Dapagliflozin, Spironolactone or Both for HFpEF (SOGALDI-PEF)

Sodium-glucose Cotransporter 2 Inhibitor, Aldosterone Antagonist, or Both for Heart Failure With Preserved Ejection Fraction: a Two-centre Randomised Three-treatment Three-period Crossover Trial

Heart failure (HF) is a condition in which the heart does not contract ("pump") or relax well, leading to insufficient perfusion of vital organs. Ankle swelling, fatigue, and breathlessness are some of the features of this syndrome. There are different causes for HF (eg., infarct and hypertension) and two distinct types: HFrEF - HF with reduced ejection fraction - where the heart does not "pump" properly, and HFpEF - HF with preserved ejection fraction - the heart "pumps" but does not relax well. Treatment for HFrEF is better established than for HFpEF. In HFpEF, only mineralocorticoid receptors antagonists (MRAs) have been shown to reduce hospitalizations, circulating markers of cardiac dysfunction and fibrosis, and blood pressure. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a therapeutic class that reduces morbidity and mortality in patients with high cardiovascular risk and diabetes and in patients with HFrEF with and without diabetes. Trials are underway to test whether SGLT2i may also be useful for the treatment of HFpEF. This work aims to compare the effects of MRAs and SGLT2i alone, plus their combination in patients with HFpEF.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Dapagliflozin; Drug: Spironolactone; Drug: Spironolactone + Dapagliflozin

• Study Type: Interventional
• Enrollment (Estimated): 108
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Janete Santos, PhD; Phone Number: (+351) 961239890; Email: investigaclinica@med.up.pt
• Study Contact Backup: Name: João P. Ferreira, MD, PhD; Phone Number: (+351) 220426820; Email: jpferreira@med.up.pt

Study Locations

• Portugal
  • Porto, Portugal, 4200-319
    • Recruiting
    • Centro Hospitalar Universitario Sao Joao
    • Contact: Centro Hospitalar Universitário São João; Phone Number: (+351) 225512100; Email: geral@chsj.min-saude.pt
    • Contact: Francisca Saraiva, PhD; Email: f.saraiva@med.up.pt
    • Principal Investigator: Adelino Leite-Moreira, MD, PhD
  • Porto, Portugal, 4434-502
    • Recruiting
    • Centro Hospitalar Vila Nova de Gaia/Espinho
    • Contact: Centro Hospitalar Vila Nova de Gaia/Espinho; Phone Number: (+351) 227865100; Email: geral@chvng.min-saude.pt
    • Contact: Ana Oliveira, MSc; Email: crisoliveira@med.up.pt
    • Principal Investigator: Ricardo Fontes-Carvalho, MD, PhD
  • Porto, Portugal, 4200-319
    • Recruiting
    • Faculty of Medicine (FMUP)
    • Contact: Francisca Saraiva, PhD; Phone Number: (+351) 225512100; Email: f.saraiva@med.up.pt

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Provision of informed consent prior to any study specific procedures
• HFpEF diagnosis* (irrespective of time from diagnosis)
• Male or female patients, aged ≥50 years
• NYHA Class II-IV
• LVEF ≥45%
• NT-pro BNP ≥220 pg/mL or BNP ≥80 pg/mL if in sinus rhythm (SR)
• NT-pro BNP ≥660 pg/mL or BNP ≥240 pg/mL if in atrial fibrillation (AF)

• Echocardiography with at least one of the following criteria:

  • LAVI ≥29 ml/m2 (≥34 ml/m2 if AF)
  • Lateral E/e' ≥9
  • LVMI ≥115 g/m2 If male or ≥95 g/m2 if female
  • LV wall thickness ≥12mm
• eGFR ≥30 ml/min/1.73m2 (CKD-EPI formula)
• Blood Potassium ≤5.5 mmol/L
• Not treated with MRAs and/or SGLT2i within the previous month before inclusion and have no history of diabetic ketoacidosis while in treatment with SGLT2 inhibitors
• Stable/chronic ambulatory patients i.e., patients without need for hospitalization within the last 30 days due to heart failure decompensation episodes

• If female, she must be a woman of non-childbearing potential. That is, she must be:

  • Surgically sterilized (e.g. underwent hysterectomy, bilateral salpingectomy or bilateral oophorectomy)
  • Clinically diagnosed infertile
  • In a post-menopausal state, defined as no menses for 12 months without an alternative medical cause.

