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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

Tracking Information
First Submitted Date  ICMJE February 21, 2019
First Posted Date  ICMJE March 15, 2019
Results First Submitted Date  ICMJE July 6, 2021
Results First Posted Date  ICMJE November 17, 2021
Last Update Posted Date November 17, 2021
Actual Study Start Date  ICMJE April 4, 2019
Actual Primary Completion Date July 9, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 6, 2021)
  • 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 ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 14, 2019)
Change from baseline in 6-minute walking distance (6MWD) at Week16 [ Time Frame: From baseline to Week16 ]
To determine whether dapagliflozin is superior to placebo in increasing exercise capacity in patients with chronic heart failure New York Heart Association (NYHA) Functional Class II-IV and preserved ejection fraction (LVEF>40%)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 6, 2021)
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. ]
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 14, 2019)
Change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Total symptom score (TSS) at Week16 [ Time Frame: From baseline to Week16 ]
To determine whether dapagliflozin is superior to placebo in improving patient-reported HF symptoms. The KCCQ is a self administered 23 item instrument, measuring: physical functioning, symptoms, social functioning, self-efficacy and knowledge and quality of life. Scores are transformed to a range from 0-100 in which higher score reflects better outcome
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: March 14, 2019)
  • Change from baseline at end of study (ie, the week starting at week 14) in mean movement intensity as assessed using a wearable activity monitor (accelerometer). [ Time Frame: From baseline until the week starting at Week14 ]
    To determine whether dapagliflozin is superior to placebo in increasing movement intensity during walking.
  • Change from baseline at end of study (ie, the week starting at week 14) in vector magnitude as assessed using a wearable activity monitor (accelerometer). [ Time Frame: From baseline until the week starting at Week14 ]
    To determine whether dapagliflozin is superior to placebo in increasing vector magnitude units per minute.
  • Change from baseline in serum NT-proBNP at Week16 [ Time Frame: From baseline to Week16 ]
    To determine whether dapagliflozin is superior to placebo in reducing serum N-terminal pro b-type natriuretic peptide (NT-proBNP)
  • Change from baseline at end of study (ie, the week starting at week 14) in time spent in light to vigorous physical activity as assessed using a wearable activity monitor (accelerometer). [ Time Frame: From baseline until the week starting at Week14 ]
    To determine whether dapagliflozin is superior to placebo in increasing time spent in light to vigorous physical activity.
  • Change from baseline in proportion of patients with worsened NYHA Functional Classification at Week16. [ Time Frame: From baseline to Week16 ]
    To determine whether dapagliflozin is superior to placebo in reducing the proportion of patients with worsened NYHA Functional Classification
 
Descriptive Information
Brief Title  ICMJE DETERMINE-preserved - Dapagliflozin Effect on Exercise Capacity Using a 6-minute Walk Test in Patients With Heart Failure With Preserved Ejection Fraction
Official Title  ICMJE 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
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)
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Heart Failure With Preserved Ejection Fraction (HFpEF)
Intervention  ICMJE
  • Drug: Dapagliflozin
    Tablets administered orally once daily. Treatment start within 24h after randomisation for 16 weeks.
  • Other: Placebo
    Tablets administered orally once daily. Treatment start within 24h after randomisation for 16 weeks.
Study Arms  ICMJE
  • Experimental: Dapagliflozin
    Green, diamond shaped, film coated tablets 10 mg administered orally, once daily
    Intervention: Drug: Dapagliflozin
  • Placebo Comparator: Placebo
    Green, diamond shaped, film coated tablets placebo administered orally, once daily
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 2, 2020)
504
Original Estimated Enrollment  ICMJE
 (submitted: March 14, 2019)
400
Actual Study Completion Date  ICMJE July 9, 2020
Actual Primary Completion Date July 9, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 150 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Brazil,   Bulgaria,   Canada,   Denmark,   Italy,   Japan,   Korea, Republic of,   Slovakia,   South Africa,   Sweden,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03877224
Other Study ID Numbers  ICMJE D169EC00001
2018-003441-42 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.

Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
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.
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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date November 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP