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SGLT2 Inhibition in Combination With Diuretics in Heart Failure (RECEDE-CHF)

Primary Purpose

Heart Failure, Type 2 Diabetes Mellitus

Status
Completed
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
Empagliflozin 25mg
Placebo oral capsule
Frusemide
Sponsored by
University of Dundee
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring Heart Failure, Type 2 Diabetes Mellitus, Sodium-Glucose co-Transporter 2 (SGLT2) inhibitors, Natriuresis, Diuresis

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis of NYHA Functional class II-III HF with prior echocardiographic evidence of LVSD.
  • On stable doses of furosemide, or alternative loop diuretic for at least one month.
  • Stable Type 2 Diabetes (HbA1c, in the last 3 months, of 6.5% ≤ and ≤10.0%)
  • eGFR ≥ 45 ml/min.
  • Have stable HF symptoms for at least three months prior to consent
  • On stable HF therapy for at least three months prior to consent
  • Have not been hospitalised for HF for at least three months prior to consent.
  • Women of childbearing potential must agree to take precautions to avoid pregnancy throughout the trial and for 4 weeks after intake of the last dose.

Exclusion Criteria:

  • A diagnosis of chronic liver disease and/or liver enzymes that are twice the upper limit of normal
  • Systolic BP of <95mmHg at screening visit.
  • Participants on thiazide diuretics.
  • Participants receiving renal dialysis
  • Participants who have previously had an episode of diabetic ketoacidosis.
  • Participants with type 1 diabetes mellitus
  • Malignancy (receiving active treatment) or other life threatening disease.
  • Pregnant or lactating women
  • Participants with difficulty in micturition e.g. severe prostate enlargement
  • Allergy to any SGLT2 inhibitor or lactose or galactose intolerance
  • Past or current treatment with any SGLT2 inhibitor
  • Participants who have participated in any other clinical interventional trial of an investigational medicinal product within 30 days.
  • Participants who are unable to give informed consent
  • Any other reason considered by the physician to be inappropriate for inclusion.

Sites / Locations

  • University of Dundee, Ninewells Hospital and Medical School

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Empagliflozin/Placebo

Placebo/Empagliflozin

Arm Description

Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks, minimum of a 2 week washout period, then 6 weeks placebo

Placebo for 6 weeks, minimum of a 2 week washout period, followed by Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks

Outcomes

Primary Outcome Measures

The Effect of Empagliflozin Versus Placebo on the Change in Urine Output.
Change from urinary volume from baseline (mls).

Secondary Outcome Measures

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 (%).
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
The Effect of Empagliflozin Versus Placebo on the Change in Serum Creatinine.
Change in serum creatinine from baseline (mmol/L).
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).
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).
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).

Full Information

First Posted
July 17, 2017
Last Updated
June 22, 2021
Sponsor
University of Dundee
Collaborators
British Heart Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT03226457
Brief Title
SGLT2 Inhibition in Combination With Diuretics in Heart Failure
Acronym
RECEDE-CHF
Official Title
Renal and Cardiovascular Effect of Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibition in Combination With Loop Diuretics in Diabetic Patients With Chronic Heart Failure
Study Type
Interventional