• A female patient of childbearing potential must have a negative serum pregnancy test at Visit 1 (Day 0) and must agree to consistently and correctly use (from 28 days prior to first study treatment administration until at least 7 days after last study treatment administration) one of the following highly effective methods of contraception:

  • Abstinence of heterosexual intercourse (when this is in line with preferred and usual lifestyle of the subject)
  • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
  • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
  • Intrauterine device
  • Intrauterine hormone-releasing system
  • Bilateral tubal occlusion
  • Vasectomized partner, who has received medical assessment of the surgical success, or clinically diagnosed infertile partner

Exclusion Criteria:

• Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
• Participation in another clinical study with an investigational product during the last month
• Unwilling or unable to sign the informed consent form
• Surgical procedure, coronary, cerebral or peripheral vascular events or sepsis in the prior 90 days
• Cancer (life-limiting or less than 2 years in remission)
• Any previously confirmed autoimmune disease
• Type 1 Diabetes
• Severe hepatic impairment (Child-Pugh class C)
• Ability to walk is, in the investigator's opinion, clearly limited by joint disease or other locomotor problems or lung diseases rather than by cardiorespiratory fitness
• Previously confirmed cardiac amyloidosis
• Severe valvulopathy according to the echocardiogram report
• Patients with a known hypersensitivity or intolerance to spironolactone or dapagliflozin or any of the excipients of the products.
• Female patients currently pregnant (confirmed by a positive pregnancy test) or intent to become pregnant or breast feeding.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: [Dapagliflozin] - [Spironolactone] - [Dapagliflozin + Spironolactone]; Drug will be administered according to sequence: Dapagliflozin [week 1-12] - Spironolactone [week 17-28] - Dapagliflozin + Spironolactone [week 33-44]	Drug: Dapagliflozin; A: Dapagliflozin 10 mg once daily; Other Names: Forxiga(R); Drug: Spironolactone; B: Spironolactone 25 mg once daily (can be adjusted according to potassium and renal function); Other Names: Aldactone(R); Drug: Spironolactone + Dapagliflozin; C: Dapagliflozin 10 mg once daily plus Spironolactone 25 mg once daily (can be adjusted according to potassium and renal function); Other Names: Forxiga(R) + Aldactone(R)
Experimental: [Dapagliflozin] - [Dapagliflozin + Spironolactone] - [Spironolactone]; Drug will be administered according to sequence: Dapagliflozin [week 1-12] - Dapagliflozin + Spironolactone [week 17-28] - Spironolactone [week 33-44]	Drug: Dapagliflozin; A: Dapagliflozin 10 mg once daily; Other Names: Forxiga(R); Drug: Spironolactone; B: Spironolactone 25 mg once daily (can be adjusted according to potassium and renal function); Other Names: Aldactone(R); Drug: Spironolactone + Dapagliflozin; C: Dapagliflozin 10 mg once daily plus Spironolactone 25 mg once daily (can be adjusted according to potassium and renal function); Other Names: Forxiga(R) + Aldactone(R)
Experimental: [Spironolactone] - [Dapagliflozin] - [Dapagliflozin + Spironolactone]; Drug will be administered according to sequence: Spironolactone [week 1-12] - Dapagliflozin [week 17-28] - Dapagliflozin + Spironolactone [week 33-44]	Drug: Dapagliflozin; A: Dapagliflozin 10 mg once daily; Other Names: Forxiga(R); Drug: Spironolactone; B: Spironolactone 25 mg once daily (can be adjusted according to potassium and renal function); Other Names: Aldactone(R); Drug: Spironolactone + Dapagliflozin; C: Dapagliflozin 10 mg once daily plus Spironolactone 25 mg once daily (can be adjusted according to potassium and renal function); Other Names: Forxiga(R) + Aldactone(R)
Experimental: [Spironolactone] - [Dapagliflozin + Spironolactone] - [Dapagliflozin]; Drug will be administered according to sequence: Spironolactone [week 1-12] - Dapagliflozin + Spironolactone [week 17-28] - Dapagliflozin [week 33-44]	Drug: Dapagliflozin; A: Dapagliflozin 10 mg once daily; Other Names: Forxiga(R); Drug: Spironolactone; B: Spironolactone 25 mg once daily (can be adjusted according to potassium and renal function); Other Names: Aldactone(R); Drug: Spironolactone + Dapagliflozin; C: Dapagliflozin 10 mg once daily plus Spironolactone 25 mg once daily (can be adjusted according to potassium and renal function); Other Names: Forxiga(R) + Aldactone(R)
Experimental: [Dapagliflozin + Spironolactone] - [Spironolactone] - [Dapagliflozin]; Drug will be administered according to sequence: Dapagliflozin + Spironolactone [week 1-12] - Spironolactone [week 17-28] - Dapagliflozin [week 33-44]	Drug: Dapagliflozin; A: Dapagliflozin 10 mg once daily; Other Names: Forxiga(R); Drug: Spironolactone; B: Spironolactone 25 mg once daily (can be adjusted according to potassium and renal function); Other Names: Aldactone(R); Drug: Spironolactone + Dapagliflozin; C: Dapagliflozin 10 mg once daily plus Spironolactone 25 mg once daily (can be adjusted according to potassium and renal function); Other Names: Forxiga(R) + Aldactone(R)
Experimental: [Dapagliflozin + Spironolactone] - [Dapagliflozin] - [Spironolactone]; Drug will be administered according to sequence: Dapagliflozin + Spironolactone [week 1-12] - Dapagliflozin [week 17-28] - Spironolactone [week 33-44]	Drug: Dapagliflozin; A: Dapagliflozin 10 mg once daily; Other Names: Forxiga(R); Drug: Spironolactone; B: Spironolactone 25 mg once daily (can be adjusted according to potassium and renal function); Other Names: Aldactone(R); Drug: Spironolactone + Dapagliflozin; C: Dapagliflozin 10 mg once daily plus Spironolactone 25 mg once daily (can be adjusted according to potassium and renal function); Other Names: Forxiga(R) + Aldactone(R)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood levels of NT-pro BNP (Log transformed)	Comparison of NT-pro BNP levels between groups	month 3, month 7, month 11

