Trial Outcomes & Findings for DETERMINE-preserved - Dapagliflozin Effect on Exercise Capacity Using a 6-minute Walk Test in Patients With Heart Failure With Preserved Ejection Fraction (NCT NCT03877224)

Last Updated: 2021-11-17

Results Overview

Change from baseline in KCCQ-TSS was defined as the endpoint value at week 16 minus the baseline value. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. KCCQ-TSS incorporates symptom frequency (4 items) and symptom burden (3 items) domains into a single score. The score is transformed to a range of 0-100 (higher score reflects better health status). Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants alive at the week 16 visit but without KCCQ-TSS values. All the data for the endpoint, except for death, collected during COVID-19, are set as missing and imputed same way as pre-COVID-19 missing data.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

504 participants

Primary outcome timeframe

At baseline and at week 16 or death before week 16

Results posted on

2021-11-17

Participant Flow

Participant milestones

Participant milestones
Measure	Dapa 10 mg Dapagliflozin 10 mg, given once daily per oral use.	Placebo Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
Overall Study STARTED	253	251
Overall Study Treated	252	249
Overall Study COMPLETED	248	243
Overall Study NOT COMPLETED	5	8

Reasons for withdrawal

Reasons for withdrawal
Measure	Dapa 10 mg Dapagliflozin 10 mg, given once daily per oral use.	Placebo Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
Overall Study Death	3	2
Overall Study Withdrawal by Subject	1	6
Overall Study Participant is alive, just unable to come for visits	1	0

Baseline Characteristics

DETERMINE-preserved - Dapagliflozin Effect on Exercise Capacity Using a 6-minute Walk Test in Patients With Heart Failure With Preserved Ejection Fraction

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dapa 10 mg n=253 Participants Dapagliflozin 10 mg, given once daily per oral use.	Placebo n=251 Participants Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.	Total n=504 Participants Total of all reporting groups
Age, Continuous	72.0 Years STANDARD_DEVIATION 9.1 • n=5 Participants	71.7 Years STANDARD_DEVIATION 9.7 • n=7 Participants	71.8 Years STANDARD_DEVIATION 9.4 • n=5 Participants
Sex: Female, Male Female	91 Participants n=5 Participants	93 Participants n=7 Participants	184 Participants n=5 Participants
Sex: Female, Male Male	162 Participants n=5 Participants	158 Participants n=7 Participants	320 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	28 Participants n=5 Participants	31 Participants n=7 Participants	59 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	225 Participants n=5 Participants	220 Participants n=7 Participants	445 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White	192 Participants n=5 Participants	178 Participants n=7 Participants	370 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	17 Participants n=5 Participants	17 Participants n=7 Participants	34 Participants n=5 Participants
Race/Ethnicity, Customized Asian	36 Participants n=5 Participants	50 Participants n=7 Participants	86 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Other	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: At baseline and at week 16 or death before week 16

Population: Full Analysis Set: All participants that were randomized, regardless of whether treated or not.

Outcome measures

Outcome measures
Measure	Dapa 10mg n=253 Participants Dapagliflozin 10 mg, given once daily per oral use.	Placebo n=251 Participants Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at Week 16 (Higher Scores Represent Less HF Symptom Frequency and Burden)	5.21 Score on a scale Interval -3.13 to 12.5	1.04 Score on a scale Interval -5.73 to 15.1

PRIMARY outcome

Timeframe: At baseline and at week 16 or death before week 16

Population: Full Analysis Set: All participants that were randomized, regardless of whether treated or not, excluding participants with non-calculable baseline or week 16 KCCQ-PLS.

Change from baseline in KCCQ-PLS was defined as the endpoint value at week 16 minus the baseline value. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. KCCQ-PLS incorporates 6 physical limitation items into a single score. The score is transformed to a range of 0-100 (higher score reflects better health status). Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants who were alive at week 16 visit but without KCCQ-PLS values. All the data for the endpoint, except for death, collected during COVID-19, are set as missing and imputed same way as pre-COVID-19 missing data.

Outcome measures

Outcome measures
Measure	Dapa 10mg n=250 Participants Dapagliflozin 10 mg, given once daily per oral use.	Placebo n=250 Participants Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS) at Week 16 (Higher Scores Represent Less Physical Limitation Due to HF)	0.00 Score on a scale Interval -4.17 to 12.5	0.00 Score on a scale Interval -8.33 to 12.5

PRIMARY outcome

Timeframe: At baseline and at week 16 or death before week 16

Population: Full Analysis Set: All participants that were randomized, regardless of whether treated or not.

