DETERMINE-preserved – Dapagliflozin effect on exercise capacity using a 6-minute walk test in patients with heart failure with preserved ejection fraction

Study identifier:D169EC00001

ClinicalTrials.gov identifier:NCT03877224

EudraCT identifier:2018-003441-42

CTIS identifier:N/A

Study Complete

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

Medical condition

Heart Failure with Preserved Ejection Fraction (HFpEF)

Phase

Phase 3

Healthy volunteers

Study drug

Dapagliflozin

Sex

All

Actual Enrollment

504

Study type

Interventional

Age

40 Years - 150 Years

Date

Study Start Date: 04 Apr 2019

Primary Completion Date: 09 Jul 2020

Study Completion Date: 09 Jul 2020

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Nov 2021 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

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

Location

Research Site

Cape Town, South Africa, 7500

Location

Research Site

Diepkloof, Soweto, South Africa, 2013

Location

Research Site

Sofia, Bulgaria, 1407

Location

Research Site

Veliko Tarnovo, Bulgaria, 5000

Location

Research Site

Plovdiv, Bulgaria, 4003

Location

Research Site

Sofia, Bulgaria, 1000

Location

Research Site

Seoul, Republic of Korea, 03080

Location

Research Site

Gangwon-do, Republic of Korea, 26426

Arms	Assigned Interventions
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.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
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.

Participant Flow: Overall Study

	Dapa 10 mg	Placebo
STARTED	253	251
Treated	252	249
COMPLETED	248	243
NOT COMPLETED	5	8
Death	3	2
Withdrawal by Subject	1	6
Participant is alive, just unable to come for visits	1	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

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

Reporting Groups

	Description
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.

Baseline Measures

	Dapa 10 mg	Placebo	Total
Number of Participants [units: Participants]	253	251	504
Age Continuous [units: Years] Mean ± Standard Deviation	72.0 ± 9.1	71.7 ± 9.7	71.8 ± 9.4
Race/Ethnicity, Customized [units: Participants]
White	192	178	370
Black or African American	17	17	34
Asian	36	50	86
Native Hawaiian or other Pacific Islander	1	0	1
Other	7	6	13
American Indian or Alaska Native	0	0	0
Sex: Female, Male [units: Participants]
Female	91	93	184
Male	162	158	320
Ethnicity (NIH/OMB) [units: Participants]
Hispanic or Latino	28	31	59
Not Hispanic or Latino	225	220	445
Unknown or Not Reported	0	0	0

Outcome Measures

1. Primary Outcome Measure: 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) [ Time Frame: At baseline and at week 16 or death before week 16 ]

Measure Type	Primary
Measure Name	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)
Measure 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
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set: All participants that were randomized, regardless of whether treated or not.

Reporting Groups

	Description
Dapa 10mg	Dapagliflozin 10 mg, given once daily per oral use.
Placebo	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.

Measured Values

	Dapa 10mg	Placebo
Number of Participants Analyzed [units:participants]	253	251
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) [units: Score on a scale] Median (Inter-Quartile Range)	5.21 (-3.13 to 12.50)	1.04 (-5.73 to 15.10)

Statistical Analysis 1 for 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)

Groups^[1]	All groups
Method^[3]	Other [Rank ANCOVA]
P-Value^[4]	0.07905
Other^[5]	3.16
95% Confidence Interval	( 0.36 to 6.01 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model includes rank-based baseline, weeks impacted by COVID-19 and treatment group as covariates and is stratified by T2DM status at randomization
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate.
[5]	Other relevant estimation information:
	No text entered.

2. Primary Outcome Measure: 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) [ Time Frame: At baseline and at week 16 or death before week 16 ]

Measure Type	Primary
Measure Name	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)
Measure 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
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Dapa 10mg	Dapagliflozin 10 mg, given once daily per oral use.
Placebo	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.

Measured Values

	Dapa 10mg	Placebo
Number of Participants Analyzed [units:participants]	250	250
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) [units: Score on a scale] Median (Inter-Quartile Range)	0.00 (-4.17 to 12.50)	0.00 (-8.33 to 12.50)

Statistical Analysis 1 for 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)

Groups^[1]	All groups
Method^[3]	Other [Rank ANCOVA]
P-Value^[4]	0.23215
Other^[5]	3.12
95% Confidence Interval	( -0.09 to 5.37 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model includes rank-based baseline, weeks impacted by COVID-19 and treatment group as covariates and is stratified by T2DM status at randomization
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate.
[5]	Other relevant estimation information:
	No text entered.

3. Primary Outcome Measure: Change from baseline in 6-minute walk distance (6MWD) at week 16 (larger distances represent better functional capacity) [ Time Frame: At baseline and at week 16 or death before week 16 ]

Measure Type	Primary
Measure Name	Change from baseline in 6-minute walk distance (6MWD) at week 16 (larger distances represent better functional capacity)
Measure 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
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set: All participants that were randomized, regardless of whether treated or not.

Reporting Groups

	Description
Dapa 10mg	Dapagliflozin 10 mg, given once daily per oral use.
Placebo	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.

Measured Values

	Dapa 10mg	Placebo
Number of Participants Analyzed [units:participants]	253	251
Change from baseline in 6-minute walk distance (6MWD) at week 16 (larger distances represent better functional capacity) [units: meters] Median (Inter-Quartile Range)	9.0 (-15.0 to 37.0)	8.5 (-14.5 to 35.5)

Statistical Analysis 1 for Change from baseline in 6-minute walk distance (6MWD) at week 16 (larger distances represent better functional capacity)

Groups^[1]	All groups
Method^[3]	Other [Rank ANCOVA]
P-Value^[4]	0.66801
Other^[5]	1.6
95% Confidence Interval	( -5.9 to 9.0 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	The model includes rank-based baseline, treatment group as covariates and is stratified by T2DM status at randomization
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate.
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: 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). [ Time Frame: At baseline and at end of study or death before week 16. ]

Measure Type	Secondary
Measure Name	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).
Measure 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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Dapa 10mg	Dapagliflozin 10 mg, given once daily per oral use.
Placebo	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.

Measured Values

	Dapa 10mg	Placebo
Number of Participants Analyzed [units:participants]	67	71
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). [units: hours/day] Median (Inter-Quartile Range)	-0.06 (-0.63 to 0.44)	-0.07 (-0.67 to 0.13)

Statistical Analysis 1 for 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).

Groups^[1]	All groups
Method^[3]	Other [Rank ANCOVA]
P-Value^[4]	0.12523
Other^[5]	0.19
95% Confidence Interval	( -0.06 to 0.48 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes baseline rank of outcome variable as a covariate, treatment group as a factor, and is stratified by T2DM status at randomization.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Serious 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.
Additional 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.

Reporting Groups

	Description
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.