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

Heart Failure With Reduced Ejection Fraction (HFrEF) Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03877237
• Other study ID #: D169EC00002
• Secondary ID: 2018-003442-16
• Status: Completed
• Phase: Phase 3
• Start date: April 9, 2019
• Est. completion date: March 7, 2020

Study information

• Verified date: April 2021
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 313
• Est. completion date: March 7, 2020
• Est. primary completion date: March 7, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 150 Years

Eligibility

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 antagonist

• 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

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Reduced Ejection Fraction (HFrEF)

Intervention

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.

Locations

Country	Name	City	State
Brazil	Research Site	Blumenau
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Sao Paulo
Brazil	Research Site	São Paulo
Canada	Research Site	Ajax	Ontario
Canada	Research Site	Gatineau	Quebec
Canada	Research Site	Longueuil	Quebec
Canada	Research Site	Moncton	New Brunswick
Canada	Research Site	Montreal	Quebec
Canada	Research Site	North York	Ontario
Canada	Research Site	Oshawa	Ontario
Canada	Research Site	Quebec
Canada	Research Site	Quebec
Canada	Research Site	Quebec
Canada	Research Site	Scarborough	Ontario
Canada	Research Site	St-Georges	Quebec
Canada	Research Site	St. John's	Newfoundland and Labrador
Canada	Research Site	Stoney Creek	Ontario
Canada	Research Site	Winnipeg	Manitoba
Canada	Research Site	York	Ontario
Denmark	Research Site	Århus N
Denmark	Research Site	Esbjerg
Denmark	Research Site	Hellerup
Denmark	Research Site	Hjørring
Denmark	Research Site	Hvidovre
Denmark	Research Site	København
Denmark	Research Site	Næstved
Denmark	Research Site	Odense C
Denmark	Research Site	Randers
Denmark	Research Site	Svendborg
Japan	Research Site	Daito-shi
Japan	Research Site	Kobe-shi
Japan	Research Site	Matsubara-shi
Japan	Research Site	Naha
Japan	Research Site	Osaka-shi
Japan	Research Site	Sayama-shi,
Japan	Research Site	Shunan-shi
Japan	Research Site	Takarazuka-shi
Korea, Republic of	Research Site	Gangwon-do
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Slovakia	Research Site	Lucenec
Slovakia	Research Site	Martin
Slovakia	Research Site	Presov
South Africa	Research Site	Cape Town
South Africa	Research Site	Cape Town
South Africa	Research Site	Diepkloof, Soweto
Sweden	Research Site	Göteborg
Sweden	Research Site	Lund
Sweden	Research Site	Ostersund
Sweden	Research Site	Stockholm
Sweden	Research Site	Stockholm
Sweden	Research Site	Umeå
United States	Research Site	Abington	Pennsylvania
United States	Research Site	Alexander City	Alabama
United States	Research Site	Beverly Hills	California
United States	Research Site	Buffalo	New York
United States	Research Site	Burlington	North Carolina
United States	Research Site	Fairhope	Alabama
United States	Research Site	Falls Church	Virginia
United States	Research Site	Fort Payne	Alabama
United States	Research Site	Kansas City	Missouri
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Mobile	Alabama
United States	Research Site	Munster	Indiana
United States	Research Site	New Brunswick	New Jersey
United States	Research Site	New York	New York
United States	Research Site	Petoskey	Michigan
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Rosedale	New York
United States	Research Site	Seattle	Washington
United States	Research Site	Stamford	Connecticut
United States	Research Site	Torrance	California
United States	Research Site	Tucker	Georgia
United States	Research Site	Tullahoma	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Denmark,  Japan,  Korea, Republic of,  Slovakia,  South Africa,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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. The KCCQ-TSS incorporates the symptom frequency (4 items) and symptom burden (3 items) domains into a single summary score. The score is transformed to a range of 0-100, in which a 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 the visit at week 16 but did not have KCCQ-TSS values.	At baseline and at week 16 or death before week 16
Primary	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. The KCCQ-PLS incorporates the 6 physical limitation items into a single score. The score is transformed to a range of 0-100, in which a 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. 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 KCCQ-PLS values.	At baseline and at week 16 or death before week 16
Primary	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 prior to week 16
Secondary	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.

External Links

•   redacted Clinical Study Protocol (CSP)
•   redacted Statistical Analysis Plan (SAP)