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

• ClinicalTrials.gov Identifier: NCT03877237
• Recruitment Status: Active, not recruiting
• First Posted: March 15, 2019
• Last Update Posted: November 13, 2019
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

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 Reduced Ejection Fraction (HFrEF)

Condition or disease	Intervention/treatment	Phase
Heart Failure With Reduced Ejection Fraction (HFrEF)	Drug: Dapagliflozin; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 312 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• 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 Reduced Ejection Fraction
• Actual Study Start Date: April 9, 2019
• Estimated Primary Completion Date: February 26, 2020
• Estimated Study Completion Date: February 26, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. 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%)

Secondary Outcome Measures :

1. 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
2. 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.
3. 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.
4. 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)
5. 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.
6. 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 150 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Provision of signed informed consent prior to any study specific procedures
• Male or female, aged ≥18 years
• Documented diagnosis of symptomatic HFrEF (NYHA functional class II-IV), which has been present for at least 8 weeks
• LVEF≤40%
• Elevated NT-proBNP levels

• Patients should receive background standard of care as described below: All HFrEF patients should be treated according to locally recognised guidelines on standard of care treatment with both drugs and devices, as appropriate. Guideline-recommended medications should be used at recommended doses unless contraindicated or not tolerated. Therapy should have been individually optimised and stable for ≥4 weeks (this does not apply to diuretics) before visit 1 and include (unless contraindicated or not tolerated):

  • an ACE inhibitor, or ARB or sacubitril/valsartan and
  • a beta-blocker and
  • if considered appropriate by the patient's treating physician; a mineral corticoid receptor antagonis
• 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 flutter/fibrillation, 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

Contacts and Locations

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Sponsors and Collaborators

AstraZeneca

More Information

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03877237 History of Changes
• Other Study ID Numbers: D169EC00002; 2018-003442-16 ( EudraCT Number )
• First Posted: March 15, 2019
• Last Update Posted: November 13, 2019
• Last Verified: November 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases; 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Physiological Effects of Drugs