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Trial registered on ANZCTR


Registration number
ACTRN12622000494730
Ethics application status
Approved
Date submitted
18/03/2022
Date registered
28/03/2022
Date last updated
7/04/2024
Date data sharing statement initially provided
28/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Exertional breathlessness in pulmonary arterial hypertension
Scientific title
Exertional dyspnoea and exercise intolerance in pulmonary arterial hypertension: the role of pulmonary baroreceptors (sub-study two)
Secondary ID [1] 306715 0
None
Universal Trial Number (UTN)
U1111-1275-6386
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary arterial hypertension 325691 0
Condition category
Condition code
Cardiovascular 323040 323040 0 0
Other cardiovascular diseases
Respiratory 323041 323041 0 0
Other respiratory disorders / diseases
Cardiovascular 323145 323145 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The central hypothesis of this study is that aberrant activation of skeletal muscle afferents, pulmonary baroreceptors and/or peripheral chemoreceptors drive exertional dyspnoea and limits exercise capacity in patients with pulmonary arterial hypertension (PAH). This is tested through 3 inter-related sub-studies.

This sub-study (sub-study two) tests the specific hypothesis that altered pulmonary baroreceptor responses drives excess sympathetic nervous system activation leading to exertional dyspnoea and limited exercise capacity in patients with PAH.

Data will be collected in the Human Cardiorespiratory Physiology Laboratory, Department of Respiratory Physiology, Auckland City Hospital, Auckland District Health Board. Each study visit will occur in the presence of the chief investigator Dr Michael Plunkett, a qualified Respiratory Physician, and experienced in management of medical emergencies, having completed Advanced Cardiac Life Support (ACLS) certification, and having prior work experience in Intensive Care Medicine.

This study will consist of two visits to the study laboratory.
1. an initial familiarisation visit (~60 min) where an investigator will explain the nature of the procedures, answer any questions and obtain written informed consent form (as described above). Once consent has been obtained, a review of the participant’s electronic medical records will be conducted and thorough medical history and clinical assessment (Health Screening Questionnaire attached) will be performed to assess inclusion/exclusion criteria. Provided the inclusion criteria are met and there are no exclusion criteria, the participant will be enrolled into the study. Anthropometric (height, weight) resting oxygen saturation measurements will be undertaken. Questionnaires will be used to assess activity-related dyspnoea (Modified Medical Research Council Dyspnoea Scale), health related quality of life (emPHasis-10), and anxiety and depression (Hospital Anxiety and Depression Scale). The participant’s most recent pulmonary function tests (spirometric volumes, static volumes and test of gas transfer) will be collected from the participant’s electronic medical records. Baseline spirometry will then performed (participants will breathe in and out through a handheld spirometer for approximately 10 seconds while wearing a nose clip), according to established guidelines. Participant will be familiarised with the study procedure (all measuring instruments will be attached except for microneurography probes, and the investigator will explain the experiment process). Participants will perform a 6 minute walk test.

At one laboratory visit (~3.5 hours), the participant will be asked to lie in a semi-recumbent position on a bed and be instrumented for the measurement of heart rate, BP, ventilation, and sympathetic nerve activity recordings. To measure sympathetic nerve activity, microneurogaphy will be performed, involving the insertion of a small, sterile wire (unipolar tungsten microelectrode, tip measuring 1-5um). The participant will then lie supine towards a slightly lateral decubitus position (to facilitate echocardiogram). During a rest period of 15 minutes, echocardiogram will be performed for baseline measurement of PASP and cardiac output (CO). The participant will inhale nebulised normal saline (control) and then nebulised iloprost (5µg) in order to reduce blood pressure in the pulmonary arteries. The participant will be blinded as to the order. Iloprost is a prostacyclin derivative and acts as a selective pulmonary vasodilator. It is routinely used in the treatment of PAH, and also in clinical practice during acute vasoreactivity testing. It has a favourable safety profile. Compared to inhaled nitric oxide (another pulmonary vasodilator), iloprost leads to greater reduction in pulmonary pressures in PAH, is simpler to administer, and is more routinely used in clinical settings.

Participants will inhale normal saline (NaCl 0.9%) via nebuliser (over ~ 10 minutes) as a control. 15 minutes following completion of normal saline nebulisation, echocardiogram will be performed to assess PASP and CO. Following a rest period of ~20 minutes, participants will inhale iloprost, 5µg via nebuliser (over ~ 10 minutes) to vasodilate the pulmonary circulation. 15 minutes following completion of iloprost nebulisation, echocardiogram will be performed to assess PASP and CO. The participant will remain until 60 minutes post end of nebulisation of iloprost for monitoring.

