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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03877224
• Collaborator: (none)
• Enrollment: 504
• Locations: 101
• Arms: 2
• Actual Duration (Months): 15.2
• Patients Per Site: 5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

International, Multicentre, Parallel-group, Randomised, Double-blind, Placebo-controlled, Phase III Study Evaluating the effect of Dapagliflozin on Exercise Capacity in Heart Failure Patients with Preserved Ejection Fraction (HFpEF)

Condition or Disease	Intervention/Treatment	Phase
Heart Failure With Preserved Ejection Fraction (HFpEF)	Drug: Dapagliflozin; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 504 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: International, Multicentre, Parallel-group, Randomised, Double-blind, Placebo-controlled, Phase III Study Evaluating the Effect of Dapagliflozin on Exercise Capacity in Heart Failure Patients With Preserved Ejection Fraction
• Actual Study Start Date: Apr 4, 2019
• Actual Primary Completion Date: Jul 9, 2020
• Actual Study Completion Date: Jul 9, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dapagliflozin Green, diamond shaped, film coated tablets 10 mg administered orally, once daily	Drug: Dapagliflozin; Tablets administered orally once daily. Treatment start within 24h after randomisation for 16 weeks.
Placebo Comparator: Placebo Green, diamond shaped, film coated tablets placebo administered orally, once daily	Other: Placebo; Tablets administered orally once daily. Treatment start within 24h after randomisation for 16 weeks.

Outcome Measures

Primary Outcome Measures

1. 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) [At baseline and at week 16 or death before week 16]

   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.

2. 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) [At baseline and at week 16 or death before week 16]

   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.

3. Change From Baseline in 6-minute Walk Distance (6MWD) at Week 16 (Larger Distances Represent Better Functional Capacity) [At baseline and at week 16 or death before week 16]

   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.

Secondary Outcome Measures

1. 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). [At baseline and at end of study or death before week 16.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 150 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Provision of signed informed consent prior to any study specific procedures

• Male or female, aged ≥40 years

• Established documented diagnosis of symptomatic HFpEF (NYHA functional class II-IV), which has been present for at least 8 weeks

• LVEF>40% and evidence of structural heart disease

• Elevated NT-proBNP levels

• Patients should receive background standard of care as described below: All patients will be treated according to locally recognised guidelines on standard of care treatment for patients with HFpEF. Therapy should have been individually optimised and stable for ≥4 weeks (this does not apply to diuretics) and include (unless contraindicated or not tolerated) treatment of co morbidities (including high blood pressure, ischaemic heart disease, atrial fibrillation/flutter).

• 6MWD≥100 metres and ≤425 metres at enrolment and randomization

Exclusion Criteria:

• Presence of any condition that precludes exercise testing

• Participation in a structured exercise training programme in the 1 month prior to screening or planned to start during the trial

• Receiving therapy with an SGLT2 inhibitor within 4 weeks prior to enrolment or previous intolerance of an SGLT2 inhibitor

• Type 1 diabetes mellitus

• eGFR <25 mL/min/1.73 m2 (CKD-EPI formula) at enrolment, unstable or rapidly progressing renal disease at time of randomisation

• Systolic BP <95 mmHg on 2 consecutive measurements

• Systolic BP ≥160 mmHg if not on treatment with ≥3 blood pressure lowering medications or ≥180 mmHg irrespective of treatments, on 2 consecutive measurements

• Current acute decompensated HF or hospitalisation due to decompensated HF <4 weeks prior to enrolment

• MI, unstable angina, coronary revascularization ablation of atrial fibrillation/flutter, valve repair/replacement, implantation of a cardiac resynchronization therapy device within 12 weeks prior to enrolment or planned to undergo any of these operations after randomization.

• Stroke or transient ischemic attack within 12 weeks prior to enrolment.

• Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary disease including COPD.

• Previous cardiac transplantation or implantation of a ventricular assistance device or similar device, or implantation expected after randomization

