Not Yet RecruitingPhase 1ACTRN12625000817448

Guanethidine for Pulmonary Hypertension with Heart Failure with a Preserved Ejection Fraction (PH-HFpEF)

Effect of Guanethidine on Central Venous Pressure (CVP) and Pulmonary Capillary Wedge Pressure for Pulmonary Hypertension with Heart Failure with a Preserved Ejection Fraction (PH-HFpEF)

Sponsor

Alfred Health

Enrollment

15 participants

Start Date

Oct 1, 2025

Study Type

Interventional

Conditions

Heart Failure with a Preserved Ejection Fraction

Summary

This is an open label, short term, ascending multiple dose study to investigate the safety, tolerability, and efficacy of guanethidine in patients with pulmonary hypertension heart failure and a preserved ejection fraction (PH-HFpEF). The primary objective of this study is to determine if guanethidine can reduce exercise-induced increases of central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) in patients with PH-HFpEF. The secondary objectives of this study are to: • Evaluate the safety and tolerability of guanethidine in patients with PH-HFpEF. • Determine the optimal dose for phase II-III trials of guanethidine in PH-HFpEF. Up to 15 patients will be enrolled in this study. The duration of individual patient participation will be a maximum of 5 months, including up to a 4-week screening period, up to 3 months of daily administration of guanethidine after the initial catheterization, and telephone follow-up contact 4 weeks after the second catheterization and discontinuation of guanethidine. Eligible participants will be administered escalating doses of guanethidine daily, starting at 5 mg/day. Drug dose will be increased every 2 weeks as tolerated by orthostatic blood pressure evaluations, symptomatic orthostasis, a blood pressure not less than 120 mmHg or dose limiting toxicity (DLT), sequentially, to 10, 15 and 25 mg/day. If a dose is not tolerated, it will be decreased to the prior tolerated dose. A repeat exercise hemodynamic assessment will be performed on the final tolerated dose of guanethidine (up to 25 mg daily) which has been administered for at least 2 weeks.

Eligibility

Sex: Both males and femalesMin Age: 41 Yearss

Inclusion Criteria10

o Age over 40 years of age male or female
o Chronic heart failure defined as:
a. Signs or symptoms of HF requiring current treatment with diuretics for over 30 days, AND
b. NYHA class II or III in the past year and at screening AND
c. Ongoing stable guideline directed medical therapy (GDMT) for HF (unless unable to tolerate GDMT) and
management of potential comorbidities according to the 2022 American College of Cardiology (ACC) /American Heart Association (AHA) Guideline for the Management of Heart Failure, with no significant changes [ over 100% increase or 50% decrease] for a minimum of 1 month prior to screening, that is expected to be maintained without change for at least 1 month.
o Left Ventricular Ejection Fraction (LVEF) greater than or equal to 45% within the past 6 months.
o Site determined elevated PCWP documented resting mean pulmonary artery (PA) pressure over than 25 mm Hg by right heart catheterization with end expiratory PCWP greater than or equal to 25 mmHg during supine ergometer exercise on the day of the Index procedure with a pulmonary vascular resistance (PVR) less than 3 woods units.
o The subject is willing and able to provide appropriate study-specific informed consent, follow protocol procedures, and comply with follow-up visit requirements.
o Able to complete greater than or equal to 150 metres on the 6 Minute Walk Test at screening

Exclusion Criteria27

o Systolic BP < 125 mmHg or > 170 mmHg despite appropriate medical management.
o Symptomatic orthostatic hypotension or orthostatic hypotension requiring treatment (orthostatic hypotension is defined as a systolic blood pressure decrease of >20mmHg and/or increase in heart rate >20 bpm upon going from supine to standing position).
o Myocardial infarction (MI) (type I) and/or percutaneous cardiac intervention (PCI) within 3 months prior to screening; Coronary Artery Bypass Graft Surgery (CABG) in past 3 months prior to screening, or current indication for coronary revascularization.
o Patients with previously low and recovered ejection fraction.
o Advanced heart failure defined as one or more of the below:
o ACC/AHA/ European Society of Cardiology (ESC) Stage D heart failure, non-ambulatory NYHA Class IV HF
o Cardiac index < 2.0 L/min/m2
o Inotropic infusion (continuous or intermittent) within 6 months prior to screening
o Subject is on the cardiac transplant waiting list.
o BMI > 40 kg/m2
o Use of Monoamine oxidase (MAO) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, tricyclic antidepressants, bretylium, methamphetamines, prochlorperazine, haloperidol, ephedrine, dextroamphetamine, midodrine and selective serotonin reuptake inhibitors
o Daily dose of loop diuretics in furosemide equivalents is >120 mg/day and subjects is on concomitant thiazide diuretics
o Admission for HF within the 30 days prior to baseline cardiac catheterization.
o Arterial oxygen saturation < 92 % on room air.
o Presence of significant valve disease including:
o Greater than mild mitral valve stenosis.
o Greater than moderate mitral valve regurgitation.
o Greater than moderate to severe tricuspid valve regurgitation.
o Greater than mild aortic valve disease.
o Hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, cardiac amyloidosis, or other infiltrative cardiomyopathy (e.g., hemochromatosis, sarcoidosis)
o History of liver cirrhosis.
o Dialysis dependent; or estimated Glomerular Filtration Rate (GFR) 100 beats per minute.
o Chronic pulmonary disease requiring continuous home oxygen OR hospitalization for exacerbation (including intubation) in the 12 months before study entry OR known history of Global Initiative for Chronic Obstructive Lung Disease (GOLD) Class III or higher Chronic Obstructive Pulmonary Disease (COPD).
o Participating in another investigational drug or device study within 30 days of the screening visit.
o Life expectancy <12 months for non-cardiovascular reasons.
o Any condition, or history of illness or surgery that, in the opinion of the Investigator, might confound the results of the study or pose additional risks to the patient.
o Females who are pregnant or lactating or planning to become pregnant during the next six months..

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Interventions

Eligible participants will be administered escalating doses of guanethidine daily, starting at 5 mg/day. Drug dose will be increased every 2 weeks as tolerated by orthostatic blood pressure evaluations, symptomatic orthostasis, a blood pressure not less than 120 mmHg or dose limiting toxicity (DLT), sequentially, to 10, 15 and 25 mg/day. If a dose is not tolerated, it will be decreased to the prior tolerated dose. The Investigational Medicinal Product (IMP) accountability will be achieved by patient returning IMP to site on each visit and IMP count will be completed by the research team to monitor compliance throughout the trial. Clinical laboratory tests will be completed at certain time points as per protocol. Mode of administration is oral tablet. Duration of the administration can be up to 3 months for each participant. Total duration of the study period will be 2 years. Qualified cardiologists and delegated study investigators will perform right heart catheterisation (RHC): Frist RHC will be performed on Day 0 before the first dose of the guanethidine administration, and the second RHC will be performed 2 weeks after the maximally tolerated guanethidine administration. RHC will be performed in the supine position with a pulmonary artery catheter inserted percutaneously under fluoroscopic and/or ultrasound guidance into the internal jugular. In brief, patients will have 2 min of rest followed by leg raised for 2 min and then 2 min of unloaded cycling at 40 to 60 revolutions per minute. Work rate will then be increased continuously using a ramp protocol at 20, 40, 60 (and higher in 20W increments) until peak exercise is achieved as evident by a peak heart rate of > 85% predicted. Pulmonary and systemic hemodynamics will be monitored continuously and simultaneously during exercise. Pulmonary pressures will be recorded at the end of passive exhalation.

Locations(1)

The Alfred - Melbourne

VIC, Australia

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ACTRN12625000817448