Heart Failure
Conditions
Keywords
Heart Failure, Ejection Fraction, Preserved, Myeloperoxidase Inhibitor, Exercise
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.
Interventions
DRUGAZD4831 Oral Myeloperoxidase Inhibitor
A single administration dose of 30 mg oral MPO inhibitor given orally following baseline, resting and exercise testing in patients during right heart catheterization.
DRUGPlacebo oral capsule
A single administration dose of 30 mg placebo given orally following baseline, resting and exercise testing in patients during right heart catheterization.
Sponsors
National Center for Advancing Translational Sciences (NCATS)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Only research pharmacy staff will be aware of randomization scheme and all study personnel and subjects will remain blinded.
Intervention model description
Single Administration of study drug
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males and females of non-childbearing potential 2. Age ≥ 30 years 3. Symptoms of dyspnea (II-IV) at the time of screening 4. Ejection Fraction (EF) ≥ 50% as determined on imaging study within 12 months of enrollment 5. Catheterization documented elevated filling pressures at rest (PCWP ≥15) or with exercise (PCWP ≥25)
Exclusion criteria
1. Use of nitrates, phosphodiesterase 5 inhibitors or other NO-providing therapy in the past 24 hours of screening 2. Significant valvular disease (\>moderate left-sided regurgitation, \>mild stenosis) 3. Requirement of intravenous heparin at the start of case 4. Severe pulmonary parenchymal disease 5. Acute coronary syndrome or coronary disease requiring revascularization in the judgement of investigators 6. Resting systolic blood pressure \< 100 mmHg 7. Constrictive pericarditis 8. Infiltrative, restrictive, or hypertrophic obstructive cardiomyopathies 9. Previous anaphylaxis to any drug 10. Pregnancy or breastfeeding mothers 11. High Output heart failure 12. Active thyroid disease 13. Treatment with a new chemical entity (defined as a compound which has not been approved for marketing) within the preceding 3 months 14. Patients with any prior allergy to propylthiouracil
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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. |
| 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 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AZD4831 Oral Myeloperoxidase Inhibitor Patient may take 30 mg of oral myeloperoxidase inhibitor following baseline right heart catheterization.
AZD4831 Oral Myeloperoxidase Inhibitor: A single administration dose of 30 mg oral MPO inhibitor given orally following baseline, resting and exercise testing in patients during right heart catheterization. | 15 |
| Placebo Patient may take 30 mg of placebo oral capsule following baseline right heart catheterization.
Placebo oral capsule: A single administration dose of 30 mg placebo given orally following baseline, resting and exercise testing in patients during right heart catheterization. | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | AZD4831 Oral Myeloperoxidase Inhibitor | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 70 years STANDARD_DEVIATION 12 | 70 years STANDARD_DEVIATION 9 | 70 years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 30 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 30 Participants | 15 Participants |
| Region of Enrollment United States | 15 participants | 30 participants | 15 participants |
| Sex: Female, Male Female | 5 Participants | 11 Participants | 6 Participants |
| Sex: Female, Male Male | 10 Participants | 19 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 2 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 1 / 15 |
Outcome results
Primary
Change in Exercise Pulmonary Capillary Wedge Pressure (PCWP)
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.
Time frame: Baseline, approximately 30 minutes after study drug administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD4831 Oral Myeloperoxidase Inhibitor | Change in Exercise Pulmonary Capillary Wedge Pressure (PCWP) | -1 mmHg | Standard Deviation 3 |
| Placebo | Change in Exercise Pulmonary Capillary Wedge Pressure (PCWP) | -4 mmHg | Standard Deviation 5 |
p-value: 0.04ANCOVA
Primary
Exercise Pulmonary Capillary Wedge Pressure (PCWP)
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.
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD4831 Oral Myeloperoxidase Inhibitor | Exercise Pulmonary Capillary Wedge Pressure (PCWP) | 31 mmHg | Standard Deviation 6 |
| Placebo | Exercise Pulmonary Capillary Wedge Pressure (PCWP) | 32 mmHg | Standard Deviation 7 |
Secondary
Change in Exercise Central Pressures
Exercise values after receiving study drug minus exercise values before study drug, obtained at 20 Watt workload, measured in mmHg.