• HF due to infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, cardiac tamponade, known genetic hypertrophic cardiomyopathy or obstructive hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia, or uncorrected primary valvular disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Alexander City	Alabama	United States	35010
2	Research Site	Fort Payne	Alabama	United States	35967
3	Research Site	Beverly Hills	California	United States	90211
4	Research Site	Torrance	California	United States	90502
5	Research Site	Jacksonville	Florida	United States	32209
6	Research Site	Miami	Florida	United States	33133
7	Research Site	Miami	Florida	United States	33173
8	Research Site	Tucker	Georgia	United States	30084
9	Research Site	Arlington Heights	Illinois	United States	60005
10	Research Site	Hazel Crest	Illinois	United States	60429
11	Research Site	Munster	Indiana	United States	46321
12	Research Site	Louisville	Kentucky	United States	40205
13	Research Site	Bossier City	Louisiana	United States	71111
14	Research Site	Annapolis	Maryland	United States	21401
15	Research Site	New Brunswick	New Jersey	United States	08901
16	Research Site	Ridgewood	New Jersey	United States	07450
17	Research Site	Rosedale	New York	United States	11422
18	Research Site	Burlington	North Carolina	United States	27215
19	Research Site	Winston-Salem	North Carolina	United States	27157
20	Research Site	Cincinnati	Ohio	United States	45267
21	Research Site	Abington	Pennsylvania	United States	19001
22	Research Site	Doylestown	Pennsylvania	United States	18901
23	Research Site	Pittsburgh	Pennsylvania	United States	15212
24	Research Site	Spring	Texas	United States	77380
25	Research Site	Seattle	Washington	United States	98101
26	Research Site	Caba		Argentina	C1425AGC
27	Research Site	Ciudad Autonoma de Buenos Aire		Argentina	C1407GTN
28	Research Site	Ciudad Autonomade Buenos Aires		Argentina	1426
29	Research Site	Blumenau		Brazil	89020-430
30	Research Site	Brasillia		Brazil	72145-450
31	Research Site	Porto Alegre		Brazil	91350-200
32	Research Site	Sao Paulo		Brazil	01141-020
33	Research Site	São Paulo		Brazil	05403-000
34	Research Site	Plovdiv		Bulgaria	4003
35	Research Site	Sofia		Bulgaria	1000
36	Research Site	Sofia		Bulgaria	1407
37	Research Site	Veliko Tarnovo		Bulgaria	5000
38	Research Site	Edmonton	Alberta	Canada	T5A 4L8
39	Research Site	Moncton	New Brunswick	Canada	E1G 1A7
40	Research Site	Mount Pearl	Newfoundland and Labrador	Canada	A1N 1W7
41	Research Site	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
42	Research Site	Ajax	Ontario	Canada	L1Z 0B1
43	Research Site	Guelph	Ontario	Canada	N1H 1B1
44	Research Site	North York	Ontario	Canada	M3M 3E5
45	Research Site	Scarborough	Ontario	Canada	M1E 5E9
46	Research Site	Scarborough	Ontario	Canada	M1P 2T7
47	Research Site	Chicoutimi	Quebec	Canada	G7H 7K9
48	Research Site	Gatineau	Quebec	Canada	J8Y 6S8
49	Research Site	Longueuil	Quebec	Canada	J4M 2X1
50	Research Site	Montreal	Quebec	Canada	H2X 0A9
51	Research Site	Montreal	Quebec	Canada	H3G 1A4
52	Research Site	St-Georges	Quebec	Canada	G5Y 4T8
53	Research Site	Quebec		Canada	G1G 3Y8
54	Research Site	Quebec		Canada	G2J 0C4
55	Research Site	Quebec		Canada	G3K 2P8
56	Research Site	Esbjerg		Denmark	6700
57	Research Site	Hellerup		Denmark	2900
58	Research Site	Hjørring		Denmark	9800
59	Research Site	Hvidovre		Denmark	2650
60	Research Site	København		Denmark	2300
61	Research Site	Næstved		Denmark	4700
62	Research Site	Odense C		Denmark	5000
63	Research Site	Randers		Denmark	8930
64	Research Site	Svendborg		Denmark	DK-5700
65	Research Site	Århus N		Denmark	8200
66	Research Site	Bergamo		Italy	24127
67	Research Site	Milano		Italy	20162
68	Research Site	Napoli		Italy	80131
69	Research Site	Palermo		Italy	90127
70	Research Site	Roma		Italy	00189
71	Research Site	San Giovanni Rotondo		Italy	71013
72	Research Site	Akashi-shi		Japan	674-0063
73	Research Site	Daito-shi		Japan	574-0074
74	Research Site	Kasugai-shi		Japan	487-0016
75	Research Site	Matsubara-shi		Japan	580-0032
76	Research Site	Naha		Japan	902-8511
77	Research Site	Omihachiman-shi		Japan	523-0082
78	Research Site	Osaka-shi		Japan	530-0001
79	Research Site	Shunan-shi		Japan	745-0822
80	Research Site	Takarazuka-shi		Japan	665-0873
81	Research Site	Toshima-ku		Japan	171-0014
82	Research Site	Gangwon-do		Korea, Republic of	26426
83	Research Site	Gwangju		Korea, Republic of	61469
84	Research Site	Seongnam-si		Korea, Republic of	463-707
85	Research Site	Seoul		Korea, Republic of	03080
86	Research Site	Seoul		Korea, Republic of	03722
87	Research Site	Brezno		Slovakia	97742
88	Research Site	Lucenec		Slovakia	984 01
89	Research Site	Martin		Slovakia	036 01
90	Research Site	Presov		Slovakia	080 01
91	Research Site	Ruzomberok		Slovakia	034 26
92	Research Site	Cape Town		South Africa	7500
93	Research Site	Diepkloof, Soweto		South Africa	2013
94	Research Site	Pinelands		South Africa	7405
95	Research Site	Borås		Sweden	506 30
96	Research Site	Göteborg		Sweden	413 45
97	Research Site	Lund		Sweden	222 21
98	Research Site	Ostersund		Sweden	831 83
99	Research Site	Stockholm		Sweden	114 46
100	Research Site	Stockholm		Sweden	118 83
101	Research Site	Umeå		Sweden	90737

