Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000817448p
Ethics application status
Submitted, not yet approved
Date submitted
1/07/2025
Date registered
30/07/2025
Date last updated
30/07/2025
Date data sharing statement initially provided
30/07/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Guanethidine for Pulmonary Hypertension with Heart Failure with a Preserved Ejection Fraction (PH-HFpEF)
Scientific title
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)
Secondary ID [1] 314788 0
M2SP-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure with a Preserved Ejection Fraction 338023 0
Condition category
Condition code
Cardiovascular 334335 334335 0 0
Other cardiovascular diseases
Respiratory 334400 334400 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 331388 0
Treatment: Drugs
Comparator / control treatment
NIL
Control group
Uncontrolled

Outcomes
Primary outcome [1] 342017 0
Changes in resting and exercise induced elevations in central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) in patients with PH-HFpEF. This will be assessed as a composite outcome.
Timepoint [1] 342017 0
Baseline and 2 weeks after maximally tolerated daily guanethidine administration.
Secondary outcome [1] 449323 0
Overall subjective health status measured using the Patient Global Assessment (PGA)
Timepoint [1] 449323 0
At the date of the initial right heart catheterization and 2 weeks after initiating guanethidine.
Secondary outcome [2] 449324 0
Impact of heart failure on Quality of Life measured using Kansas City Cardiomyopathy Questionnaire (KCCQ)
Timepoint [2] 449324 0
KCCQ will be assessed at screening, on the day of the RHC and 2 weeks after starting guanethidine.
Secondary outcome [3] 449540 0
The rate of DLTs
Timepoint [3] 449540 0
Throughout the study period
Secondary outcome [4] 449542 0
Incidence of symptomatic orthostatic hypotension
Timepoint [4] 449542 0
Every two weeks during the entire study
Secondary outcome [5] 449543 0
Incidence of change of worsening estimated Glomerular Filtration Rate (eGFR) >30%
Timepoint [5] 449543 0
Screening, at the time of initial RHC and at the time of repeating RHC

Eligibility
Key inclusion criteria
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
Minimum age
41 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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..

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/10/2025
Actual
Date of last participant enrolment
Anticipated
31/12/2026
Actual
Date of last data collection
Anticipated
1/09/2027
Actual
Sample size
Target
15
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 28163 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 44375 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 319343 0
Other Collaborative groups
Name [1] 319343 0
M2SP LLC
Country [1] 319343 0
United States of America
Primary sponsor type
Hospital
Name
Alfred Health
Address
Country
Australia
Secondary sponsor category [1] 321828 0
None
Name [1] 321828 0
Address [1] 321828 0
Country [1] 321828 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 317924 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 317924 0
Ethics committee country [1] 317924 0
Australia
Date submitted for ethics approval [1] 317924 0
23/06/2025
Approval date [1] 317924 0
Ethics approval number [1] 317924 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 142574 0
Prof David Kaye
Address 142574 0
Cardiology Dept, The Alfred, 55 Commercial Road, Melbourne, Victoria 3004
Country 142574 0
Australia
Phone 142574 0
+61 03 9076 2157
Fax 142574 0
Email 142574 0
[email protected]
Contact person for public queries
Name 142575 0
Julia Ma
Address 142575 0
Cardiology Dept, The Alfred, 55 Commercial Road, Melbourne, Victoria 3004
Country 142575 0
Australia
Phone 142575 0
+61 03 9076 2000
Fax 142575 0
Email 142575 0
[email protected]
Contact person for scientific queries
Name 142576 0
Prof David Kaye
Address 142576 0
Cardiology Dept, The Alfred, 55 Commercial Road, Melbourne, Victoria 3004
Country 142576 0
Australia
Phone 142576 0
+61 03 9076 2000
Fax 142576 0
Email 142576 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No
No IPD sharing reason/comment: NA



What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.