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

NCT03877237 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: D169EC000022018-003442-16
• Study Type: interventional
• Target: 313
• Locations: 9 countries
• Sites: 76

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)

Conditions

Heart Failure With Reduced Ejection Fraction (HFrEF)

Outcome Measures

Primary Outcomes (3)

• 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

• 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

• 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 Outcomes (1)

• 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).

  At baseline and at end of study or death before week 16.

Study Arms (2)

Dapagliflozin

EXPERIMENTAL

Green, diamond shaped, film coated tablets 10 mg administered orally, once daily

Drug: Dapagliflozin

Placebo

PLACEBO COMPARATOR

Green, diamond shaped, film coated tablets placebo administered orally, once daily

Other: Placebo

Interventions

Dapagliflozin DRUG

Tablets administered orally once daily. Treatment start within 24h after randomisation for 16 weeks.

Dapagliflozin

Placebo OTHER

Tablets administered orally once daily. Treatment start within 24h after randomisation for 16 weeks.

Placebo

Eligibility Criteria

• Age: 18 Years - 150 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• MWD≥100 metres and ≤425 metres at enrolment and randomization.

You may not qualify if:

• 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

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (76)

Research Site

Alexander City, Alabama, 35010, United States

Location

Research Site

Fairhope, Alabama, 36532, United States

Location

Research Site

Fort Payne, Alabama, 35967, United States

Location

Research Site

Mobile, Alabama, 36608, United States

Location

Research Site

Beverly Hills, California, 90211, United States

Location

Research Site

Torrance, California, 90502, United States

Location

Research Site

Stamford, Connecticut, 06905, United States

Location

Research Site

Miami, Florida, 33133, United States

Location

Research Site

Miami, Florida, 33173, United States

Location

Research Site

Tucker, Georgia, 30084, United States

Location

Research Site

Munster, Indiana, 46321, United States

Location

Research Site

Petoskey, Michigan, 49770, United States

Location

Research Site

Kansas City, Missouri, 64111, United States

Location

Research Site

New Brunswick, New Jersey, 08901, United States

Location

Research Site

Buffalo, New York, 14215, United States

Location

Research Site

New York, New York, 10001, United States

Location

Research Site

Rosedale, New York, 11422, United States

Location

Research Site

Burlington, North Carolina, 27215, United States

Location

Research Site

Abington, Pennsylvania, 19001, United States

Location

Research Site

Pittsburgh, Pennsylvania, 15212, United States

Location

Research Site

Tullahoma, Tennessee, 37388, United States

Location

Research Site

Falls Church, Virginia, 22042, United States

Location

Research Site

Seattle, Washington, 98101, United States

Location

Research Site

Blumenau, 89020-430, Brazil

Location

Research Site

Porto Alegre, 91350-200, Brazil

Location

Research Site

São Paulo, 01141-020, Brazil

Location

Research Site

São Paulo, 05403-000, Brazil

Location

Research Site

Winnipeg, Manitoba, R2H 2A6, Canada

Location

Research Site

Moncton, New Brunswick, E1G 1A7, Canada

Location

Research Site

St. John's, Newfoundland and Labrador, A1B 3V6, Canada

Location

Research Site

Ajax, Ontario, L1Z 0B1, Canada

Location

Research Site

North York, Ontario, M3M 3E5, Canada

Location

Research Site

Oshawa, Ontario, L1J 2K1, Canada

Location

Research Site

Scarborough Village, Ontario, M1E 5E9, Canada

Location

Research Site

Stoney Creek, Ontario, L8J 3W2, Canada

Location

Research Site

York, Ontario, M9N 1W4, Canada

Location

Research Site

Gatineau, Quebec, J8Y 6S8, Canada

Location

Research Site

