiride; TAK-875 25 milligram (mg); TAK-875 50 mg.

Participant milestones

Participant milestones
Measure	Glimepiride TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (\>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.	TAK-875 25 mg TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.	TAK-875 50 mg TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.
Overall Study STARTED	824	817	813
Overall Study Treated	822	816	813
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	824	817	813

Reasons for withdrawal

Reasons for withdrawal
Measure	Glimepiride TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (\>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.	TAK-875 25 mg TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.	TAK-875 50 mg TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.
Overall Study Adverse Event	26	26	42
Overall Study Major Protocol Deviation	3	7	1
Overall Study Lost to Follow-up	8	12	11
Overall Study Withdrawal by Subject	37	33	37
Overall Study Study Termination	730	729	713
Overall Study Pregnancy	0	0	1
Overall Study Lack of Efficacy	3	3	1
Overall Study Contraindications	1	1	0
Overall Study Other	1	1	0
Overall Study Participant Started Taking Glipizide	1	0	0
Overall Study Participant Moved Out of Area	2	0	1
Overall Study Participant Moved Out of Country	1	0	1
Overall Study Investigator Decision	3	2	1
Overall Study Sponsor Decision	0	1	3
Overall Study Non-Compliant With Study Drug	0	1	1
Overall Study Investigator's Discretion	2	0	0
Overall Study Death	2	1	0
Overall Study Hypoglycemic Event	4	0	0

