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

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ClinicalTrials.gov Identifier: NCT03877224
Recruitment Status : Completed
First Posted : March 15, 2019
Results First Posted : November 17, 2021
Last Update Posted : November 17, 2021
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Heart Failure With Preserved Ejection Fraction (HFpEF)
Interventions Drug: Dapagliflozin
Other: Placebo
Enrollment 504
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Dapa 10 mg Placebo
Hide 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
Reason Not Completed
Death             3             2
Withdrawal by Subject             1             6
Participant is alive, just unable to come for visits             1             0
Arm/Group Title Dapa 10 mg Placebo Total
Hide 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 Number of Baseline Participants 253 251 504
Hide Baseline Analysis Population Description
Full Analysis Set: All participants that were randomized, regardless of whether treated or not.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 253 participants 251 participants 504 participants
72.0  (9.1) 71.7  (9.7) 71.8  (9.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 253 participants 251 participants 504 participants
Female
91
  36.0%
93
  37.1%
184
  36.5%
Male
162
  64.0%
158
  62.9%
320
  63.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 253 participants 251 participants 504 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%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 253 participants 251 participants 504 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
   0.0%
1
   0.2%
Other
7
   2.8%
6
   2.4%
13
   2.6%
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
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)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All participants that were randomized, regardless of whether treated or not.
Arm/Group Title Dapa 10mg Placebo
Hide 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.
Overall Number of Participants Analyzed 253 251
Median (Inter-Quartile Range)
Unit of Measure: Score on a scale
5.21
(-3.13 to 12.50)
1.04
(-5.73 to 15.10)
Hide 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 [Not Specified]
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
Estimation Comments [Not Specified]
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)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 250 250
Median (Inter-Quartile Range)
Unit of Measure: Score on a scale
0.00
(-4.17 to 12.50)
0.00
(-8.33 to 12.50)
Hide 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 [Not Specified]
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
Estimation Comments [Not Specified]
3.Primary Outcome
Title Change From Baseline in 6-minute Walk Distance (6MWD) at Week 16 (Larger Distances Represent Better Functional Capacity)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set: All participants that were randomized, regardless of whether treated or not.
Arm/Group Title Dapa 10mg Placebo
Hide 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.
Overall Number of Participants Analyzed 253 251
Median (Inter-Quartile Range)
Unit of Measure: meters
9.0
(-15.0 to 37.0)
8.5
(-14.5 to 35.5)
Hide 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 [Not Specified]
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
Estimation Comments [Not Specified]
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).
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 67 71
Median (Inter-Quartile Range)
Unit of Measure: hours/day
-0.06
(-0.63 to 0.44)
-0.07
(-0.67 to 0.13)
Hide 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 [Not Specified]
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
Estimation Comments [Not Specified]
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
Hide 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 (%) Affected / at Risk (%)
Total   3/252 (1.19%)   2/249 (0.80%) 
Hide Serious Adverse Events
Dapa 10 mg Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   26/252 (10.32%)   19/249 (7.63%) 
Cardiac disorders     
Acute left ventricular failure  1  1/252 (0.40%)  0/249 (0.00%) 
Acute myocardial infarction  1  1/252 (0.40%)  1/249 (0.40%) 
Atrial fibrillation  1  2/252 (0.79%)  1/249 (0.40%) 
Cardiac arrest  1  0/252 (0.00%)  1/249 (0.40%) 
Cardiac failure  1  2/252 (0.79%)  4/249 (1.61%) 
Cardiac failure acute  1  1/252 (0.40%)  2/249 (0.80%) 
Cardiac failure congestive  1  2/252 (0.79%)  0/249 (0.00%) 
Cardiopulmonary failure  1  1/252 (0.40%)  0/249 (0.00%) 
Conduction disorder  1  1/252 (0.40%)  0/249 (0.00%) 
Sinus node dysfunction  1  1/252 (0.40%)  0/249 (0.00%) 
Ventricular fibrillation  1  1/252 (0.40%)  0/249 (0.00%) 
Ventricular tachycardia  1  1/252 (0.40%)  0/249 (0.00%) 
Gastrointestinal disorders     
Hiatus hernia  1  1/252 (0.40%)  0/249 (0.00%) 
General disorders     
Death  1  1/252 (0.40%)  0/249 (0.00%) 
Hepatobiliary disorders     
Cholelithiasis  1  0/252 (0.00%)  1/249 (0.40%) 
Infections and infestations     
Clostridial infection  1  0/252 (0.00%)  1/249 (0.40%) 
Influenza  1  1/252 (0.40%)  0/249 (0.00%) 
Pneumonia  1  2/252 (0.79%)  3/249 (1.20%) 
Urinary tract infection  1  4/252 (1.59%)  0/249 (0.00%) 
Injury, poisoning and procedural complications     
Fall  1  0/252 (0.00%)  1/249 (0.40%) 
Post procedural haematuria  1  1/252 (0.40%)  0/249 (0.00%) 
Skin laceration  1  2/252 (0.79%)  0/249 (0.00%) 
Metabolism and nutrition disorders     
Decreased appetite  1  1/252 (0.40%)  0/249 (0.00%) 
Metabolic acidosis  1  1/252 (0.40%)  0/249 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthritis  1  0/252 (0.00%)  1/249 (0.40%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Bladder cancer  1  1/252 (0.40%)  0/249 (0.00%) 
Nervous system disorders     
Cerebrovascular accident  1  0/252 (0.00%)  1/249 (0.40%) 
Ischaemic stroke  1  1/252 (0.40%)  0/249 (0.00%) 
Transient ischaemic attack  1  0/252 (0.00%)  1/249 (0.40%) 
Renal and urinary disorders     
Acute kidney injury  1  1/252 (0.40%)  1/249 (0.40%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  0/252 (0.00%)  2/249 (0.80%) 
Epistaxis  1  2/252 (0.79%)  0/249 (0.00%) 
Pulmonary embolism  1  1/252 (0.40%)  0/249 (0.00%) 
Skin and subcutaneous tissue disorders     
Skin ulcer  1  1/252 (0.40%)  0/249 (0.00%) 
Vascular disorders     
Aortic dissection  1  0/252 (0.00%)  1/249 (0.40%) 
Haematoma  1  1/252 (0.40%)  0/249 (0.00%) 
1
Term from vocabulary, MedDRA 23.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0.05%
Dapa 10 mg Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/252 (0.00%)   0/249 (0.00%) 
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.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Łyżwa, Dawid
Organization: Astrazeneca
Phone: +48 882 345 259
EMail: dawid.lyzwa@astrazeneca.com
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03877224    
Other Study ID Numbers: D169EC00001
2018-003441-42 ( EudraCT Number )
First Submitted: February 21, 2019
First Posted: March 15, 2019
Results First Submitted: July 6, 2021
Results First Posted: November 17, 2021
Last Update Posted: November 17, 2021