Adherence to the protocol and intervention will be ensured as each study visit takes place in the presence of, and is supervised by the chief investigator.
Intervention code [1] 323165 0
Early detection / Screening
Comparator / control treatment
The control group will be inhalation of nebulised saline (as above).
Control group
Placebo

Outcomes
Primary outcome [1] 330805 0
Muscle sympathetic nerve activity as assessed by microneurography at the peroneal nerve
Timepoint [1] 330805 0
Assessed at specific time points during the experimental session
- at rest
- following inhalation of iloprost or control, until 30 minutes.
Primary outcome [2] 330806 0
Dyspnoea intensity as assessed using the modified Borg Scale
Timepoint [2] 330806 0
At end of 6 minute walk test during familiarisation visit
Secondary outcome [1] 407625 0
Minute ventilation measured using an oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
Timepoint [1] 407625 0
Breath-by-breath measurements during the trials
Secondary outcome [2] 407626 0
Respiratory rate measured using a oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
Timepoint [2] 407626 0
Breath-by-breath measurements during both control and intervention trials
Secondary outcome [3] 407627 0
Heart rate measured using an electrocardiogram (3-lead)
Timepoint [3] 407627 0
beat-by-beat measurements during both control and intervention trials
Secondary outcome [4] 407628 0
Oxyhaemoglobin saturation using finger oximeter
Timepoint [4] 407628 0
Continuous measurements during both control and intervention trials
Secondary outcome [5] 407629 0
Diaphragm surface electromyography using surface electrodes
Timepoint [5] 407629 0
Continuous measurements during both control and intervention trials
Secondary outcome [6] 407630 0
Tidal volume measured using an oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
Timepoint [6] 407630 0
Breath-by-breath measurements during both control and intervention trials
Secondary outcome [7] 407631 0
Blood pressure using finger photoplethysmography
Timepoint [7] 407631 0
Continuous measurements during both control and intervention trials
Secondary outcome [8] 407632 0
Partial pressure of end-tidal carbon dioxide through gas analyser line attached to oronasal mask
Timepoint [8] 407632 0
Continuous measurements during both control and intervention trials
Secondary outcome [9] 407633 0
Partial pressure of end-tidal oxygen through gas analyser line attached to oronasal mask
Timepoint [9] 407633 0
Continuous measurements during both control and intervention trials
Secondary outcome [10] 407634 0
Pulmonary artery systolic pressure calculated by echocardiogram measurement of tricuspid regurgitation velocity and right atrial pressure estimation
Timepoint [10] 407634 0
Measured at standardised times in both intervention and control at 15 minutes following completion of nebulisation.
Secondary outcome [11] 407635 0
Cardiac output calculated by echocardiogram measurement of stroke volume multiplied by heart rate measured by 3 lead ECG
Timepoint [11] 407635 0
Measured at standardised times for both intervention and control, at 15 minutes following completion of nebulisation

Eligibility
Key inclusion criteria
• Patients with Group 1 PAH as per 6th World Symposium on Pulmonary Hypertension
• Exertional dyspnoea (WHO functional class II and III)
• Men and women
• Aged 18 years or over
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Group 2, 3, 4, 5 pulmonary hypertension
• Six minute walk distance < 300m
• Dyspnoea at rest (WHO functional class IV)
• Significant left ventricular dysfunction (Left ventricular ejection fraction <40% or significant diastolic dysfunction)
• Obstructive or restrictive lung disease
o Pulmonary fibrosis or emphysema on chest radiograph or computed tomography scan
o Total lung capacity <80% of predicted
o Forced expiratory volume in first second of expiration/ forced vital capacity <70%
o Currently taking regular inhaled therapy for airways disease
• Serious co-morbidities that may contribute to dyspnoea and/or reduce exercise capacity including:
o Severe cardiac disease (e.g., heart failure, coronary artery disease)
o Severe respiratory disease other than PAH (e.g., chronic obstructive pulmonary disease, interstitial lung disease)
o Severe obesity (Body mass index > 35 kg/m2)
o Severe orthopaedic impairment or rheumatologic/ connective tissue disease
o Significant neurological disease
o Significant renal or liver disease
o Infection or pyrexial illness
o Uncontrolled thyroid disorders
o Current active treatment for cancer
• Presence of any contraindications to cardiopulmonary exercise testing
o Unstable angina or recent acute myocardial infarction
o Uncontrolled arrhythmias causing symptoms or haemodynamic compromise
o Symptomatic severe aortic stenosis
o Oxygen saturation <85% at rest on room air
o Uncontrolled heart failure
o Uncontrolled asthma
o Uncontrolled thyroid disorders
o Mental impairment leading to inability to cooperate
o Long-term oxygen therapy
• Current pregnancy
• Allergy or intolerance to medications used in the study (iloprost)
• Contra-indication to study medication (iloprost)
• Current users of recreational drugs
• Current abusers of alcohol
• Inability to fully or appropriately provide consent (e.g., language issue, reading capability)
• Underlying medical conditions, which in the opinion of the Investigator place the participant at unacceptably high risk for participating in the study.