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients reaching a 20% or greater reduction in NT-proBNP levels	Measured in blood samples	month 3, month 7, month 11
Circulating levels of PICP, PIIINP and CITP	Measured in blood samples the circulating levels of procollagen type I carboxy-terminal propeptide (PICP), N-terminal propeptide of procollagen type III (PIIINP), C-terminal telopeptide of collagen type I (CITP)	month 3, month 7, month 11
Indexed Left Atrial Volume (LAVi)	Transthoracic echocardiogram	month 3, month 7, month 11
Left Ventricular Ejection Fraction (LVEF)	Transthoracic echocardiogram	month 3, month 7, month 11
Lateral E/e	Transthoracic echocardiogram	month 3, month 7, month 11
Indexed Left Ventricular Mass (LVMi)	Transthoracic echocardiogram	month 3, month 7, month 11
Pulmonary Artery Systolic Pressure (PASP)	Transthoracic echocardiogram	month 3, month 7, month 11
Systolic and Diastolic Blood Pressure (SBP/DBP)	Measure in the clinical appointment after 5min of seated rest. Mean of 3 automatic oscillometric measurements	month 3, month 7, month 11
Estimated glomerular filtration rate (eGFR)	Calculated from the serum creatinine using the 2021 CKD-EPI creatinine-based formula	month 3, month 7, month 11
Microalbuminuria (log-transformed)	Spot urine	month 3, month 7, month 11
Urinary sodium/natriuresis	Spot urine	month 3, month 7, month 11
Serum potassium (K+)	Concentration of potassium in the blood	month 3, month 7, month 11
Health-related quality of life (HR-QoL)	HR-QoL assessed by the Kansas City Cardiomyopathy Questionnaire a 23-item instrument. All items are measured on a Likert scale with 5-7 response options. KCCQ scores are scaled from 0 to 100 and summarized in 25-point ranges, where scores represent health status as follows: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent	month 3, month 7, month 11

Collaborators and Investigators

• Sponsor: Universidade do Porto
• Collaborators: Centro Hospitalar de Vila Nova de Gaia/Espinho, E.P.E.; Centro Hospitalar Universitário de São João, E.P.E.; Faculty of Medicine (FMUP)
• Investigators: Study Director: Adelino Leite-Moreira, MD, PhD, Faculty of Medicine (FMUP)

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2022
• Primary Completion (Estimated): September 15, 2024
• Study Completion (Estimated): December 15, 2024

Study Registration Dates

• First Submitted: December 6, 2022
• First Submitted That Met QC Criteria: January 4, 2023
• First Posted (Actual): January 9, 2023

Study Record Updates

• Last Update Posted (Actual): October 19, 2023
• Last Update Submitted That Met QC Criteria: October 18, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Sodium-Glucose Transporter 2 Inhibitors; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Dapagliflozin; Spironolactone
• Other Study ID Numbers: SOGALDI-PEF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No