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

Study Overview
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Brief Summary
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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)

Official Title
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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

Conditions
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Heart Failure With Preserved Ejection Fraction (HFpEF)

Intervention / Treatment
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* Drug: Dapagliflozin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 150 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | At baseline and at end of study or death before week 16. |