Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000493741
Ethics application status
Approved
Date submitted
18/03/2022
Date registered
28/03/2022
Date last updated
8/05/2024
Date data sharing statement initially provided
28/03/2022
Date results provided
8/05/2024
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 skeletal muscle afferents (sub-study one)
Secondary ID [1] 306696 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 325660 0
Condition category
Condition code
Cardiovascular 323010 323010 0 0
Other cardiovascular diseases
Respiratory 323011 323011 0 0
Other respiratory disorders / diseases
Cardiovascular 323144 323144 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 one) tests the specific hypothesis that aberrant skeletal muscle afferent drives exertional dyspnoea and limits 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, the investigator will explain the experiment process, participants will practice the handgrip manoeuvre, a blood pressure cuff will be inflated around the upper arm at 200mmHg for 1 minute). Maximal voluntary contraction (MVC) will be determined by instructing participants to perform 3 maximal handgrip efforts (squeezing a custom-made handgrip dynamometer with their dominant hand), separated by 1 minute. The highest will be taken as the MVC.

2. an experimental visit (about 2 hours). This will take place approximately 7 days following the familiarisation visit. Participants will be instrumented with equipment (noted below). Participants will perform two 8 minute handgrip trials. One will involve a normal recovery (control trial) and the other will involve post exercise circulatory occlusion (PECO) being induced in the exercising arm (PECO trial), thereby isolating the stimulation of skeletal muscle afferents after exercise. The test order will be randomised and separated by ~30 min. Participants will be supine on a laboratory couch rolled slightly toward a lateral decubitus position and hold a custom-made handgrip dynamometer with their dominant hand. Prior to the trials participants will rest for 15 minutes to establish steady-state ventilation variables and for baseline echocardiographic measurement of pulmonary artery systolic pressure (PASP) and cardiac output (CO). Both trials will consist of 2 minute baseline recording period then a 2 minute rhythmic isometric handgrip exercise task. During the handgrip exercise participants will be instructed to perform 1 second contraction of 50% MVC to 1 second of relaxation. Participants then either rest for 4 minutes (control trial) or a cuff will be rapidly inflated to 200mmHg around the upper right arm starting 2-3 contractions prior to the end of the exercise period. The cuff is deflated after 2 minutes and participants will rest for 2 minutes (PECO trial). Echocardiogram measurements of PASP and CO will take place during exercise, PECO/control and recovery.

Ventilation will be measured continuously with a oro-nasal mask or mouthpiece (Hans Rudolph). Heart rate will be continuously measured using an electrocardiogram (3-lead). Blood pressure will be continuously measured with finger photoplethysmography. Oxygen saturation will be continuously measured with finger pulse oximeter. Diaphragmatic EMG will be measured using surface diaphragmatic electrodes attached to the skin. Echocardiography will be performed using a commercially available ultrasound machine with a cardiac transducer (1-3MHz). Participants will be asked about their perceived level of exertion and breathlessness.

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] 323145 0
Treatment: Other
Comparator / control treatment
The control will be the handgrip exercise (as above) followed by rest for 4 minutes without post-exercise circulatory occlusion.
Control group
Active

Outcomes
Primary outcome [1] 330778 0
Dyspnoea intensity as assessed using the modified Borg Scale
Timepoint [1] 330778 0
For intervention trials this will be end of exercise period and end of cuff occlusion period

