Study in HFpEF Patients to Compare the Effect of AZD9977 and Spironolactone on Serum Potassium

Study Overview
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Brief Summary
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This is a Phase I, Multicentre study to Compare the Effect of AZD9977 and Spironolactone on Serum Potassium [sK+] during 28 days in Patients with HFmrEF or HFpEF and eGFR in the range of ≥40 and ≤70 mL/min/1.73m2.

Official Title
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A Phase I, Open Label, Randomized, Parallel Group, Multicentre Study to Compare the Effect of AZD9977 and Spironolactone on Serum Potassium [sK+] During 28 Days in Patients With HFmrEF or HFpEF and eGFR in the Range of ≥40 and ≤70 mL/Min/1.73m2.

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: AZD9977
* Drug: Spironolactone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Symptoms and signs consistent with a diagnosis of heart failure (HF) Left ventricular ejection fraction (LVEF) ≥40% by transthoracic echocardiography within the past 12 months Plasma NT-proBNP level ≥125 pg/ml (≥ 600pg/mL if patient has persistent or permanent atrial fibrillation, atrial flutter, or atrial tachycardia) Estimated glomerular filtration rate (eGFR) ≥40 and ≤70ml/min/1.73m2 (by CKD-EPI formula). Baseline serum potassium (sK+) level ≥3.5 and ≤4.8mmol/l. Stable doses of the following medications at baseline for at least 4 weeks prior to randomisation: Angiotensin receptor blocker (ARB) or Angiotensin converting enzyme inhibitor (ACEi) Loop diuretic (up to a 120mg furosemide dose or equivalent Exclusion Criteria: Patients with documented LVEF <40% at any time (i.e. patients with previously impaired LVEF that has now improved are not permitted). Patients experiencing acute decompensation of heart failure requiring hospital admission or escalation in therapy. Primary cardiomyopathy (e.g. constrictive, restrictive, infiltrative, toxic, hypertrophic, congenital or any primary cardiomyopathy in judgment of Investigator). Hyponatraemia, defined as serum Na+ <135 mmol/L at the time of enrollment. Persistent resting sinus tachycardia >110 bpm or sinus bradycardia <45bpm. Systolic blood pressure (BP) <110mmHg or >180mmHg. Diastolic BP <60 mmHg or >100 mmHg. Patients previously intolerant to MRA (e.g. spironolactone or eplerenone) for any reason. Medical conditions associated with development of hyperkalaemia (e.g. Addison's disease). Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.0 times the upper limit of normal (ULN). Patients who have been taking an MR antagonist within 1 month prior to randomization.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Spironolactone<br>Spironolactone treatment for 28 days | Drug: Spironolactone<br>* Spironolactone tablets taken orally for 28 days.<br>|
| Experimental: AZD9977<br>AZD9977 treatment for 28 days | Drug: AZD9977<br>* AZD9977 capsules taken orally for 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative change (%) from baseline in serum potassium | To compare the effect of AZD9977 with spironolactone on serum potassium (sK+) | Measurements on day 1, 7, 14, 21 and 28 will be used. The primary comparison between Spironolactone and AZD9977 will be done at day 28. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma trough concentrations (Ctrough) values of spironolactone and AZD9977 | To evaluate the pharmacokinetics (PK) of AZD9977 and spironolactone | PK samples will be taken (within 60 min prior to dose) at day 1, 7, 14, 21 and 28. | 
| Relative change (%) from baseline in serum potassium | To compare the effects of AZD9977 with spironolactone on serum potassium at Day 14. | Measurements on day 1, 7 and 14 will be used. The primary comparison between Spironolactone and AZD9977 will be done at day 14. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure., Oral selective mineralocorticoid receptor modulator., Heart failure with preserved ejection fraction (HFpEF).