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)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
Due to limited relevant data in PAH, sample size estimates for the studies are based on studies in COPD, heart failure and healthy controls. It is estimated that 15 participants are required. Estimates are based on a study in PAH (n=17, Velez-Roa, Circulation, 2004) showing significantly elevated MSNA in patients compared to healthy controls, and decreased MSNA with peripheral chemoreflex deactivation, as well as a study of inhaled nitric oxide to selectively vasodilate the pulmonary vasculature in healthy participants (n=13, Simpson, J Physiol, 2020) showing a significant reduction in MSNA.

Body mass index (BMI) will be expressed as the ratio between participant’s weight and the square of their height. Analogue signals for ECG, BP, will be sampled simultaneously, and beat-to-beat or breath-by-breath time series derived, before averages are calculated for each experimental period (ADInstruments).

Anthropometric (e.g., BMI), demographic (e.g., age) and pulmonary function test data will be quantified using basic statistics (mean, SD, Median, IQR) and graphical presentations (boxplots, histograms, scatter plots). Likewise, levels of primary and secondary outcomes will be similarly reported. Outcome variables will be compared between control and test conditions. Comparisons of physiological variables will be assessed using a t-test. Funding is available to seek assistance from University of Auckland Statistics consulting services.

Statistical analysis will be performed using Sigmaplot 13.0 (Systat Software Inc, London, UK). Significance will be set at p < 0.05. Normally distributed data will be presented as mean (SD) while non-normally distributed data will be presented as median [interquartile range].

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2024
Actual
Date of last participant enrolment
Anticipated
31/10/2024
Actual
Date of last data collection
Anticipated
30/11/2024
Actual
Sample size
Target
15
Accrual to date
Final
Recruitment outside Australia
Country [1] 24675 0
New Zealand
State/province [1] 24675 0

Funding & Sponsors
Funding source category [1] 311041 0
Charities/Societies/Foundations
Name [1] 311041 0
Greenlane Research and Education Fund
Country [1] 311041 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
Faculty of Medical and Health Sciences
85 Park Road
Grafton
Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 312372 0
None
Name [1] 312372 0
Address [1] 312372 0
Country [1] 312372 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310590 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 310590 0
Ethics committee country [1] 310590 0
New Zealand
Date submitted for ethics approval [1] 310590 0
17/03/2022
Approval date [1] 310590 0
31/05/2022
Ethics approval number [1] 310590 0
2022 FULL 12454

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

Contacts
Principal investigator
Name 118186 0
Dr Michael Plunkett
Address 118186 0
Faculty of Medical and Health Sciences
University of Auckland
85 Park Road
Grafton
Auckland 1023
Country 118186 0
New Zealand
Phone 118186 0
+64212116388
Fax 118186 0
Email 118186 0
[email protected]
Contact person for public queries
Name 118187 0
Michael Plunkett
Address 118187 0
Faculty of Medical and Health Sciences
University of Auckland
85 Park Road
Grafton
Auckland 1023
Country 118187 0
New Zealand
Phone 118187 0
+64212116388
Fax 118187 0
Email 118187 0
[email protected]
Contact person for scientific queries
Name 118188 0
Michael Plunkett
Address 118188 0
Faculty of Medical and Health Sciences
University of Auckland
85 Park Road
Grafton
Auckland 1023
Country 118188 0
New Zealand
Phone 118188 0
+64212116388
Fax 118188 0
Email 118188 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.