Longueuil, Quebec, J4M 2X1, Canada

Location

Research Site

Montreal, Quebec, H2X 0A9, Canada

Location

Research Site

Québec, Quebec, G1G 3Z4, Canada

Location

Research Site

Québec, Quebec, G2J 0C4, Canada

Location

Research Site

Québec, Quebec, G3K 2P8, Canada

Location

Research Site

Saint-Georges, Quebec, G5Y 4T8, Canada

Location

Research Site

Århus N, 8200, Denmark

Location

Research Site

Copenhagen, 2300, Denmark

Location

Research Site

Esbjerg, 6700, Denmark

Location

Research Site

Hellerup, 2900, Denmark

Location

Research Site

Hjørring, 9800, Denmark

Location

Research Site

Hvidovre, 2650, Denmark

Location

Research Site

Næstved, 4700, Denmark

Location

Research Site

Odense C, 5000, Denmark

Location

Research Site

Randers, 8930, Denmark

Location

Research Site

Svendborg, DK-5700, Denmark

Location

Research Site

Daito-shi, 574-0074, Japan

Location

Research Site

Kobe, 654-0155, Japan

Location

Research Site

Matsubara-shi, 580-0032, Japan

Location

Research Site

Naha, 902-8511, Japan

Location

Research Site

Osaka, 530-0001, Japan

Location

Research Site

Sayama-shi,, 350-1305, Japan

Location

Research Site

Shunan-shi, 745-0822, Japan

Location

Research Site

Takarazuka-shi, 665-0873, Japan

Location

Research Site

Lučenec, 984 01, Slovakia

Location

Research Site

Martin, 036 01, Slovakia

Location

Research Site

Prešov, 080 01, Slovakia

Location

Research Site

Cape Town, 7405, South Africa

Location

Research Site

Cape Town, 7500, South Africa

Location

Research Site

Diepkloof, Soweto, 2013, South Africa

Location

Research Site

Gangwon-do, 26426, South Korea

Location

Research Site

Seoul, 03080, South Korea

Location

Research Site

Seoul, 03722, South Korea

Location

Research Site

Gothenburg, 413 45, Sweden

Location

Research Site

Lund, 222 21, Sweden

Location

Research Site

Östersund, 831 83, Sweden

Location

Research Site

Stockholm, 114 46, Sweden

Location

Research Site

Stockholm, 118 83, Sweden

Location

Research Site

Umeå, 90737, Sweden

Location

Related Publications (2)

• Docherty KF, Buendia Lopez R, Folkvaljon F, de Boer RA, Cowie MR, Hammarstedt A, Kitzman DW, Kosiborod MN, Langkilde AM, Reicher B, Senni M, Shah SJ, Verma S, Solomon SD, McMurray JJV. Effect of Dapagliflozin on Accelerometer-Based Measures of Physical Activity in Patients With Heart Failure: An Analysis of the DETERMINE Trials. Circ Heart Fail. 2024 Oct;17(10):e012349. doi: 10.1161/CIRCHEARTFAILURE.124.012349. Epub 2024 Aug 30.

  PMID: 39212948 DERIVED

• McMurray JJV, Docherty KF, de Boer RA, Hammarstedt A, Kitzman DW, Kosiborod MN, Maria Langkilde A, Reicher B, Senni M, Shah SJ, Wilderang U, Verma S, Solomon SD. Effect of Dapagliflozin Versus Placebo on Symptoms and 6-Minute Walk Distance in Patients With Heart Failure: The DETERMINE Randomized Clinical Trials. Circulation. 2024 Mar 12;149(11):825-838. doi: 10.1161/CIRCULATIONAHA.123.065061. Epub 2023 Dec 7.

  PMID: 38059368 DERIVED

Related Links

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

MeSH Terms

Interventions

dapagliflozin

Limitations and Caveats

In this study, a subset of participants received wearable activity monitors to wear at home for 3 periods of 7 days. Data collection from the wearable device was challenging and a substantial amount of data was missing. This limits the use of the data based on the wearable activity monitors to investigate the potential impact of study drug on the amount, duration, and intensity of physical activity.

Results Point of Contact

• Title: Łyżwa, Dawid
• Organization: Astrazeneca

dawid.lyzwa@astrazeneca.com

+48 882 345 259

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2019
• First Posted: March 15, 2019
• Study Start: April 9, 2019
• Primary Completion: March 7, 2020
• Study Completion: March 7, 2020
• Last Updated: May 5, 2021
• Results First Posted: May 5, 2021

Record last verified: 2021-04

Locations

SE (6); JP (8); DK (10); ZA (3); CA (16); KR (3); BR (4); SL (3); US (23)