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

NCT03877224 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: D169EC000012018-003441-42
• Study Type: interventional
• Target: 504
• Locations: 12 countries
• Sites: 101

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)

Conditions

Heart Failure With Preserved Ejection Fraction (HFpEF)

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. 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 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: 40 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 ≥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).
• 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 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

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (101)

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Alexander City, Alabama, 35010, United States

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Fort Payne, Alabama, 35967, United States

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Beverly Hills, California, 90211, United States

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Torrance, California, 90502, United States

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Jacksonville, Florida, 32209, United States

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Miami, Florida, 33133, United States

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Miami, Florida, 33173, United States

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Tucker, Georgia, 30084, United States

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Arlington Heights, Illinois, 60005, United States

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Hazel Crest, Illinois, 60429, United States

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Munster, Indiana, 46321, United States

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Louisville, Kentucky, 40205, United States

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Bossier City, Louisiana, 71111, United States

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Annapolis, Maryland, 21401, United States

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New Brunswick, New Jersey, 08901, United States

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Ridgewood, New Jersey, 07450, United States

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Rosedale, New York, 11422, United States

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Burlington, North Carolina, 27215, United States

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Winston-Salem, North Carolina, 27157, United States

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Cincinnati, Ohio, 45267, United States

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Abington, Pennsylvania, 19001, United States

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Doylestown, Pennsylvania, 18901, United States

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Pittsburgh, Pennsylvania, 15212, United States

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Spring, Texas, 77380, United States

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Seattle, Washington, 98101, United States

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CABA, C1425AGC, Argentina

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Ciudad Autonoma de Buenos Aire, C1407GTN, Argentina

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Ciudad Autonomade Buenos Aires, 1426, Argentina

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Blumenau, 89020-430, Brazil

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Brasillia, 72145-450, Brazil

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Porto Alegre, 91350-200, Brazil

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São Paulo, 01141-020, Brazil

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São Paulo, 05403-000, Brazil

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Plovdiv, 4003, Bulgaria

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Sofia, 1000, Bulgaria

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Sofia, 1407, Bulgaria

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Veliko Tarnovo, 5000, Bulgaria

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Edmonton, Alberta, T5A 4L8, Canada

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Moncton, New Brunswick, E1G 1A7, Canada

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Mount Pearl, Newfoundland and Labrador, A1N 1W7, Canada

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

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Ajax, Ontario, L1Z 0B1, Canada

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Guelph, Ontario, N1H 1B1, Canada

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North York, Ontario, M3M 3E5, Canada

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Scarborough Village, Ontario, M1E 5E9, Canada

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Scarborough Village, Ontario, M1P 2T7, Canada

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Chicoutimi, Quebec, G7H 7K9, Canada

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Gatineau, Quebec, J8Y 6S8, Canada

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Longueuil, Quebec, J4M 2X1, Canada

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Montreal, Quebec, H2X 0A9, Canada

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Montreal, Quebec, H3G 1A4, Canada

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Québec, Quebec, G1G 3Y8, Canada

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Québec, Quebec, G2J 0C4, Canada

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Québec, Quebec, G3K 2P8, Canada

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Saint-Georges, Quebec, G5Y 4T8, Canada

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Århus N, 8200, Denmark

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Copenhagen, 2300, Denmark

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Esbjerg, 6700, Denmark

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Hellerup, 2900, Denmark

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Hjørring, 9800, Denmark

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Hvidovre, 2650, Denmark

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Næstved, 4700, Denmark

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Odense C, 5000, Denmark

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Randers, 8930, Denmark

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Svendborg, DK-5700, Denmark

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Bergamo, 24127, Italy

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Milan, 20162, Italy

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Napoli, 80131, Italy

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Palermo, 90127, Italy

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Roma, 00189, Italy

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San Giovanni Rotondo, 71013, Italy

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Akashi-shi, 674-0063, Japan

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Daito-shi, 574-0074, Japan

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Kasugai-shi, 487-0016, Japan

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Matsubara-shi, 580-0032, Japan

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Naha, 902-8511, Japan

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Osaka, 530-0001, Japan

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Ōmihachiman, 523-0082, Japan

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Shunan-shi, 745-0822, Japan

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Takarazuka-shi, 665-0873, Japan

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Toshima-ku, 171-0014, Japan

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Brezno, 97742, Slovakia

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Lučenec, 984 01, Slovakia

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Martin, 036 01, Slovakia

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Prešov, 080 01, Slovakia

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Ružomberok, 034 26, Slovakia

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Cape Town, 7500, South Africa

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Diepkloof, Soweto, 2013, South Africa

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Pinelands, 7405, South Africa

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Gangwon-do, 26426, South Korea

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Gwangju, 61469, South Korea

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Seongnam-si, 463-707, South Korea

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Seoul, 03080, South Korea

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Seoul, 03722, South Korea

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Borås, 506 30, Sweden

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Gothenburg, 413 45, Sweden

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Lund, 222 21, Sweden

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Östersund, 831 83, Sweden

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Stockholm, 114 46, Sweden

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Stockholm, 118 83, Sweden

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Umeå, 90737, Sweden

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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

• Clinical Study Protocol
• Statistical Analysis Plan
• CSR synopsis

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
• Restrictive Agreement: No

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 4, 2019
• Primary Completion: July 9, 2020
• Study Completion: July 9, 2020
• Last Updated: November 17, 2021
• Results First Posted: November 17, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, 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.

Locations

SL (5); DK (10); JP (10); ZA (3); SE (7); BU (4); US (25); KR (5); CA (18); AR (3); BR (5); IT (6)