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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
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Scientific title
Exertional dyspnoea and exercise intolerance in pulmonary arterial hypertension: the role of pulmonary baroreceptors (sub-study two)
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Secondary ID [1]
306715
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None
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Universal Trial Number (UTN)
U1111-1275-6386
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Pulmonary arterial hypertension
325691
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Condition category
Condition code
Cardiovascular
323040
323040
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0
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Other cardiovascular diseases
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Respiratory
323041
323041
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0
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Other respiratory disorders / diseases
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Cardiovascular
323145
323145
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0
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Hypertension
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
323165
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Early detection / Screening
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Comparator / control treatment
The control group will be inhalation of nebulised saline (as above).
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Control group
Placebo
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Outcomes
Primary outcome [1]
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Muscle sympathetic nerve activity as assessed by microneurography at the peroneal nerve
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Assessment method [1]
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Timepoint [1]
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Assessed at specific time points during the experimental session
- at rest
- following inhalation of iloprost or control, until 30 minutes.
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Primary outcome [2]
330806
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Dyspnoea intensity as assessed using the modified Borg Scale
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Assessment method [2]
330806
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Timepoint [2]
330806
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At end of 6 minute walk test during familiarisation visit
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Secondary outcome [1]
407625
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Minute ventilation measured using an oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
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Assessment method [1]
407625
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Timepoint [1]
407625
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Breath-by-breath measurements during the trials
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Secondary outcome [2]
407626
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Respiratory rate measured using a oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
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Assessment method [2]
407626
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Timepoint [2]
407626
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Breath-by-breath measurements during both control and intervention trials
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Secondary outcome [3]
407627
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Heart rate measured using an electrocardiogram (3-lead)
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Assessment method [3]
407627
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Timepoint [3]
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beat-by-beat measurements during both control and intervention trials
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Secondary outcome [4]
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Oxyhaemoglobin saturation using finger oximeter
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Assessment method [4]
407628
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Timepoint [4]
407628
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Continuous measurements during both control and intervention trials
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Secondary outcome [5]
407629
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Diaphragm surface electromyography using surface electrodes
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Assessment method [5]
407629
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Timepoint [5]
407629
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Continuous measurements during both control and intervention trials
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Secondary outcome [6]
407630
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Tidal volume measured using an oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
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Assessment method [6]
407630
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Timepoint [6]
407630
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Breath-by-breath measurements during both control and intervention trials
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Secondary outcome [7]
407631
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Blood pressure using finger photoplethysmography
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Assessment method [7]
407631
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Timepoint [7]
407631
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Continuous measurements during both control and intervention trials
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Secondary outcome [8]
407632
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Partial pressure of end-tidal carbon dioxide through gas analyser line attached to oronasal mask
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Assessment method [8]
407632
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Timepoint [8]
407632
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Continuous measurements during both control and intervention trials
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Secondary outcome [9]
407633
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Partial pressure of end-tidal oxygen through gas analyser line attached to oronasal mask
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Assessment method [9]
407633
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Timepoint [9]
407633
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Continuous measurements during both control and intervention trials
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Secondary outcome [10]
407634
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Pulmonary artery systolic pressure calculated by echocardiogram measurement of tricuspid regurgitation velocity and right atrial pressure estimation
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Assessment method [10]
407634
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Timepoint [10]
407634
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Measured at standardised times in both intervention and control at 15 minutes following completion of nebulisation.
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Secondary outcome [11]
407635
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Cardiac output calculated by echocardiogram measurement of stroke volume multiplied by heart rate measured by 3 lead ECG
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Assessment method [11]
407635
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Timepoint [11]
407635
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Measured at standardised times for both intervention and control, at 15 minutes following completion of nebulisation
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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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
N/A
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
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Intervention assignment
Crossover
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Other design features
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Phase
Not Applicable
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Type of endpoint/s
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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].
