DETERMINE-reduced - Dapagliflozin Effect on Exercise Capa... | NCT03877237

ID	Type	Description	Link
2018-003442-16	EudraCT Number

Label	Type	Description	Intervention Names
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

Name	Type	Description	Arm Group Labels	Other Names
Dapagliflozin	Drug	Tablets administered orally once daily. Treatment start within 24h after randomisation for 16 weeks.	Dapagliflozin

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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).

Secondary Outcomes

Measure	Description	Time Frame
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.

Eligibility Module

Eligibility 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 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

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Alexander City	Alabama	35010	United States
Research Site

PubMed Identifier	Type	Citation	Retractions
39603408	Derived	Docherty KF, Buendia Lopez R, Folkvaljon F, Boer RA, Chen J, Hammarstedt A, Kitzman DW, Kosiborod MN, Langkilde AM, Reicher B, Senni M, Wilderang U, Verma S, Cowie MR, Solomon SD, McMurray JJV. Wearable Accelerometer-Derived Measures of Physical Activity in Heart Failure: Insights From the DETERMINE trials. J Card Fail. 2025 Apr;31(4):689-703. doi: 10.1016/j.cardfail.2024.10.439. Epub 2024 Nov 26.
39212948

Label	URL
redacted Clinical Study Protocol (CSP)	View source

ID	Title	Description
FG000	Dapa 10mg	Dapagliflozin 10 mg, given once daily per oral use.
FG001	Placebo	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Mar 4, 2020	Mar 3, 2021

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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.

Full Analysis Set: All participants that were randomized, regardless of whether treated or not.

Posted

Median

Inter-Quartile Range

Score on a scale

At baseline and at week 16 or death before week 16

ID	Title	Description
OG000	Dapa 10mg	Dapagliflozin 10 mg, given once daily per oral use.
OG001	Placebo	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.

Units	Counts
Participants	OG000156 OG001157

Title

Denominators

Categories

Title	Measurements
	OG0002.08(-4.17 to 14.58) OG0010.00(-10.42 to 9.38)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	For the primary efficacy endpoint KCCQ-TSS, the following hypothesis was tested using the significance level 0.04990 H0: m(r(A)) = m(r(C)) versus H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in the primary efficacy endpoint, KCCQ-TSS, from baseline to week 16, among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.	Rank ANCOVA	Model includes baseline rank of outcome variable as a covariate, treatment group as a factor, and is stratified by T2DM status at randomization.	0.02164	To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate.	Hodges-Lehmann median diff. vs placebo	4.23			2-Sided	95	0.96	8.22

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.

Full Analysis Set: All participants that were randomized, regardless of whether treated or not, excluding participants with non-calculable baseline or week 16 KCCQ-PLS.

Posted

Median

Inter-Quartile Range

Score on a scale

At baseline and at week 16 or death before week 16

ID	Title	Description
OG000	Dapa 10mg	Dapagliflozin 10 mg, given once daily per oral use.
OG001	Placebo

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.

Full Analysis Set: All participants that were randomized, regardless of whether treated or not.

Posted

Median

Inter-Quartile Range

meters

At baseline and at week 16 or death prior to week 16

ID	Title	Description
OG000	Dapa 10mg	Dapagliflozin 10 mg, given once daily per oral use.
OG001	Placebo	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.

Units	Counts
Participants

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.

Full Analysis Set: All participants that were randomized, regardless of whether treated or not, including participants from investigator sites having wearable activity monitor data collected.

Posted

Median

Inter-Quartile Range

hours

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

ID	Title	Description
OG000	Dapa 10mg	Dapagliflozin 10 mg, given once daily per oral use.
OG001	Placebo	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Cardiac failure	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0003 affected156 at risk EG0016 affected157 at risk
Cardiac arrest	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0002 affected156 at risk EG0010 affected157 at risk
Acute myocardial infarction	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0012 affected157 at risk
Atrial fibrillation	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0012 affected157 at risk
Cardiac failure acute	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0014 affected157 at risk
Left ventricular failure	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0010 affected157 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0012 affected157 at risk
Ventricular tachycardia	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0012 affected157 at risk
Chagas' cardiomyopathy	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0010 affected157 at risk
Erysipelas	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0010 affected157 at risk
Pneumonia	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0010 affected157 at risk
Sepsis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0011 affected157 at risk
Infected skin ulcer	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0011 affected157 at risk
Multiple organ dysfunction syndrome	General disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0010 affected157 at risk
Non-cadiac chest pain	General disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0010 affected157 at risk
Death	General disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0011 affected157 at risk
Gout	Metabolism and nutrition disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0010 affected157 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0010 affected157 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0002 affected156 at risk EG0010 affected157 at risk
Cerebral infarction	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0011 affected157 at risk
Iron deficiency anaemia	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0010 affected157 at risk
Skin ulcer haemorrhage	Skin and subcutaneous tissue disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0010 affected157 at risk
Skin ulcer	Skin and subcutaneous tissue disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0012 affected157 at risk
Peripheral ischaemia	Vascular disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected156 at risk EG0010 affected157 at risk
Orthostatic hypotension	Vascular disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0011 affected157 at risk
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0011 affected157 at risk
Hepatic function abnormal	Hepatobiliary disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0011 affected157 at risk
Postoperative thoracic procedure complication	Injury, poisoning and procedural complications	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0011 affected157 at risk
Acute kidney injury	Renal and urinary disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0012 affected157 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0011 affected157 at risk
Mediastinal haemorrhage	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0011 affected157 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected156 at risk EG0011 affected157 at risk

ID	Title	Description
BG000	Dapa 10mg	Dapagliflozin 10 mg, given once daily per oral use.
BG001	Placebo	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Dapa 10mg	Dapagliflozin 10 mg, given once daily per oral use.	3	156	19	156	0	156
EG001	Placebo	Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.	2	157	23	157	0	157