Change from baseline in 6-minute walk distance (6MWD) (exercise capacity) at week 16 was defined as the distance walked in 6 minutes at week 16 minus the baseline value. Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants who were alive at the visit at week 16 but did not have 6MWD values.

Outcome measures

Outcome measures
Measure	Dapa 10mg n=253 Participants Dapagliflozin 10 mg, given once daily per oral use.	Placebo n=251 Participants Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
Change From Baseline in 6-minute Walk Distance (6MWD) at Week 16 (Larger Distances Represent Better Functional Capacity)	9.0 meters Interval -15.0 to 37.0	8.5 meters Interval -14.5 to 35.5

SECONDARY outcome

Timeframe: At baseline and at end of study or death before week 16.

Population: Full Analysis Set: All participants that were randomized, regardless of whether treated or not, including participants from investigator sites having wearable activity monitor data collected.

Change from baseline at the end of the study in total time spent in light to vigorous physical activity (LVPA), as assessed using a wearable activity monitor, was defined as the total time \[per day\] spent in LVPA at the end of the study minus the baseline value. Baseline is the 7 day period starting on the day of enrolment and ending before randomization. End of study is defined as the period starting on the day of week 14 and prior to the week 16 visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive.

Outcome measures

Outcome measures
Measure	Dapa 10mg n=67 Participants Dapagliflozin 10 mg, given once daily per oral use.	Placebo n=71 Participants Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
Change From Baseline at the End of the Study in the Total Time Spent in Light to Vigorous Physical Activity, as Assessed Using a Wearable Activity Monitor (Accelerometer).	-0.06 hours/day Interval -0.63 to 0.44	-0.07 hours/day Interval -0.67 to 0.13

Adverse Events

Dapa 10 mg

Serious events: 26 serious events

Other events: 0 other events

Deaths: 3 deaths

Placebo

Serious events: 19 serious events

Other events: 0 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

Additional Information

Łyżwa, Dawid

Astrazeneca

Phone: +48 882 345 259

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Dapa 10 mg n=252 participants at risk Dapagliflozin 10 mg, given once daily per oral use.	Placebo n=249 participants at risk Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
Cardiac disorders Acute left ventricular failure	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Cardiac disorders Acute myocardial infarction	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.40% 1/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Cardiac disorders Atrial fibrillation	0.79% 2/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.40% 1/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Cardiac disorders Cardiac arrest	0.00% 0/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.40% 1/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Cardiac disorders Cardiac failure	0.79% 2/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	1.6% 4/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Cardiac disorders Cardiac failure acute	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.80% 2/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Cardiac disorders Cardiac failure congestive	0.79% 2/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Cardiac disorders Cardiopulmonary failure	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Cardiac disorders Conduction disorder	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Cardiac disorders Sinus node dysfunction	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Cardiac disorders Ventricular fibrillation	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Cardiac disorders Ventricular tachycardia	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Gastrointestinal disorders Hiatus hernia	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
General disorders Death	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Hepatobiliary disorders Cholelithiasis	0.00% 0/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.40% 1/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Infections and infestations Clostridial infection	0.00% 0/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.40% 1/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Infections and infestations Influenza	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Infections and infestations Pneumonia	0.79% 2/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	1.2% 3/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Infections and infestations Urinary tract infection	1.6% 4/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Fall	0.00% 0/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.40% 1/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Post procedural haematuria	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Skin laceration	0.79% 2/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Metabolism and nutrition disorders Decreased appetite	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Metabolism and nutrition disorders Metabolic acidosis	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Arthritis	0.00% 0/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.40% 1/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Nervous system disorders Cerebrovascular accident	0.00% 0/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.40% 1/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Nervous system disorders Ischaemic stroke	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Nervous system disorders Transient ischaemic attack	0.00% 0/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.40% 1/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Renal and urinary disorders Acute kidney injury	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.40% 1/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.80% 2/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.79% 2/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Skin ulcer	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Vascular disorders Aortic dissection	0.00% 0/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.40% 1/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.
Vascular disorders Haematoma	0.40% 1/252 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.	0.00% 0/249 • Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug, up to 119 days. For analysis of Adverse Events Safety analysis set is used. Safety analysis set: All randomized participants who received at least one dose of study drug.