Baseline Characteristics

Efficacy and Safety of TAK-875 Compared to Glimepiride When Used With Metformin in Participants With Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Glimepiride n=824 Participants TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (\>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.	TAK-875 25 mg n=817 Participants TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.	TAK-875 50 mg n=813 Participants TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.	Total n=2454 Participants Total of all reporting groups
Age, Continuous	57.3 years STANDARD_DEVIATION 9.56 • n=5 Participants	56.8 years STANDARD_DEVIATION 9.34 • n=7 Participants	56.6 years STANDARD_DEVIATION 9.81 • n=5 Participants	56.9 years STANDARD_DEVIATION 9.57 • n=4 Participants
Age, Customized Less than (<) 65 years	637 participants n=5 Participants	646 participants n=7 Participants	648 participants n=5 Participants	1931 participants n=4 Participants
Age, Customized >=65 years	187 participants n=5 Participants	171 participants n=7 Participants	165 participants n=5 Participants	523 participants n=4 Participants
Sex: Female, Male Female	428 Participants n=5 Participants	422 Participants n=7 Participants	362 Participants n=5 Participants	1212 Participants n=4 Participants
Sex: Female, Male Male	396 Participants n=5 Participants	395 Participants n=7 Participants	451 Participants n=5 Participants	1242 Participants n=4 Participants
Race/Ethnicity, Customized Hispanic or Latino	68 participants n=5 Participants	66 participants n=7 Participants	70 participants n=5 Participants	204 participants n=4 Participants
Race/Ethnicity, Customized Non-Hispanic or Latino	105 participants n=5 Participants	110 participants n=7 Participants	106 participants n=5 Participants	321 participants n=4 Participants
Race/Ethnicity, Customized Not Available	651 participants n=5 Participants	641 participants n=7 Participants	637 participants n=5 Participants	1929 participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	8 participants n=5 Participants	20 participants n=7 Participants	12 participants n=5 Participants	40 participants n=4 Participants
Race/Ethnicity, Customized Asian	101 participants n=5 Participants	99 participants n=7 Participants	93 participants n=5 Participants	293 participants n=4 Participants
Race/Ethnicity, Customized Black or African American	62 participants n=5 Participants	70 participants n=7 Participants	77 participants n=5 Participants	209 participants n=4 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	3 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants	14 participants n=4 Participants
Race/Ethnicity, Customized White	617 participants n=5 Participants	598 participants n=7 Participants	601 participants n=5 Participants	1816 participants n=4 Participants
Race/Ethnicity, Customized Multiracial	33 participants n=5 Participants	26 participants n=7 Participants	23 participants n=5 Participants	82 participants n=4 Participants
Region of Enrollment Argentina	37 participants n=5 Participants	39 participants n=7 Participants	37 participants n=5 Participants	113 participants n=4 Participants
Region of Enrollment Australia	4 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants	9 participants n=4 Participants
Region of Enrollment Bulgaria	17 participants n=5 Participants	18 participants n=7 Participants	16 participants n=5 Participants	51 participants n=4 Participants
Region of Enrollment Canada	42 participants n=5 Participants	40 participants n=7 Participants	39 participants n=5 Participants	121 participants n=4 Participants
Region of Enrollment Colombia	2 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	3 participants n=4 Participants
Region of Enrollment Czech Republic	31 participants n=5 Participants	31 participants n=7 Participants	31 participants n=5 Participants	93 participants n=4 Participants
Region of Enrollment Estonia	12 participants n=5 Participants	12 participants n=7 Participants	12 participants n=5 Participants	36 participants n=4 Participants
Region of Enrollment Hong Kong	9 participants n=5 Participants	10 participants n=7 Participants	10 participants n=5 Participants	29 participants n=4 Participants
Region of Enrollment Israel	50 participants n=5 Participants	50 participants n=7 Participants	50 participants n=5 Participants	150 participants n=4 Participants
Region of Enrollment Latvia	15 participants n=5 Participants	14 participants n=7 Participants	14 participants n=5 Participants	43 participants n=4 Participants
Region of Enrollment Lithuania	21 participants n=5 Participants	23 participants n=7 Participants	22 participants n=5 Participants	66 participants n=4 Participants
Region of Enrollment Malaysia	17 participants n=5 Participants	16 participants n=7 Participants	17 participants n=5 Participants	50 participants n=4 Participants
Region of Enrollment Mexico	14 participants n=5 Participants	14 participants n=7 Participants	15 participants n=5 Participants	43 participants n=4 Participants
Region of Enrollment New Zealand	15 participants n=5 Participants	14 participants n=7 Participants	15 participants n=5 Participants	44 participants n=4 Participants
Region of Enrollment Philippines	39 participants n=5 Participants	38 participants n=7 Participants	37 participants n=5 Participants	114 participants n=4 Participants
Region of Enrollment Poland	64 participants n=5 Participants	66 participants n=7 Participants	63 participants n=5 Participants	193 participants n=4 Participants
Region of Enrollment Romania	52 participants n=5 Participants	52 participants n=7 Participants	51 participants n=5 Participants	155 participants n=4 Participants
Region of Enrollment Russian Federation	26 participants n=5 Participants	26 participants n=7 Participants	26 participants n=5 Participants	78 participants n=4 Participants
Region of Enrollment South Africa	83 participants n=5 Participants	81 participants n=7 Participants	83 participants n=5 Participants	247 participants n=4 Participants
Region of Enrollment Taiwan, Province Of China	11 participants n=5 Participants	11 participants n=7 Participants	12 participants n=5 Participants	34 participants n=4 Participants
Region of Enrollment Ukraine	80 participants n=5 Participants	80 participants n=7 Participants	79 participants n=5 Participants	239 participants n=4 Participants
Region of Enrollment United Kingdom	18 participants n=5 Participants	16 participants n=7 Participants	17 participants n=5 Participants	51 participants n=4 Participants
Region of Enrollment United States	165 participants n=5 Participants	164 participants n=7 Participants	163 participants n=5 Participants	492 participants n=4 Participants
Height	166.2 centimeter (cm) STANDARD_DEVIATION 10.66 • n=5 Participants	166.2 centimeter (cm) STANDARD_DEVIATION 10.23 • n=7 Participants	167.3 centimeter (cm) STANDARD_DEVIATION 10.19 • n=5 Participants	166.6 centimeter (cm) STANDARD_DEVIATION 10.37 • n=4 Participants
Weight	86.95 kilogram (kg) STANDARD_DEVIATION 18.415 • n=5 Participants	87.35 kilogram (kg) STANDARD_DEVIATION 18.283 • n=7 Participants	88.37 kilogram (kg) STANDARD_DEVIATION 18.796 • n=5 Participants	87.55 kilogram (kg) STANDARD_DEVIATION 18.501 • n=4 Participants
Body Mass Index (BMI)	31.34 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.334 • n=5 Participants	31.50 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.253 • n=7 Participants	31.43 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.403 • n=5 Participants	31.42 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.329 • n=4 Participants
Smoking Classification Never smoked	552 participants n=5 Participants	533 participants n=7 Participants	502 participants n=5 Participants	1587 participants n=4 Participants
Smoking Classification Current smoker	114 participants n=5 Participants	143 participants n=7 Participants	126 participants n=5 Participants	383 participants n=4 Participants
Smoking Classification Ex-smoker	158 participants n=5 Participants	141 participants n=7 Participants	185 participants n=5 Participants	484 participants n=4 Participants
Baseline Glycosylated Hemoglobin (HbA1c) Category < 8.5 percent (%)	584 participants n=5 Participants	584 participants n=7 Participants	592 participants n=5 Participants	1760 participants n=4 Participants
Baseline Glycosylated Hemoglobin (HbA1c) Category >=8.5%	238 participants n=5 Participants	232 participants n=7 Participants	221 participants n=5 Participants	691 participants n=4 Participants
Baseline Glycosylated Hemoglobin (HbA1c) Category Not Available	2 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	3 participants n=4 Participants
Duration of Diabetes	6.372 years STANDARD_DEVIATION 5.293 • n=5 Participants	6.566 years STANDARD_DEVIATION 5.132 • n=7 Participants	5.995 years STANDARD_DEVIATION 4.711 • n=5 Participants	6.312 years STANDARD_DEVIATION 5.056 • n=4 Participants

