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| Name | Class |
|---|---|
| British Heart Foundation | OTHER |
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The RECEDE-CHF trial is a single centre phase IV, randomised, double-blind, placebo-controlled, crossover trial conducted in NHS Tayside, Scotland comparing empagliflozin 25mg, to placebo in patients with Type 2 Diabetes and mild Chronic Heart Failure with left ventricular systolic dysfunction who are already on a loop diuretic. Renal physiological testing will be performed at two points on each arm to assess the effect of empagliflozin, on urinary volume, compared to placebo. The secondary outcomes are to assess the effect of empagliflozin in addition to loop diuretics on natriuresis, to assess the safety of add-on SGLT2 inhibitor therapy as measured by changes to serum creatinine and eGFR, to assess effects of empagliflozin on urinary protein/creatinine ratio, albumin/creatinine ratio and cystatin C when compared to placebo.
Type 2 Diabetes (T2D) and Heart Failure (HF) are a frequent combination, where treatment options remain limited. There has been increasing interest around the sodium-glucose co-transporter 2 (SGLT2) inhibitors and their use in patients with HF. This is following publication of EMPA-REG OUTCOME trial that reported a 14% reduction in the primary composite outcome of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and >30% reductions in cardiovascular mortality, overall mortality and HF hospitalisations in patients randomised to the SGLT2 inhibitor, empagliflozin, when compared to placebo. Data on the effect of SGLT2 inhibitor use with diuretics is limited. We hypothesize that, in the diabetic CHF population, SGLT2 inhibition may augment the effects of loop diuretics.
Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. The investigational medicinal product will be administered, followed by an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose.
This proof of concept trial will aim to shed light on the mechanism of the cardiovascular and renal outcomes demonstrated in the recent EMPA-REG study by documenting the influence of the SGLT2 inhibitors when used in combination with a loop diuretic on diuresis and natriuresis when compared to placebo.
The RECEDE-CHF trial is funded by the British Heart Foundation (BHF grant number: 807998). NAM is a BHF funded clinical research fellow.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Empagliflozin/Placebo | Active Comparator | Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks, minimum of a 2 week washout period, then 6 weeks placebo |
|
| Placebo/Empagliflozin | Active Comparator | Placebo for 6 weeks, minimum of a 2 week washout period, followed by Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Empagliflozin 25mg | Drug | Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| The Effect of Empagliflozin Versus Placebo on the Change in Urine Output. | Change from urinary volume from baseline (mls). | Change from baseline to 6 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| The Effect of Empagliflozin Versus Placebo on the Change in Urinary Sodium Excretion. | The effect of empagliflozin versus placebo on the change in urinary sodium excretion: change in fractional urinary sodium excretion from baseline (%). | Change from baseline to 6 weeks |
| Number of Participants With a Change in CKD Category as Dictated by the Glomerular Filtration Rate |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Natalie A Mordi, MBChB MRCP | University of Dundee | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Dundee, Ninewells Hospital and Medical School | Dundee | Angus | DD1 9SY | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32865004 | Derived | Mordi NA, Mordi IR, Singh JS, McCrimmon RJ, Struthers AD, Lang CC. Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure: The RECEDE-CHF Trial. Circulation. 2020 Nov 3;142(18):1713-1724. doi: 10.1161/CIRCULATIONAHA.120.048739. Epub 2020 Aug 29. | |
| 29042392 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Empagliflozin/Placebo | Treatment Sequence: Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered. Minimum of a 2 week washout period. 6 weeks of placebo |
| FG001 | Placebo/Empagliflozin | Treatment Sequence: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered. Minimum of 2 week washout period 6 weeks of Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment 1: 6 Weeks |
| |||||||||||||
| Washout Period: Minimum 2 Weeks |
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| Treatment 2: 6 Weeks |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Baseline Characteristics | N = 23, Crossover study design. Baseline characteristics |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | The Effect of Empagliflozin Versus Placebo on the Change in Urine Output. | Change from urinary volume from baseline (mls). | Posted | Least Squares Mean | 95% Confidence Interval | mL | Change from baseline to 6 weeks |
|
For the duration of the participants inclusion in the study to the point of completion e.g. 14 to 16 weeks in the trial, with a further review at 4 weeks following discontinuation of the investigational medicinal product e.g. 18 to 20 weeks in total.
Because of the large volume of multicenter studies reporting on the safety and adverse events of SGLT2 inhibitors, for this trial the focus was on the effects on the coprescription with loop diuretic. Adverse event data were also collected.
As a crossover study, the adverse event reporting is separated into the events that occurred on the specific intervention/treatment arms.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Empagliflozin | Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks Empagliflozin 25mg: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hospitalization with heart failure following discontinuation of investigational medicinal product | Cardiac disorders | MedDRA 21.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gout | Musculoskeletal and connective tissue disorders | MedDRA 21.1 | Systematic Assessment | Gout |
Small, single-center crossover study. The dose investigated was 25mg empagliflozin, whereas in routine practice 10mg dose is most commonly used. We did not measure urine glucose in this study. Patients were only observed for 2 hours after administration of investigational medical. Any significant diuretic or natriuretic effect beyond this may have not been observed during this short time frame.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Natalie Mordi (Principle Investigator) | University of Dundee | + 44 (0) 1382 383 667 | n.a.mordi@dundee.ac.uk |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 22, 2018 | Apr 22, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Nov 1, 2018 | Apr 22, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D006333 | Heart Failure |
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
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| ID | Term |
|---|---|
| C570240 | empagliflozin |
| D005665 | Furosemide |
| ID | Term |
|---|---|
| D013424 | Sulfanilamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
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6 week period of Investigational Medicinal Product (Empagliflozin 25 mg od) or placebo. A 2 week washout period will then be observed, followed by the second arm with a further 6 week period of placebo or IMP. At week 1 and week 6 of each arm, detailed Renal Physiology Test days will be performed.
