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

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.

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.

Study Overview

• Status: Terminated
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Spironolactone; Drug: AZD9977

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 1

Contacts and Locations

Study Locations

• Bulgaria
  • Plovdiv, Bulgaria, 4002
    • Research Site
  • Sofia, Bulgaria, 1784
    • Research Site
  • Sofia, Bulgaria, 1309
    • Research Site
• Czechia
  • Brandys nad Labem, Czechia, 250 01
    • Research Site
  • Ceska Lipa, Czechia, 470 77
    • Research Site
  • Jaromer, Czechia, 551 01
    • Research Site
  • Louny, Czechia, 440 01
    • Research Site
  • Pardubice, Czechia, 530 02
    • Research Site
  • Praha, Czechia, 140 59
    • Research Site
  • Praha, Czechia, 130 00
    • Research Site
• Poland
  • Katowice, Poland, 40-081
    • Research Site
  • Kraków, Poland, 31-202
    • Research Site
  • Legnica, Poland, 59-220
    • Research Site
  • Warszawa, Poland, 02-097
    • Research Site
  • Wrocław, Poland, 50-981
    • Research Site
• United Kingdom
  • Hull, United Kingdom, HU3 2JZ
    • Research Site
  • Leicester, United Kingdom, LE3 9PQ
    • Research Site
  • Sheffield, United Kingdom, S5 7AU
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Spironolactone; Spironolactone treatment for 28 days	Drug: Spironolactone; Spironolactone tablets taken orally for 28 days.
EXPERIMENTAL: AZD9977; AZD9977 treatment for 28 days	Drug: AZD9977; AZD9977 capsules taken orally for 28 days.

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 1, 2018
• Primary Completion (ACTUAL): March 31, 2020
• Study Completion (ACTUAL): March 31, 2020

Study Registration Dates

• First Submitted: September 21, 2018
• First Submitted That Met QC Criteria: September 21, 2018
• First Posted (ACTUAL): September 24, 2018

Study Record Updates

• Last Update Posted (ACTUAL): May 1, 2020
• Last Update Submitted That Met QC Criteria: April 30, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Heart failure.; Oral selective mineralocorticoid receptor modulator.; Heart failure with preserved ejection fraction (HFpEF).
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: D6401C00004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No