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

June 22, 2021 updated by: Natalie Mordi, University of Dundee

Renal and Cardiovascular Effect of Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibition in Combination With Loop Diuretics in Diabetic Patients With Chronic Heart Failure

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

23

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • Angus
      • Dundee, Angus, United Kingdom, DD1 9SY
        • University of Dundee, Ninewells Hospital and Medical School

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Empagliflozin/Placebo
Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks, minimum of a 2 week washout period, then 6 weeks placebo
Drug: Empagliflozin 25mg
Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks
Other Names:
  • Jardiance
Drug: 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
Other Names:
  • Placebo
Drug: 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.
Active Comparator: Placebo/Empagliflozin
Placebo for 6 weeks, minimum of a 2 week washout period, followed by Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks
Drug: Empagliflozin 25mg
Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks
Other Names:
  • Jardiance
Drug: 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
Other Names:
  • Placebo
Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Effect of Empagliflozin Versus Placebo on the Change in Urine Output.
Time Frame: Change from baseline to 6 weeks
Change from urinary volume from baseline (mls).
Change from baseline to 6 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Effect of Empagliflozin Versus Placebo on the Change in Urinary Sodium Excretion.
Time Frame: Change from baseline to 6 weeks
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
Time Frame: From baseline to 6 weeks

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.
Time Frame: Change from baseline to 6 weeks
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.
Time Frame: Change from baseline to 6 weeks
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.
Time Frame: Change from baseline to 6 weeks
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.
Time Frame: Change from baseline to 6 weeks
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Dundee

Collaborators

British Heart Foundation

Investigators

  • Principal Investigator: Natalie A Mordi, MBChB MRCP, University of Dundee

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 11, 2017

Primary Completion (Actual)

December 11, 2018

Study Completion (Actual)

January 9, 2019

Study Registration Dates

First Submitted

July 17, 2017

First Submitted That Met QC Criteria

July 20, 2017

First Posted (Actual)

July 21, 2017

Study Record Updates

Last Update Posted (Actual)

June 30, 2021

Last Update Submitted That Met QC Criteria

June 22, 2021

Last Verified

June 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BHF:807998

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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