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
1/05/2024
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Actual
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Date of last participant enrolment
Anticipated
31/10/2024
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Actual
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Date of last data collection
Anticipated
30/11/2024
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Actual
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Sample size
Target
15
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Accrual to date
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Final
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Recruitment outside Australia
Country [1]
24675
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New Zealand
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State/province [1]
24675
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Funding & Sponsors
Funding source category [1]
311041
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Charities/Societies/Foundations
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Name [1]
311041
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Greenlane Research and Education Fund
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Address [1]
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Greenlane Research and Education Fund
PO Box 110042, Auckland City Hospital, Grafton, Auckland 1148
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Country [1]
311041
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New Zealand
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Primary sponsor type
University
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Name
University of Auckland
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Address
Faculty of Medical and Health Sciences
85 Park Road
Grafton
Auckland 1023
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Country
New Zealand
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Secondary sponsor category [1]
312372
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None
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Name [1]
312372
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Address [1]
312372
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Country [1]
312372
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
310590
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Northern B Health and Disability Ethics Committee
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Ethics committee address [1]
310590
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HDEC
133 Molesworth Street
Thorndon
Wellington 6011
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Ethics committee country [1]
310590
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New Zealand
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Date submitted for ethics approval [1]
310590
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17/03/2022
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Approval date [1]
310590
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31/05/2022
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Ethics approval number [1]
310590
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2022 FULL 12454
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Summary
Brief summary
Pulmonary arterial hypertension (PAH) is a severe condition that causes progressive high blood pressure in the blood vessels of the lungs. Shortness of breath, particularly on exertion, is the most common symptom in PAH. It is distressing, limits patients’ ability to do activities, and reduces quality of life. Despite the current treatments for PAH, it is still a significant issue for patients. The reasons for breathlessness in PAH, and why PAH develops are not fully understood.
New scientific evidence supports the idea that increased nerve activity (i.e., sympathetic nervous system) and changes in the sensing of blood pressure in the pulmonary blood vessels may be involved in PAH and dyspnoea. The purpose of the present investigation is to better understand if, and why this happens.
We are specifically investigating whether specialised sensors in the body that respond to changes in blood pressure respond differently in people who have PAH and lead to an over-active sympathetic nervous system. These sensors are located in lung blood vessels (known as pulmonary “baroreceptors”). It is hoped that our work will pave the way for future studies targeting these “baroreceptors” to reduce shortness of breath, and blood pressure in the lung.
This is a non-randomised crossover study involving participants with PAH. Participants will attend 2 study visits:
Visit one: participants will complete health-related questionnaires, undergo spirometry, be familiarised with study procedures and complete a 6 minute walk test
Visit two: participants will have a very thin electrode inserted into their leg to measure nerve activity. They will undergo 2 trials. In the first trial, they will inhale nebulised normal saline (control), and a heart ultrasound (echocardiogram) will be performed to measure blood pressure in the pulmonary blood vessels. Breathing, blood pressure, heart rate, muscle nerve activity will be recorded. After a rest period, they will inhale nebulised iloprost, a medication used to reduce blood pressure in the pulmonary blood vessels. The same measurements, as in the first trial, will be performed after this.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Dr Michael Plunkett
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Address
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Faculty of Medical and Health Sciences
University of Auckland
85 Park Road
Grafton
Auckland 1023
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Country
118186
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New Zealand
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Phone
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+64212116388
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Fax
118186
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Email
118186
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[email protected]
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Contact person for public queries
Name
118187
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Dr Michael Plunkett
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Address
118187
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Faculty of Medical and Health Sciences
University of Auckland
85 Park Road
Grafton
Auckland 1023
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Country
118187
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New Zealand
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Phone
118187
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+64212116388
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Fax
118187
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Email
118187
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[email protected]
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Contact person for scientific queries
Name
118188
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Dr Michael Plunkett
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Address
118188
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Faculty of Medical and Health Sciences
University of Auckland
85 Park Road
Grafton
Auckland 1023
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Country
118188
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New Zealand
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Phone
118188
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+64212116388
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Fax
118188
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Email
118188
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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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.
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