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Double-Blind
| Placebo oral capsule | Drug | Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks |
|
|
| Frusemide | Drug | Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered. |
|
The effect of empagliflozin versus placebo on the change in glomerular filtration rate: Change in estimated glomerular filtration rate from baseline (ml/min/1.73m2). Data was recorded as a persistent reduction in CKD category in the empagliflozin group versus placebo |
| From baseline to 6 weeks |
| The Effect of Empagliflozin Versus Placebo on the Change in Serum Creatinine. | Change in serum creatinine from baseline (mmol/L). | Change from baseline to 6 weeks |
| The Effect of Empagliflozin Versus Placebo on the Change to Urinary Protein/Creatinine Ratio. | The effect of empagliflozin versus placebo on the change to urinary protein/creatinine ratio: Change in urinary protein/creatinine ratio from baseline (mg/mmol). | Change from baseline to 6 weeks |
| The Effect of Empagliflozin Versus Placebo on the Change to Urinary Albumin/Creatinine Ratio. | The effect of empagliflozin versus placebo on the change to urinary albumin/creatinine ratio: Change in urinary albumin/creatinine ratio from baseline (mg/mmol). | Change from baseline to 6 weeks |
| The Effect of Empagliflozin Versus Placebo on the Change to the Renal Biomarker, Cystatin C. | The effect of empagliflozin versus placebo on the change to the renal biomarker, cystatin C: Change in Cystatin C from baseline (ng/ml). | Change from baseline to 6 weeks |
| Mordi NA, Mordi IR, Singh JS, Baig F, Choy AM, McCrimmon RJ, Struthers AD, Lang CC. Renal and Cardiovascular Effects of sodium-glucose cotransporter 2 (SGLT2) inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure (RECEDE-CHF): protocol for a randomised controlled double-blind cross-over trial. BMJ Open. 2017 Oct 16;7(10):e018097. doi: 10.1136/bmjopen-2017-018097. |
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| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
|
| Placebo |
Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered. |
|
|
|
| Secondary | The Effect of Empagliflozin Versus Placebo on the Change in Urinary Sodium Excretion. | The effect of empagliflozin versus placebo on the change in urinary sodium excretion: change in fractional urinary sodium excretion from baseline (%). | Posted | Least Squares Mean | 95% Confidence Interval | percentage of change in FENa | Change from baseline to 6 weeks |
|
|
|
| Secondary | Number of Participants With a Change in CKD Category as Dictated by the Glomerular Filtration Rate | The effect of empagliflozin versus placebo on the change in glomerular filtration rate: Change in estimated glomerular filtration rate from baseline (ml/min/1.73m2). Data was recorded as a persistent reduction in CKD category in the empagliflozin group versus placebo | Posted | Count of Participants | Participants | From baseline to 6 weeks |
|
|
|
| Secondary | The Effect of Empagliflozin Versus Placebo on the Change in Serum Creatinine. | Change in serum creatinine from baseline (mmol/L). | Posted | Least Squares Mean | 95% Confidence Interval | mmol/L | Change from baseline to 6 weeks |
|
|
|
| Secondary | The Effect of Empagliflozin Versus Placebo on the Change to Urinary Protein/Creatinine Ratio. | The effect of empagliflozin versus placebo on the change to urinary protein/creatinine ratio: Change in urinary protein/creatinine ratio from baseline (mg/mmol). | Posted | Least Squares Mean | 95% Confidence Interval | mg/mmol | Change from baseline to 6 weeks |
|
|
|
| Secondary | The Effect of Empagliflozin Versus Placebo on the Change to Urinary Albumin/Creatinine Ratio. | The effect of empagliflozin versus placebo on the change to urinary albumin/creatinine ratio: Change in urinary albumin/creatinine ratio from baseline (mg/mmol). | Posted | Least Squares Mean | 95% Confidence Interval | mg/mmol | Change from baseline to 6 weeks |
|
|
|
| Secondary | The Effect of Empagliflozin Versus Placebo on the Change to the Renal Biomarker, Cystatin C. | The effect of empagliflozin versus placebo on the change to the renal biomarker, cystatin C: Change in Cystatin C from baseline (ng/ml). | Posted | Least Squares Mean | 95% Confidence Interval | ng/ml | Change from baseline to 6 weeks |
|
|
|
| 0 |
| 23 |
| 2 |
| 23 |
| 1 |
| 23 |
| EG001 | Placebo | Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator Placebo oral capsule: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks Frusemide: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered. | 0 | 23 | 0 | 23 | 2 | 23 |
|
| Hypotension | Cardiac disorders | MedDRA 21.1 | Systematic Assessment |
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| D008659 |
| Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D000814 |
| Aniline Compounds |
| D000588 | Amines |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |