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

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

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)

Study Overview

• Status: Completed
• Conditions: Heart Failure With Preserved Ejection Fraction (HFpEF)
• Intervention / Treatment: Drug: Dapagliflozin; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 504
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1425AGC
    • Research Site
  • Ciudad Autonoma de Buenos Aire, Argentina, C1407GTN
    • Research Site
  • Ciudad Autonomade Buenos Aires, Argentina, 1426
    • Research Site
• Brazil
  • Blumenau, Brazil, 89020-430
    • Research Site
  • Brasillia, Brazil, 72145-450
    • Research Site
  • Porto Alegre, Brazil, 91350-200
    • Research Site
  • Sao Paulo, Brazil, 01141-020
    • Research Site
  • São Paulo, Brazil, 05403-000
    • Research Site
• Bulgaria
  • Plovdiv, Bulgaria, 4003
    • Research Site
  • Sofia, Bulgaria, 1000
    • Research Site
  • Sofia, Bulgaria, 1407
    • Research Site
  • Veliko Tarnovo, Bulgaria, 5000
    • Research Site
• Canada
  • Quebec, Canada, G1G 3Y8
    • Research Site
  • Quebec, Canada, G3K 2P8
    • Research Site
  • Quebec, Canada, G2J 0C4
    • Research Site
  • Alberta
    • Edmonton, Alberta, Canada, T5A 4L8
      • Research Site
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1G 1A7
      • Research Site
  • Newfoundland and Labrador
    • Mount Pearl, Newfoundland and Labrador, Canada, A1N 1W7
      • Research Site
    • St. John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Research Site
  • Ontario
    • Ajax, Ontario, Canada, L1Z 0B1
      • Research Site
    • Guelph, Ontario, Canada, N1H 1B1
      • Research Site
    • North York, Ontario, Canada, M3M 3E5
      • Research Site
    • Scarborough, Ontario, Canada, M1E 5E9
      • Research Site
    • Scarborough, Ontario, Canada, M1P 2T7
      • Research Site
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Research Site
    • Gatineau, Quebec, Canada, J8Y 6S8
      • Research Site
    • Longueuil, Quebec, Canada, J4M 2X1
      • Research Site
    • Montreal, Quebec, Canada, H2X 0A9
      • Research Site
    • Montreal, Quebec, Canada, H3G 1A4
      • Research Site
    • St-Georges, Quebec, Canada, G5Y 4T8
      • Research Site
• Denmark
  • Esbjerg, Denmark, 6700
    • Research Site
  • Hellerup, Denmark, 2900
    • Research Site
  • Hjørring, Denmark, 9800
    • Research Site
  • Hvidovre, Denmark, 2650
    • Research Site
  • København, Denmark, 2300
    • Research Site
  • Næstved, Denmark, 4700
    • Research Site
  • Odense C, Denmark, 5000
    • Research Site
  • Randers, Denmark, 8930
    • Research Site
  • Svendborg, Denmark, DK-5700
    • Research Site
  • Århus N, Denmark, 8200
    • Research Site
• Italy
  • Bergamo, Italy, 24127
    • Research Site
  • Milano, Italy, 20162
    • Research Site
  • Napoli, Italy, 80131
    • Research Site
  • Palermo, Italy, 90127
    • Research Site
  • Roma, Italy, 00189
    • Research Site
  • San Giovanni Rotondo, Italy, 71013
    • Research Site
• Japan
  • Akashi-shi, Japan, 674-0063
    • Research Site
  • Daito-shi, Japan, 574-0074
    • Research Site
  • Kasugai-shi, Japan, 487-0016
    • Research Site
  • Matsubara-shi, Japan, 580-0032
    • Research Site
  • Naha, Japan, 902-8511
    • Research Site
  • Omihachiman-shi, Japan, 523-0082
    • Research Site
  • Osaka-shi, Japan, 530-0001
    • Research Site
  • Shunan-shi, Japan, 745-0822
    • Research Site
  • Takarazuka-shi, Japan, 665-0873
    • Research Site
  • Toshima-ku, Japan, 171-0014
    • Research Site
• Korea, Republic of
  • Gangwon-do, Korea, Republic of, 26426
    • Research Site
  • Gwangju, Korea, Republic of, 61469
    • Research Site
  • Seongnam-si, Korea, Republic of, 463-707
    • Research Site
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Research Site
• Slovakia
  • Brezno, Slovakia, 97742
    • Research Site
  • Lucenec, Slovakia, 984 01
    • Research Site
  • Martin, Slovakia, 036 01
    • Research Site
  • Presov, Slovakia, 080 01
    • Research Site
  • Ruzomberok, Slovakia, 034 26
    • Research Site
• South Africa
  • Cape Town, South Africa, 7500
    • Research Site
  • Diepkloof, Soweto, South Africa, 2013
    • Research Site
  • Pinelands, South Africa, 7405
    • Research Site
• Sweden
  • Borås, Sweden, 506 30
    • Research Site
  • Göteborg, Sweden, 413 45
    • Research Site
  • Lund, Sweden, 222 21
    • Research Site
  • Ostersund, Sweden, 831 83
    • Research Site
  • Stockholm, Sweden, 118 83
    • Research Site
  • Stockholm, Sweden, 114 46
    • Research Site
  • Umeå, Sweden, 90737
    • Research Site
• United States
  • Alabama
    • Alexander City, Alabama, United States, 35010
      • Research Site
    • Fort Payne, Alabama, United States, 35967
      • Research Site
  • California
    • Beverly Hills, California, United States, 90211
      • Research Site
    • Torrance, California, United States, 90502
      • Research Site
  • Florida
    • Jacksonville, Florida, United States, 32209
      • Research Site
    • Miami, Florida, United States, 33173
      • Research Site
    • Miami, Florida, United States, 33133
      • Research Site
  • Georgia
    • Tucker, Georgia, United States, 30084
      • Research Site
  • Illinois
    • Arlington Heights, Illinois, United States, 60005
      • Research Site
    • Hazel Crest, Illinois, United States, 60429
      • Research Site
  • Indiana
    • Munster, Indiana, United States, 46321
      • Research Site
  • Kentucky
    • Louisville, Kentucky, United States, 40205
      • Research Site
  • Louisiana
    • Bossier City, Louisiana, United States, 71111
      • Research Site
  • Maryland
    • Annapolis, Maryland, United States, 21401
      • Research Site
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Research Site
    • Ridgewood, New Jersey, United States, 07450
      • Research Site
  • New York
    • Rosedale, New York, United States, 11422
      • Research Site
  • North Carolina
    • Burlington, North Carolina, United States, 27215
      • Research Site
    • Winston-Salem, North Carolina, United States, 27157
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Research Site
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Research Site
    • Doylestown, Pennsylvania, United States, 18901
      • Research Site
    • Pittsburgh, Pennsylvania, United States, 15212
      • Research Site
  • Texas
    • Spring, Texas, United States, 77380
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98101
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 36 years to 146 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• Clinical Study Protocol
• Statistical Analysis Plan
• CSR synopsis

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2019
• Primary Completion (Actual): July 9, 2020
• Study Completion (Actual): July 9, 2020

Study Registration Dates

• First Submitted: February 21, 2019
• First Submitted That Met QC Criteria: March 14, 2019
• First Posted (Actual): March 15, 2019

Study Record Updates

• Last Update Posted (Actual): November 17, 2021
• Last Update Submitted That Met QC Criteria: November 15, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: D169EC00001; 2018-003441-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No