Time frame: Baseline, approximately 30 minutes after study drug administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD4831 Oral Myeloperoxidase Inhibitor | Change in Exercise Central Pressures | Pulmonary artery systolic pressure | -2 mmHg | Standard Deviation 5 |
| AZD4831 Oral Myeloperoxidase Inhibitor | Change in Exercise Central Pressures | Mean pulmonary artery pressure | -1 mmHg | Standard Deviation 4 |
| AZD4831 Oral Myeloperoxidase Inhibitor | Change in Exercise Central Pressures | Right atrial pressure | 0 mmHg | Standard Deviation 3 |
| Placebo | Change in Exercise Central Pressures | Pulmonary artery systolic pressure | -4 mmHg | Standard Deviation 5 |
| Placebo | Change in Exercise Central Pressures | Mean pulmonary artery pressure | -4 mmHg | Standard Deviation 5 |
| Placebo | Change in Exercise Central Pressures | Right atrial pressure | 0 mmHg | Standard Deviation 2 |
Comparison: Right atrial pressurep-value: 0.805t-test, 2 sided
Comparison: pulmonary artery systolic pressurep-value: 0.148t-test, 2 sided
Comparison: Mean pulmonary artery pressurep-value: 0.09t-test, 2 sided
Secondary
Change in Exercise Transmyocardial Lactate Ratio
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.
Time frame: Baseline, approximately 30 minutes after drug administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD4831 Oral Myeloperoxidase Inhibitor | Change in Exercise Transmyocardial Lactate Ratio | 0.05 ratio | Standard Deviation 0.17 |
| Placebo | Change in Exercise Transmyocardial Lactate Ratio | -0.01 ratio | Standard Deviation 0.15 |
p-value: 0.418t-test, 2 sided
Secondary
Change in Resting Central Pressures
Resting values after receiving study drug minus resting values before study drug, measured in mmHg.
Time frame: Baseline, approximately 30 minutes after study drug administration
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD4831 Oral Myeloperoxidase Inhibitor | Change in Resting Central Pressures | Right atrial pressure | 0 mmHg | Standard Deviation 2 |
| AZD4831 Oral Myeloperoxidase Inhibitor | Change in Resting Central Pressures | Pulmonary artery systolic pressure | -3 mmHg | Standard Deviation 5 |
| AZD4831 Oral Myeloperoxidase Inhibitor | Change in Resting Central Pressures | Mean pulmonary artery pressure | -1 mmHg | Standard Deviation 3 |
| Placebo | Change in Resting Central Pressures | Right atrial pressure | 0 mmHg | Standard Deviation 1 |
| Placebo | Change in Resting Central Pressures | Pulmonary artery systolic pressure | -3 mmHg | Standard Deviation 5 |
| Placebo | Change in Resting Central Pressures | Mean pulmonary artery pressure | -2 mmHg | Standard Deviation 3 |
Comparison: Right atrial pressurep-value: 0.786t-test, 2 sided
Comparison: Pulmonary artery systolic pressurep-value: 0.796t-test, 2 sided
Comparison: Mean pulmonary artery pressurep-value: 0.703t-test, 2 sided
Secondary
Change in Resting Pulmonary Capillary Wedge Pressure (PCWP)
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.
Time frame: Baseline, approximately 30 minutes after study drug administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD4831 Oral Myeloperoxidase Inhibitor | Change in Resting Pulmonary Capillary Wedge Pressure (PCWP) | -2 mmHg | Standard Deviation 3 |
| Placebo | Change in Resting Pulmonary Capillary Wedge Pressure (PCWP) | -2 mmHg | Standard Deviation 2 |
p-value: 0.777t-test, 2 sided
Secondary
Change in Resting Transmyocardial Lactate Ratio
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.
Time frame: Baseline, approximately 30 minutes after drug administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD4831 Oral Myeloperoxidase Inhibitor | Change in Resting Transmyocardial Lactate Ratio | 0.16 ratio | Standard Deviation 0.49 |
| Placebo | Change in Resting Transmyocardial Lactate Ratio | 0.10 ratio | Standard Deviation 0.23 |
p-value: 0.669t-test, 2 sided