Sponsors and Collaborators

• AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Mar 4, 2020
• Statistical Analysis Plan - Sep 21, 2020

More Information

Additional Information:

• Clinical Study Protocol
• Statistical Analysis Plan
• CSR synopsis

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03877224
• Other Study ID Numbers: D169EC00001; 2018-003441-42
• First Posted: Mar 15, 2019
• Last Update Posted: Nov 17, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Heart Failure; Dapagliflozin

Study Results

Participant Flow

Arm/Group Title	Dapa 10 mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg, given once daily per oral use.	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
Period Title: Overall Study
STARTED	253	251
Treated	252	249
COMPLETED	248	243
NOT COMPLETED	5	8

Baseline Characteristics

Arm/Group Title	Dapa 10 mg	Placebo	Total
Arm/Group Description	Dapagliflozin 10 mg, given once daily per oral use.	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.	Total of all reporting groups
Overall Participants	253	251	504
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	72.0 (9.1)	71.7 (9.7)	71.8 (9.4)
Sex: Female, Male (Count of Participants)
Female	91 36%	93 37.1%	184 36.5%
Male	162 64%	158 62.9%	320 63.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	28 11.1%	31 12.4%	59 11.7%
Not Hispanic or Latino	225 88.9%	220 87.6%	445 88.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	192 75.9%	178 70.9%	370 73.4%
Black or African American	17 6.7%	17 6.8%	34 6.7%
Asian	36 14.2%	50 19.9%	86 17.1%
Native Hawaiian or other Pacific Islander	1 0.4%	0 0%	1 0.2%
Other	7 2.8%	6 2.4%	13 2.6%
American Indian or Alaska Native	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	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)
Description	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.
Time Frame	At baseline and at week 16 or death before week 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Dapa 10mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg, given once daily per oral use.	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
Measure Participants	253	251
Median (Inter-Quartile Range) [Score on a scale]	5.21	1.04

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapa 10mg, Placebo
	Comments	For the primary efficacy endpoint KCCQ-TSS, the following hypothesis was tested using the significance level 0.04990 • H0: m(r(A)) = m(r(C)) versus • H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in the primary efficacy endpoint, KCCQ-TSS, from baseline to week 16, among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.07905
	Comments	To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate.
	Method	Rank ANCOVA
	Comments	The model includes rank-based baseline, weeks impacted by COVID-19 and treatment group as covariates and is stratified by T2DM status at randomization
Method of Estimation	Estimation Parameter	Hodges-Lehmann median diff. vs placebo
	Estimated Value	3.16
	Confidence Interval	(2-Sided) 95%; 0.36 to 6.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	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)
Description	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.
Time Frame	At baseline and at week 16 or death before week 16

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Dapa 10mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg, given once daily per oral use.	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
Measure Participants	250	250
Median (Inter-Quartile Range) [Score on a scale]	0.00	0.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapa 10mg, Placebo
	Comments	For the primary efficacy endpoint KCCQ-PLS, the following hypothesis was tested at significant level of 0.00005 • H0: m(r(A)) = m(r(C)) versus • H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in the primary efficacy endpoint, KCCQ-PLS, from baseline to week 16, among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.23215
	Comments	To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate.
	Method	Rank ANCOVA
	Comments	The model includes rank-based baseline, weeks impacted by COVID-19 and treatment group as covariates and is stratified by T2DM status at randomization
Method of Estimation	Estimation Parameter	Hodges-Lehmann median diff. vs placebo
	Estimated Value	3.12
	Confidence Interval	(2-Sided) 95%; -0.09 to 5.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change From Baseline in 6-minute Walk Distance (6MWD) at Week 16 (Larger Distances Represent Better Functional Capacity)
Description	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.
Time Frame	At baseline and at week 16 or death before week 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Dapa 10mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg, given once daily per oral use.	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
Measure Participants	253	251
Median (Inter-Quartile Range) [meters]	9.0	8.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapa 10mg, Placebo
	Comments	For the primary efficacy endpoint 6MWD, the following hypothesis was tested using the significance level 0.00005: H0: m(r(A)) = m(r(C)) versus H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in the primary efficacy endpoint, 6MWD, from baseline to week 16, among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.66801
	Comments	To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate.
	Method	Rank ANCOVA
	Comments	The model includes rank-based baseline, treatment group as covariates and is stratified by T2DM status at randomization
Method of Estimation	Estimation Parameter	Hodges-Lehmann median diff. vs placebo
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; -5.9 to 9.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	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).
Description	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.
Time Frame	At baseline and at end of study or death before week 16.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Dapa 10mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg, given once daily per oral use.	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
Measure Participants	67	71
Median (Inter-Quartile Range) [hours/day]	-0.06	-0.07