For control trials this will be end of exercise period and middle of recovery period
Primary outcome [2] 330779 0
Minute ventilation measured using an oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
Timepoint [2] 330779 0
Breath-by-breath measurements during the trials (each trial will be 8 minutes in duration)
Secondary outcome [1] 407571 0
Perceived rating of exertion using the Borg CR10 Rating of perceived exertion scale
Timepoint [1] 407571 0
End of exercise for both the control and intervention trial
Secondary outcome [2] 407572 0
Respiratory rate measured using a oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
Timepoint [2] 407572 0
Breath-by-breath measurements during both control and intervention trials (8 minutes each)
Secondary outcome [3] 407574 0
Heart rate measured using an electrocardiogram (3-lead)
Timepoint [3] 407574 0
beat-by-beat measurements during both control and intervention trials (8 minutes each)
Secondary outcome [4] 407575 0
Oxyhaemoglobin saturation using finger oximeter
Timepoint [4] 407575 0
Continuous measurements during both control and intervention trials (8 minutes each)
Secondary outcome [5] 407576 0
Diaphragm surface electromyography using surface electrodes
Timepoint [5] 407576 0
Continuous measurements during both control and intervention trials (8 minutes each)
Secondary outcome [6] 407577 0
Tidal volume measured using an oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
Timepoint [6] 407577 0
Breath-by-breath measurements during both control and intervention trials (8 minutes each)
Secondary outcome [7] 407578 0
Blood pressure using finger photoplethysmography
Timepoint [7] 407578 0
Continuous measurements during both control and intervention trials (8 minutes each)
Secondary outcome [8] 407579 0
Partial pressure of end-tidal carbon dioxide through gas analyser line attached to oronasal mask
Timepoint [8] 407579 0
Continuous measurements during both control and intervention trials (8 minutes each)
Secondary outcome [9] 407580 0
Partial pressure of end-tidal oxygen through gas analyser line attached to oronasal mask
Timepoint [9] 407580 0
Continuous measurements during both control and intervention trials (8 minutes each)
Secondary outcome [10] 407581 0
Pulmonary artery systolic pressure calculated by echocardiogram measurement of tricuspid regurgitation velocity and right atrial pressure estimation
Timepoint [10] 407581 0
Measured at standardised times
- For intervention trials this will be during baseline period, during 4th minute of handgrip exercise, during 2nd minute of cuff inflation (PECO), and during 2nd minute of recovery
- For control trials this will be during baseline period, during 4th minute of handgrip exercise, during 2nd minute of recovery and 4th minute of recovery
Secondary outcome [11] 407584 0
Cardiac output calculated by echocardiogram measurement of stroke volume multiplied by heart rate measured by 3 lead ECG
Timepoint [11] 407584 0
Measured at standardised times
- For intervention trials this will be during baseline period, during 3rd minute of handgrip exercise, during 1st minute of cuff inflation (PECO), and during 1st minute of recovery
- For control trials this will be during baseline period, during 3rd minute of handgrip exercise, during 1st minute of recovery and 3rd minute of recovery

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)
• Control participants free from PAH, age and sex-matched with no known health conditions
• 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?
Yes
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
• 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
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using coin toss
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



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 for the study 15 participants (and 15 healthy controls) are required. The estimate is based on studies of PECO with lower limb exercise in chronic heart failure (n=11, Olson, Circ Heart Fail, 2010), and spinal anaesthesia to inhibit central feedback from lower limb muscle afferents in chronic heart failure (n=9, Olson, Exp Physiol, 2014) and COPD (n=8, Gagnon, AJRCCM, 2012) showing significant changes in minute ventilation.

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 (sub-studies 1 and 2), or between patients and healthy controls (sub-study 3). 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
Completed
Date of first participant enrolment
Anticipated
1/07/2022
Actual
19/07/2022
Date of last participant enrolment
Anticipated
6/03/2023
Actual
7/12/2022
Date of last data collection
Anticipated
3/04/2023
Actual
7/12/2022
Sample size
Target
30
Accrual to date
Final
28
Recruitment outside Australia
Country [1] 24673 0
New Zealand
State/province [1] 24673 0

Funding & Sponsors
Funding source category [1] 311026 0
Charities/Societies/Foundations
Name [1] 311026 0
Greenlane Research and Education Fund
Country [1] 311026 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] 312347 0
None
Name [1] 312347 0
Address [1] 312347 0
Country [1] 312347 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310574 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 310574 0
Ethics committee country [1] 310574 0
New Zealand
Date submitted for ethics approval [1] 310574 0
17/03/2022
Approval date [1] 310574 0
31/05/2022
Ethics approval number [1] 310574 0
2022 FULL 12454

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

Contacts
Principal investigator
Name 118130 0
Dr Michael Plunkett
Address 118130 0
Faculty of Medical and Health Sciences
University of Auckland
85 Park Road
Grafton
Auckland 1023
Country 118130 0
New Zealand
Phone 118130 0
+64212116388
Fax 118130 0
Email 118130 0
[email protected]
Contact person for public queries
Name 118131 0
Michael Plunkett
Address 118131 0
Faculty of Medical and Health Sciences
University of Auckland
85 Park Road
Grafton
Auckland 1023
Country 118131 0
New Zealand
Phone 118131 0
+64212116388
Fax 118131 0
Email 118131 0
[email protected]
Contact person for scientific queries
Name 118132 0
Michael Plunkett
Address 118132 0
Faculty of Medical and Health Sciences
University of Auckland
85 Park Road
Grafton
Auckland 1023
Country 118132 0
New Zealand
Phone 118132 0
+64212116388
Fax 118132 0
Email 118132 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
SourceTitleYear of PublicationDOI
EmbaseThe skeletal muscle metaboreflex: a novel driver of ventilation, dyspnoea and pulmonary haemodynamics during exercise in pulmonary arterial hypertension.2024https://dx.doi.org/10.1183/13993003.00952-2023
N.B. These documents automatically identified may not have been verified by the study sponsor.