PRIMARY outcome

Timeframe: Baseline and Weeks 78 and 104

Population: Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline assessment.

The change in the value of HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) to be collected at Weeks 78 and 104 relative to baseline.

Outcome measures

Outcome measures
Measure	Glimepiride n=62 Participants TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (\>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.	TAK-875 25 mg n=61 Participants TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.	TAK-875 50 mg n=66 Participants TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.
Change From Baseline in HbA1c at Weeks 78 and 104 Baseline	8.00 percentage of glycosylated hemoglobin Standard Error 0.814	8.01 percentage of glycosylated hemoglobin Standard Error 0.777	7.99 percentage of glycosylated hemoglobin Standard Error 0.792
Change From Baseline in HbA1c at Weeks 78 and 104 Change at Week 78	-0.80 percentage of glycosylated hemoglobin Standard Error 0.957	-0.82 percentage of glycosylated hemoglobin Standard Error 0.865	-0.98 percentage of glycosylated hemoglobin Standard Error 0.834
Change From Baseline in HbA1c at Weeks 78 and 104 Change at Week 104	NA percentage of glycosylated hemoglobin Standard Error NA Data was not reported as none of the participants had data for this arm at this time point.	-1.03 percentage of glycosylated hemoglobin Standard Error 1.159	0.03 percentage of glycosylated hemoglobin Standard Error 0.603

SECONDARY outcome

Timeframe: Day 1 up to Weeks 78 and 104

Population: Safety analysis set included all participants who received at least 1 dose of double-blind study medication. Participants were analyzed according to the study medication they received.

Participants were provided diaries to document any hypoglycemic events that occurred between study visits. Any experience of hypoglycemic signs and symptoms (regardless of the blood glucose value by glucometer) or had a blood glucose value less than or equal to (\<=) 70 milligram per deciliter (mg/dL) (3.9 millimole per liter (mmol/L) by glucometer (regardless of symptoms) were to be recorded.

Outcome measures

Outcome measures
Measure	Glimepiride n=822 Participants TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (\>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.	TAK-875 25 mg n=816 Participants TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.	TAK-875 50 mg n=813 Participants TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.
Percentage of Participants With Hypoglycemia Day 1 up to Week 78	30.2 percentage of participants	5.4 percentage of participants	5.3 percentage of participants
Percentage of Participants With Hypoglycemia Day 1 up to Week 104	30.2 percentage of participants	5.4 percentage of participants	5.3 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 78 and 104

Population: FAS included all randomized participants who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline value during the double-blind treatment period. Data for body weight was not available at Week 104 due to early termination of the study.