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapa 10mg, Placebo
	Comments	For the secondary efficacy endpoint, total time spent in LVPA, the testing hypothesis is • H0: m(r(A)) = m(r(C)) versus • H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in secondary efficacy endpoint, total time spent in LVPA, from baseline to End of study among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.
	Type of Statistical Test	Superiority
	Comments	Total time spent in LVPA was not tested for statistical significance and the p-value is considered nominal because the test for 6MWD was not statistically significant.
Statistical Test of Hypothesis	p-Value	0.12523
	Comments
	Method	Rank ANCOVA
	Comments	Model includes baseline rank of outcome variable as a covariate, treatment group as a factor, and is stratified by T2DM status at randomization.
Method of Estimation	Estimation Parameter	Hodges-Lehmann median diff. vs placebo
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	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.
Arm/Group Title	Dapa 10 mg		Placebo
Arm/Group Description	Dapagliflozin 10 mg, given once daily per oral use.		Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
All Cause Mortality
	Dapa 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/252 (1.2%)		2/249 (0.8%)
Serious Adverse Events
	Dapa 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/252 (10.3%)		19/249 (7.6%)
Cardiac disorders
Acute left ventricular failure	1/252 (0.4%)		0/249 (0%)
Acute myocardial infarction	1/252 (0.4%)		1/249 (0.4%)
Atrial fibrillation	2/252 (0.8%)		1/249 (0.4%)
Cardiac arrest	0/252 (0%)		1/249 (0.4%)
Cardiac failure	2/252 (0.8%)		4/249 (1.6%)
Cardiac failure acute	1/252 (0.4%)		2/249 (0.8%)
Cardiac failure congestive	2/252 (0.8%)		0/249 (0%)
Cardiopulmonary failure	1/252 (0.4%)		0/249 (0%)
Conduction disorder	1/252 (0.4%)		0/249 (0%)
Sinus node dysfunction	1/252 (0.4%)		0/249 (0%)
Ventricular fibrillation	1/252 (0.4%)		0/249 (0%)
Ventricular tachycardia	1/252 (0.4%)		0/249 (0%)
Gastrointestinal disorders
Hiatus hernia	1/252 (0.4%)		0/249 (0%)
General disorders
Death	1/252 (0.4%)		0/249 (0%)
Hepatobiliary disorders
Cholelithiasis	0/252 (0%)		1/249 (0.4%)
Infections and infestations
Clostridial infection	0/252 (0%)		1/249 (0.4%)
Influenza	1/252 (0.4%)		0/249 (0%)
Pneumonia	2/252 (0.8%)		3/249 (1.2%)
Urinary tract infection	4/252 (1.6%)		0/249 (0%)
Injury, poisoning and procedural complications
Fall	0/252 (0%)		1/249 (0.4%)
Post procedural haematuria	1/252 (0.4%)		0/249 (0%)
Skin laceration	2/252 (0.8%)		0/249 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/252 (0.4%)		0/249 (0%)
Metabolic acidosis	1/252 (0.4%)		0/249 (0%)
Musculoskeletal and connective tissue disorders
Arthritis	0/252 (0%)		1/249 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	1/252 (0.4%)		0/249 (0%)
Nervous system disorders
Cerebrovascular accident	0/252 (0%)		1/249 (0.4%)
Ischaemic stroke	1/252 (0.4%)		0/249 (0%)
Transient ischaemic attack	0/252 (0%)		1/249 (0.4%)
Renal and urinary disorders
Acute kidney injury	1/252 (0.4%)		1/249 (0.4%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/252 (0%)		2/249 (0.8%)
Epistaxis	2/252 (0.8%)		0/249 (0%)
Pulmonary embolism	1/252 (0.4%)		0/249 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	1/252 (0.4%)		0/249 (0%)
Vascular disorders
Aortic dissection	0/252 (0%)		1/249 (0.4%)
Haematoma	1/252 (0.4%)		0/249 (0%)
Other (Not Including Serious) Adverse Events
	Dapa 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/252 (0%)		0/249 (0%)

Limitations/Caveats

In this study, a subset of participants received wearable activity monitors to wear at home for 3 periods of 7 days. Data collection from the wearable device was challenging and a substantial amount of data was missing. This limits the use of the data based on the wearable activity monitors to investigate the potential impact of study drug on the amount, duration, and intensity of physical activity.

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.