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Trial registered on ANZCTR


Registration number
ACTRN12622000505707
Ethics application status
Approved
Date submitted
28/03/2022
Date registered
30/03/2022
Date last updated
4/04/2024
Date data sharing statement initially provided
30/03/2022
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 peripheral chemoreceptors (sub-study three)
Secondary ID [1] 306718 0
None
Universal Trial Number (UTN)
U1111-1275-6386
Trial acronym
Linked study record
This is number 3 of three related substudies, the others are:
ACTRN12622000493741 (sub-study 1)
ACTRN12622000494730 (sub-study 2)

Health condition
Health condition(s) or problem(s) studied:
Pulmonary arterial hypertension 325697 0
Condition category
Condition code
Cardiovascular 323046 323046 0 0
Other cardiovascular diseases
Respiratory 323047 323047 0 0
Other respiratory disorders / diseases
Cardiovascular 323146 323146 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 three) tests the specific hypothesis that aberrant activation of the peripheral chemoreflex 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 three visits to the study laboratory. Each experimental visit will be separated by approximately 1 week.

1. an initial familiarisation and maximal cardiopulmonary exercise test visit (~90 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. This consists of:
-all measuring instruments will be attached to the participant
-participant will undergo 2 minutes of isocapnic hypoxia (end tidal CO2 ~40mmHg and end tidal O2 of 45mmHg)
-the investigator will explain the experiment process
They will then perform a symptom-limited incremental cycle exercise test to determine peak workload, in accordance with international guidelines.

2. Experimental visit 2 and 3 (~1.5 hours each), participants will have either i.v. low-dose dopamine (2 mcg/kg/min) or control (intravenous saline) infused via a small 23 gauge peripheral intravenous catheter inserted either in the antecubital fossa or hand. The order of low-dose dopamine or saline infusion will be randomised, single blinded, and separated by approximately 7 days. After at least 10 minutes of infusion, transthoracic echocardiography will be assessed at baseline under each condition (low-dose dopamine and saline). Resting measurements will then be performed. Hypoxic challenge respiratory monitoring will be used to determine baseline peripheral chemoreflex sensitivity (control) and degree of peripheral chemoreflex block (with low-dose dopamine). This will involve breathing in a hypoxic gas mixture, aiming for end tidal CO2 ~40mmHg and end tidal O2 of 45mmHg. After a 10 minute recovery period, participants will then perform a constant work cycle exercise test (75% peak workload). Following the exercise the infusion will be stopped and intravenous catheter removed.

During both the hypoxic challenge and cycle exercise test ventilation will be measured continuously with a oro-nasal mask or mouthpiece (Hans Rudolph). Heart rate will be continuously measured using an electrocardiogram (12-lead). Oxygen saturation will be continuously measured with finger pulse oximeter. During the exercise test blood pressure will be measured during the last 45s of each stage (each stage is 2 minutes) using an automated sphygmomanometer (SunTech). At the end of the exercise 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] 323232 0
Treatment: Drugs
Comparator / control treatment
The control will consist of intravenous 0.9% saline as described above.
Control group
Placebo

