Myeloperoxidase (MPO) Inhibitor A_Zeneca for Heart Failure With Preserved Ejection Fraction (HFpEF)

Phase 1

Completed

Conditions: Heart Failure

Interventions: Drug: Placebo oral capsule
Drug: AZD4831 Oral Myeloperoxidase Inhibitor

Registration Number: NCT03611153

Lead Sponsor: Mayo Clinic

Brief Summary: Researchers are studying the effect of a single dose of oral myeloperoxidase on heart failure versus placebo.

Detailed Description: Enroll subjects with a normal ejection fraction referred to the catheterization laboratory for evaluation of breathlessness or shortness of breath. Perform safety lab sampling, echocardiography, arterial tonometry for pulse wave analysis, and assessment of endothelial function prior to administration of study drug. During the catheterization researchers will perform blood draws, assess baseline exercise capacity at rest and during exercise. Researchers will also do an echocardiogram to take measurements of the heart. Subjects will be randomized to one of two groups, Oral Myeloperoxidase Inhibitor or placebo group. Study drug or placebo will be administered followed by a repeat of the baseline catheterization assessments. At the conclusion of the second exercise test the subject will be moved to a room and monitored overnight for safety. Repeat blood draws, echocardiogram, endothelial function test, and heart monitoring will be completed. The subject will be asked to follow up with the researchers between 9-14 days after the study drug dosage. The subjects history and blood work will be completed at that visit.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

Inclusion Criteria

Males and females of non-childbearing potential
Age ≥ 30 years
Symptoms of dyspnea (II-IV) at the time of screening
Ejection Fraction (EF) ≥ 50% as determined on imaging study within 12 months of enrollment
Catheterization documented elevated filling pressures at rest (PCWP ≥15) or with exercise (PCWP ≥25)

Exclusion Criteria

Use of nitrates, phosphodiesterase 5 inhibitors or other NO-providing therapy in the past 24 hours of screening
Significant valvular disease (>moderate left-sided regurgitation, >mild stenosis)
Requirement of intravenous heparin at the start of case
Severe pulmonary parenchymal disease
Acute coronary syndrome or coronary disease requiring revascularization in the judgement of investigators
Resting systolic blood pressure < 100 mmHg
Constrictive pericarditis
Infiltrative, restrictive, or hypertrophic obstructive cardiomyopathies
Previous anaphylaxis to any drug
Pregnancy or breastfeeding mothers
High Output heart failure
Active thyroid disease
Treatment with a new chemical entity (defined as a compound which has not been approved for marketing) within the preceding 3 months
Patients with any prior allergy to propylthiouracil

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo oral capsule	Patient may take 30 mg of placebo oral capsule following baseline right heart catheterization.
AZD4831 Oral myeloperoxidase inhibitor	AZD4831 Oral Myeloperoxidase Inhibitor	Patient may take 30 mg of oral myeloperoxidase inhibitor following baseline right heart catheterization.

Primary Outcome Measures

Name	Time	Method
Change in Exercise Pulmonary Capillary Wedge Pressure (PCWP)	Baseline, approximately 30 minutes after study drug administration	Pulmonary capillary wedge pressure (PCWP) provides an indirect estimate of left atrial pressure (LAP). PCWP is the pressure measured by wedging a pulmonary catheter with an inflated balloon into a small pulmonary arterial branch. The exercise PCWP values are obtained at 20 Watt workload, measured in mmHg.
Exercise Pulmonary Capillary Wedge Pressure (PCWP)	Baseline	Pulmonary capillary wedge pressure (PCWP) provides an indirect estimate of left atrial pressure (LAP). PCWP is the pressure measured by wedging a pulmonary catheter with an inflated balloon into a small pulmonary arterial branch. The exercise PCWP values are obtained at 20 Watt workload, measured in mmHg.

Secondary Outcome Measures

Name	Time	Method
Change in Resting Pulmonary Capillary Wedge Pressure (PCWP)	Baseline, approximately 30 minutes after study drug administration	Pulmonary capillary wedge pressure (PCWP) provides an indirect estimate of left atrial pressure (LAP). PCWP is the pressure measured by wedging a pulmonary catheter with an inflated balloon into a small pulmonary arterial branch while in resting state, measured in mmHg.
Change in Exercise Central Pressures	Baseline, approximately 30 minutes after study drug administration	Exercise values after receiving study drug minus exercise values before study drug, obtained at 20 Watt workload, measured in mmHg.
Change in Resting Central Pressures	Baseline, approximately 30 minutes after study drug administration	Resting values after receiving study drug minus resting values before study drug, measured in mmHg.
Change in Exercise Transmyocardial Lactate Ratio	Baseline, approximately 30 minutes after drug administration	Obtained at 20 Watt workload, determined by the lactate extraction ratio, which is calculated as lactate arterial minus lactate coronary sinus (CS) divided by lactate arterial. Negative values are indicative of myocardial ischemia.
Change in Resting Transmyocardial Lactate Ratio	Baseline, approximately 30 minutes after drug administration	Obtained during resting state, determined by the lactate extraction ratio, which is calculated as lactate arterial minus lactate coronary sinus (CS) divided by lactate arterial. Negative values are indicative of myocardial ischemia.