The change between the body weight to be collected at Weeks 78 and 104 relative to baseline.

Outcome measures

Outcome measures
Measure	Glimepiride n=51 Participants TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (\>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.	TAK-875 25 mg n=44 Participants TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.	TAK-875 50 mg n=55 Participants TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.
Change From Baseline in Body Weight at Weeks 78 and 104 Baseline	84.32 kg Standard Error 0.981	84.55 kg Standard Error 1.003	85.67 kg Standard Error 0.995
Change From Baseline in Body Weight at Weeks 78 and 104 Change at Week 78	1.24 kg Standard Error 0.492	-0.07 kg Standard Error 0.524	-0.21 kg Standard Error 0.487

SECONDARY outcome

Timeframe: Baseline and Weeks 26 and 52

The change in the value of HbA1c collected at Weeks 26 and 52 relative to baseline.

Outcome measures

Outcome measures
Measure	Glimepiride n=652 Participants TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (\>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.	TAK-875 25 mg n=645 Participants TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.	TAK-875 50 mg n=641 Participants TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.
Change From Baseline in HbA1c at Weeks 26 and 52 Week 26	-0.91 percentage of glycosylated hemoglobin Standard Error 0.039	-0.63 percentage of glycosylated hemoglobin Standard Error 0.039	-0.81 percentage of glycosylated hemoglobin Standard Error 0.039
Change From Baseline in HbA1c at Weeks 26 and 52 Week 52	-0.78 percentage of glycosylated hemoglobin Standard Error 0.043	-0.65 percentage of glycosylated hemoglobin Standard Error 0.044	-0.81 percentage of glycosylated hemoglobin Standard Error 0.043

SECONDARY outcome

Timeframe: Weeks 26, 52, 78 and 104

Population: FAS included all randomized subjects who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline value during the double-blind treatment period.

Outcome measures

Outcome measures
Measure	Glimepiride n=652 Participants TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (\>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.	TAK-875 25 mg n=645 Participants TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.	TAK-875 50 mg n=641 Participants TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.
Percentage of Participants With HbA1c <7% Week 26	51.8 percentage of participants	38.3 percentage of participants	48.7 percentage of participants
Percentage of Participants With HbA1c <7% Week 52	47.8 percentage of participants	43.3 percentage of participants	54.5 percentage of participants
Percentage of Participants With HbA1c <7% Week 78	45.2 percentage of participants	37.7 percentage of participants	54.5 percentage of participants
Percentage of Participants With HbA1c <7% Week 104	NA percentage of participants Data was not reported as none of the participants had data for this arm at this time point.	33.3 percentage of participants	33.3 percentage of participants

SECONDARY outcome

Timeframe: Weeks 26, 52, 78 and 104

Population: Data for this outcome measure was not analyzed as prespecified in the protocol.

Outcome measures

Outcome data not reported

SECONDARY outcome

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

The change between the fasting plasma glucose value to be collected at Weeks 26, 52, 78 and 104 relative to baseline.

Outcome measures

Outcome measures
Measure	Glimepiride n=652 Participants TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (\>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.	TAK-875 25 mg n=816 Participants TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.	TAK-875 50 mg n=813 Participants TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.
Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 Baseline	164.5 milligram per deciliter (mg/dL) Standard Error 41.25	165.2 milligram per deciliter (mg/dL) Standard Error 38.45	163.7 milligram per deciliter (mg/dL) Standard Error 38.65
Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 Change at Week 26	-19.5 milligram per deciliter (mg/dL) Standard Error 41.90	-17.4 milligram per deciliter (mg/dL) Standard Error 34.67	-23.0 milligram per deciliter (mg/dL) Standard Error 31.99
Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 Change at Week 52	-19.8 milligram per deciliter (mg/dL) Standard Error 40.81	-19.3 milligram per deciliter (mg/dL) Standard Error 36.85	-23.7 milligram per deciliter (mg/dL) Standard Error 33.78
Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 Change at Week 78	0.0 milligram per deciliter (mg/dL) Standard Error 41.87	-17.6 milligram per deciliter (mg/dL) Standard Error 30.03	-21.4 milligram per deciliter (mg/dL) Standard Error 41.27
Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 Change at Week 104	NA milligram per deciliter (mg/dL) Standard Error NA Data was not reported as none of the participants had data for this arm at this time point.	-24.0 milligram per deciliter (mg/dL) Standard Error 1.41	-32.0 milligram per deciliter (mg/dL) Standard Error 17.58

