Dapagliflozin, Spironolactone or Both for HFpEF

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Spironolactone
* Drug: Spironolactone + Dapagliflozin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Prospective, randomised, open-label, three-treatment, three-period, cross-over trial with a factorial design
Masking: Single


Arms and Interventions

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

What is the study measuring?
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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 |