2. Study Status

Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
December 11, 2017 (Actual)
Primary Completion Date
December 11, 2018 (Actual)
Study Completion Date
January 9, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Dundee
Collaborators
British Heart Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure, Type 2 Diabetes Mellitus
Keywords
Heart Failure, Type 2 Diabetes Mellitus, Sodium-Glucose co-Transporter 2 (SGLT2) inhibitors, Natriuresis, Diuresis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Model Description
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.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Double-Blind
Allocation
Randomized
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Empagliflozin/Placebo
Arm Type
Active Comparator
Arm Description
Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks, minimum of a 2 week washout period, then 6 weeks placebo
Arm Title
Placebo/Empagliflozin
Arm Type
Active Comparator
Arm Description
Placebo for 6 weeks, minimum of a 2 week washout period, followed by Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks
Intervention Type
Drug
Intervention Name(s)
Empagliflozin 25mg
Other Intervention Name(s)
Jardiance
Intervention Description
Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo oral capsule
Other Intervention Name(s)
Placebo
Intervention Description
Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks
Intervention Type
Drug
Intervention Name(s)
Frusemide
Intervention Description
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.
Primary Outcome Measure Information:
Title
The Effect of Empagliflozin Versus Placebo on the Change in Urine Output.
Description
Change from urinary volume from baseline (mls).
Time Frame
Change from baseline to 6 weeks
Secondary Outcome Measure Information:
Title
The Effect of Empagliflozin Versus Placebo on the Change in Urinary Sodium Excretion.
Description
The effect of empagliflozin versus placebo on the change in urinary sodium excretion: change in fractional urinary sodium excretion from baseline (%).
Time Frame
Change from baseline to 6 weeks
Title
Number of Participants With a Change in CKD Category as Dictated by the Glomerular Filtration Rate
Description
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
Time Frame
From baseline to 6 weeks
Title
The Effect of Empagliflozin Versus Placebo on the Change in Serum Creatinine.
Description
Change in serum creatinine from baseline (mmol/L).
Time Frame
Change from baseline to 6 weeks
Title
The Effect of Empagliflozin Versus Placebo on the Change to Urinary Protein/Creatinine Ratio.
Description
The effect of empagliflozin versus placebo on the change to urinary protein/creatinine ratio: Change in urinary protein/creatinine ratio from baseline (mg/mmol).
Time Frame
Change from baseline to 6 weeks
Title
The Effect of Empagliflozin Versus Placebo on the Change to Urinary Albumin/Creatinine Ratio.
Description
The effect of empagliflozin versus placebo on the change to urinary albumin/creatinine ratio: Change in urinary albumin/creatinine ratio from baseline (mg/mmol).
Time Frame
Change from baseline to 6 weeks
Title
The Effect of Empagliflozin Versus Placebo on the Change to the Renal Biomarker, Cystatin C.
Description
The effect of empagliflozin versus placebo on the change to the renal biomarker, cystatin C: Change in Cystatin C from baseline (ng/ml).
Time Frame
Change from baseline to 6 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of NYHA Functional class II-III HF with prior echocardiographic evidence of LVSD. On stable doses of furosemide, or alternative loop diuretic for at least one month. Stable Type 2 Diabetes (HbA1c, in the last 3 months, of 6.5% ≤ and ≤10.0%) eGFR ≥ 45 ml/min. Have stable HF symptoms for at least three months prior to consent On stable HF therapy for at least three months prior to consent Have not been hospitalised for HF for at least three months prior to consent. Women of childbearing potential must agree to take precautions to avoid pregnancy throughout the trial and for 4 weeks after intake of the last dose. Exclusion Criteria: A diagnosis of chronic liver disease and/or liver enzymes that are twice the upper limit of normal Systolic BP of <95mmHg at screening visit. Participants on thiazide diuretics. Participants receiving renal dialysis Participants who have previously had an episode of diabetic ketoacidosis. Participants with type 1 diabetes mellitus Malignancy (receiving active treatment) or other life threatening disease. Pregnant or lactating women Participants with difficulty in micturition e.g. severe prostate enlargement Allergy to any SGLT2 inhibitor or lactose or galactose intolerance Past or current treatment with any SGLT2 inhibitor Participants who have participated in any other clinical interventional trial of an investigational medicinal product within 30 days. Participants who are unable to give informed consent Any other reason considered by the physician to be inappropriate for inclusion.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Natalie A Mordi, MBChB MRCP
Organizational Affiliation
University of Dundee
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Dundee, Ninewells Hospital and Medical School
City
Dundee
State/Province
Angus
ZIP/Postal Code
DD1 9SY
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
32865004
Citation
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. Erratum In: Circulation. 2020 Nov 3;142(18):e316.
Results Reference
derived
PubMed Identifier
29042392
Citation
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.
Results Reference
derived

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SGLT2 Inhibition in Combination With Diuretics in Heart Failure

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