SGLT2 Inhibition in Combination With Diuretics in Heart Failure
Condition: Heart Failure; Type 2 Diabetes Mellitus
MeSH terms: Heart Failure; Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Empagliflozin 25mg; Placebo oral capsule; Frusemide
Intervention description: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks; Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks; 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.
Intervention MeSH terms: Empagliflozin; Furosemide
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention 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: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Double-Blind
Enrollment: 23.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Heart Failure; Type 2 Diabetes Mellitus; Sodium-Glucose co-Transporter 2 (SGLT2) inhibitors; Natriuresis; Diuresis

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.
    

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.