Outcomes
Primary outcome [1] 330900 0
Dyspnoea intensity as assessed using Modified Borg Scale
Timepoint [1] 330900 0
At the end of exercise (estimated to be <12 minutes)
Primary outcome [2] 330901 0
Exercise endurance time measured using a timer on the cardiopulmonary exercise software
Timepoint [2] 330901 0
At the end of the exercise (estimated to be <12 minutes)
Primary outcome [3] 330902 0
Minute ventilation measured using an oronasal mask (Hans Rudolph) attached to a heated penumotachograph
Timepoint [3] 330902 0
Breath-by-breath measurements during the cycle exercise (estimated to be <12 minutes) and hypoxic challenge (5 minutes)
Secondary outcome [1] 408000 0
Perceived rating of exertion using the Borg CR10 Rating of perceived exertion scale
Timepoint [1] 408000 0
At the end of the exercise (estimated to be <12 minutes)
Secondary outcome [2] 408001 0
Heart rate measured using an electrocardiogram (12-lead)
Timepoint [2] 408001 0
Beat-by-beat measurements during exercise (estimated to be <12 minutes) and hypoxic challenge (5 minutes)
Secondary outcome [3] 408002 0
Oxyhaemoglobin saturation using finger oximeter
Timepoint [3] 408002 0
Continuous measurements during exercise (estimated to be <12 minutes) and hypoxic challenge (5 minutes)
Secondary outcome [4] 408003 0
Blood pressure using an automated sphygmomanometer (cuff wrapped around upper arm) validated for use during exercise (SunTech)
Timepoint [4] 408003 0
During last 45s of each 2 minute stage during exercise.
Secondary outcome [5] 408004 0
Oxygen consumption measured through gas analyser line attached to oronasal mask
Timepoint [5] 408004 0
Breath by breath measurement during exercise (estimated to be <12 minutes)
Secondary outcome [6] 408005 0
CO2 production measured through gas analyser line attached to oronasal mask
Timepoint [6] 408005 0
Breath-by-breath measurement during exercise (estimated to be <12 minutes)

Eligibility
Key inclusion criteria
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
• 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.
• Allergy or intolerance to dopamine
• Contraindication to dopamine

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
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Crossover
Other design features
Phase
Phase 4
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. For study 3, the estimate is based on a study of low dose dopamine during exercise in chronic heart failure (n=12, Collins, Front Physiol, 2020), showing significantly reduced end-tidal pressure of carbon dioxide compared with placebo saline infusion, and studies in chronic heart failure (n=8, n=11, van de Borne, Circulation, 1998 and Edgell, J Appl Physiol, 2015) showing reduced minute ventilation at rest with low-dose dopamine infusion.

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
Completed
Date of first participant enrolment
Anticipated
3/04/2023
Actual
19/06/2023
Date of last participant enrolment
Anticipated
1/06/2024
Actual
21/11/2023
Date of last data collection
Anticipated
1/07/2024
Actual
18/12/2023
Sample size
Target
15
Accrual to date
Final
9
Recruitment outside Australia
Country [1] 24689 0
New Zealand
State/province [1] 24689 0
Auckland

Funding & Sponsors
Funding source category [1] 311045 0
Charities/Societies/Foundations
Name [1] 311045 0
Greenlane Research and Education Fund
Country [1] 311045 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] 312377 0
None
Name [1] 312377 0
Address [1] 312377 0
Country [1] 312377 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310593 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 310593 0
Ethics committee country [1] 310593 0
New Zealand
Date submitted for ethics approval [1] 310593 0
17/03/2022
Approval date [1] 310593 0
31/05/2022
Ethics approval number [1] 310593 0
2022 FULL 12454

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

Contacts
Principal investigator
Name 118198 0
Dr Michael Plunkett
Address 118198 0
Faculty of Medical and Health Sciences
University of Auckland
85 Park Road
Grafton
Auckland 1023
Country 118198 0
New Zealand
Phone 118198 0
+64212116388
Fax 118198 0
Email 118198 0
m.plunkett@auckland.ac.nz
Contact person for public queries
Name 118199 0
Michael Plunkett
Address 118199 0
Faculty of Medical and Health Sciences
University of Auckland
85 Park Road
Grafton
Auckland 1023
Country 118199 0
New Zealand
Phone 118199 0
+64212116388
Fax 118199 0
Email 118199 0
m.plunkett@auckland.ac.nz
Contact person for scientific queries
Name 118200 0
Michael Plunkett
Address 118200 0
Faculty of Medical and Health Sciences
University of Auckland
85 Park Road
Grafton
Auckland 1023
Country 118200 0
New Zealand
Phone 118200 0
+64212116388
Fax 118200 0
Email 118200 0
m.plunkett@auckland.ac.nz

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.