SGLT2 Inhibition in Combination With Diuretics in Heart Failure

NCT03226457 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: BHF:807998
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

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.

Conditions

Heart Failure; Type 2 Diabetes Mellitus

Keywords

Heart Failure; Type 2 Diabetes Mellitus; Sodium-Glucose co-Transporter 2 (SGLT2) inhibitors; Natriuresis; Diuresis

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (6)

• The Effect of Empagliflozin Versus Placebo on the Change in Urinary Sodium Excretion.

  Change from baseline to 6 weeks

• Number of Participants With a Change in CKD Category as Dictated by the Glomerular Filtration Rate

  From baseline to 6 weeks

• The Effect of Empagliflozin Versus Placebo on the Change in Serum Creatinine.

  Change from baseline to 6 weeks

• The Effect of Empagliflozin Versus Placebo on the Change to Urinary Protein/Creatinine Ratio.

  Change from baseline to 6 weeks

• The Effect of Empagliflozin Versus Placebo on the Change to Urinary Albumin/Creatinine Ratio.

  Change from baseline to 6 weeks

Study Arms (2)

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

Drug: Empagliflozin 25mg; Drug: Placebo oral capsule; Drug: Frusemide

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

Drug: Empagliflozin 25mg; Drug: Placebo oral capsule; Drug: Frusemide

Interventions

Empagliflozin 25mg DRUG

Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks

Also known as: Jardiance

Empagliflozin/Placebo; Placebo/Empagliflozin

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

Also known as: Placebo

Empagliflozin/Placebo; Placebo/Empagliflozin

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.

Empagliflozin/Placebo; Placebo/Empagliflozin

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Dundee: lead
• British Heart Foundation: collaborator

Study Sites (1)

University of Dundee, Ninewells Hospital and Medical School

Dundee, Angus, DD1 9SY, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 32865004 DERIVED

• 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.

  PMID: 29042392 DERIVED

MeSH Terms

Conditions

Heart Failure; Diabetes Mellitus, Type 2

Interventions

empagliflozin; Furosemide

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Sulfanilamides; Sulfonamides; Amides; Organic Chemicals; Aniline Compounds; Amines; Sulfones; Sulfur Compounds

Limitations and Caveats

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.

Results Point of Contact

• Title: Dr Natalie Mordi (Principle Investigator)
• Organization: University of Dundee

n.a.mordi@dundee.ac.uk

+ 44 (0) 1382 383 667

Study Officials

• Natalie A Mordi, MBChB MRCP

  University of Dundee

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-Blind
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: British Heart Foundation Clinical Research Fellow

Model Details: 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.

Study Record Dates

• First Submitted: July 17, 2017
• First Posted: July 21, 2017
• Study Start: December 11, 2017
• Primary Completion: December 11, 2018
• Study Completion: January 9, 2019
• Last Updated: June 30, 2021
• Results First Posted: June 30, 2021

Record last verified: 2021-06

Locations

GB (1)