Adverse Events

Glimepiride

Serious events: 63 serious events

Other events: 334 other events

Deaths: 0 deaths

TAK-875 25 mg

Serious events: 41 serious events

Other events: 337 other events

Deaths: 0 deaths

TAK-875 50 mg

Serious events: 58 serious events

Other events: 323 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Glimepiride n=822 participants at risk TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (\>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.	TAK-875 25 mg n=816 participants at risk TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.	TAK-875 50 mg n=813 participants at risk TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.
Eye disorders Retinal haemorrhage	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Ventricular extrasystoles	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Palpitations	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrioventricular block first degree	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Bundle branch block right	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiomyopathy	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Ischaemic cardiomyopathy	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Coronary artery disease	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.25% 2/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Coronary artery occlusion	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac failure congestive	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac failure	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac failure acute	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Angina unstable	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.49% 4/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Myocardial infarction	0.24% 2/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.25% 2/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Acute myocardial infarction	0.24% 2/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Acute coronary syndrome	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrial fibrillation	0.61% 5/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrial flutter	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.25% 2/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Supraventricular tachycardia	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac arrest	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Ear and labyrinth disorders Meniere's disease	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Ear and labyrinth disorders Vertigo	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Eye disorders Cataract	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Eye disorders Retinal artery thrombosis	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Lumbar hernia	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Abdominal hernia obstructive	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Appendicitis	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.25% 2/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Intestinal polyp haemorrhage	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Gastritis	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Schizophrenia	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Abdominal pain	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Haemorrhoids	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Megacolon	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Oesophagitis	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Umbilical hernia, obstructive	0.00% 0/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Transient ischaemic attack	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.12% 1/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Death	0.12% 1/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Other adverse events
Measure	Glimepiride n=822 participants at risk TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (\>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.	TAK-875 25 mg n=816 participants at risk TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.	TAK-875 50 mg n=813 participants at risk TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin \>=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.
Gastrointestinal disorders Diarrhoea	3.4% 28/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.3% 35/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.4% 36/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Investigations Blood creatine phosphokinase increased	3.2% 26/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.8% 15/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.1% 17/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Dizziness	2.4% 20/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 16/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.1% 9/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Nausea	2.2% 18/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.2% 18/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 16/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Pain in extremity	2.4% 20/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.6% 13/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.7% 14/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Cough	2.9% 24/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.2% 26/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.0% 16/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Urinary tract infection	3.4% 28/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.7% 22/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.6% 29/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Bronchitis	3.0% 25/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.7% 22/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.1% 25/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Headache	5.7% 47/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.1% 42/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.2% 34/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Pharyngitis	1.9% 16/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.2% 10/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.1% 17/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Nasopharyngitis	5.4% 44/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.7% 38/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	5.5% 45/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Upper respiratory tract infection	6.7% 55/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.9% 73/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	7.3% 59/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Influenza	4.6% 38/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.8% 31/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.8% 31/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Hypertension	5.7% 47/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.4% 28/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.2% 26/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Arthralgia	3.5% 29/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.4% 28/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.7% 22/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Investigations Alanine aminotransferase increased	2.1% 17/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.7% 22/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.0% 24/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Metabolism and nutrition disorders Hyperuricaemia	2.3% 19/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.5% 12/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.8% 15/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Fatigue	1.2% 10/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.74% 6/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.1% 17/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Metabolism and nutrition disorders Dyslipidaemia	1.8% 15/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.2% 10/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.1% 17/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Gastroenteritis	1.3% 11/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.5% 12/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.1% 17/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Back pain	3.8% 31/822 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.0% 33/816 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.6% 29/813 • Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual participant follow-up ranged from 1 to 735 days. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.