Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001018909
Ethics application status
Approved
Date submitted
25/08/2020
Date registered
7/10/2020
Date last updated
21/03/2022
Date data sharing statement initially provided
7/10/2020
Date results provided
21/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Understanding breathlessness in interstitial lung disease
Scientific title
Understanding dyspnoea and exercise limitation in interstitial lung disease: the role of skeletal muscle afferents (sub-study 3)
Secondary ID [1] 302135 0
none
Universal Trial Number (UTN)
U1111-1247-2800
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Interstitial Lung Disease 317784 0
Condition category
Condition code
Respiratory 315848 315848 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
It is known that peripheral chemoreceptors, lung afferents and skeletal muscle afferents all contribute to the regulation of breathing during physical exertion. Moreover, in chronic obstructive pulmonary disease (COPD), another common cause of exertion-related dyspnoea, there is emerging evidence that the sensitivity of these sensory afferent populations is dysregulated leading to exaggerated respiratory and cardiovascular responses. However, despite such sensory afferent pathways representing a potentially important therapeutic target for ameliorating exertional-dyspnoea in interstitial lung disease (ILD), their role in the control of breathing during exercise in ILD has not been studied. Therefore, our overarching hypothesis is that aberrant activation of chemoreceptors, lung receptor afferents and/or skeletal muscle afferents drives exertional-dyspnoea and limits exercise capacity in patients with fibrotic ILD.

In order to test this hypothesis, three inter-related sub-studies will be conducted. This describes the intervention/exposure of sub-study three:

Brief name: Effect of skeletal muscle afferents on dyspnoea and exercise capacity

All sessions (familiarization and experimental visits) will be conducted at the Human Cardiorespiratory Physiology Laboratory, Level 7, Respiratory Physiology Department, Auckland City Hospital, Auckland District Health Board. Each visit will be conducted in a 'one-on-one' setting.

1) initial familiarization visit (~60min): the investigator will explain the nature of the procedures, answer any questions and obtain written informed consent form. Anthropometric (height, weight), demographic, thorough medical history and clinical assessment (Health screening Questionnaire, measurement of oxygen saturation) will be conducted. Questionnaires will be used to assess activity-related dyspnoea (Modified Medical Research Council Dyspnoea Scale) , health related quality of life (King’s Brief Interstitial Lung Disease Questionnaire) , and anxiety and depression (Hospital Anxiety and Depression Scale). Baseline spirometry will be performed according to established guidelines (participants will breathe in and out through a handheld spirometer for approximately 10 seconds while wearing a nose clip). 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 maneuver, a blood pressure cuff will be inflated around the upper arm at 200mmHg for 1 minute).

2) experimental visit (~60min): This will take place approximately 7 days following the familiarisation visit. Participants will be instrumented with equipment (noted below). Participants will perform two 8-min handgrip trials. One will involve a normal recovery (control trial) and the other will involve post exercise circulatory occlusion being induced in the exercising arm ("interventional" trial), isolating the stimulation of skeletal muscle afferents after exercise. The test order will be randomised and separated by ~30 min. Participants will be seated in an upright position and hold a custom-made handgrip dynamometer with their right hand. Prior to the trials participants will rest for 5 minutes in order to establish steady state ventilation variables. Maximal voluntary contraction (MVC) will be determined by instructing participants to perform 3 maximal handgrip efforts, separated by 1 minute. The highest will be taken as the MVC. The 'interventional' trial 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. At the end of the exercise task, 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.

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. Participants will be asked about their perceived level of exertion and breathlessness.

The investigator (carrying out all trials) is a qualified medical doctor and holds a current Advanced Cardiac Life Support (ACLS) Level 7 certification. The investigator is experienced with all the procedures employed.
Intervention code [1] 318430 0
Treatment: Other
Comparator / control treatment
The control will be separated from the "interventional" trial by ~30 minutes. The control trial consists 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. At the end of the exercise task participants will be asked to relax for 4 minutes.

The instrumentation and outcomes will be as documented for the interventional trial.

Control group
Active

Outcomes
Primary outcome [1] 324054 0
Dyspnoea intensity as assessed using Modified Borg Scale
Timepoint [1] 324054 0
standardised times
-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] 324056 0
Minute ventilation measured using an oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
Timepoint [2] 324056 0
Breath-by-breath measurements during the trials (each trial will be 8 minutes in duration)
Secondary outcome [1] 383633 0
Perceived rating of exertion using the Borg CR10 Rating of perceived exertion scale
Timepoint [1] 383633 0
End of exercise for both the control and intervention trial
Secondary outcome [2] 383634 0
Respiratory rate measured using a oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
Timepoint [2] 383634 0
Breath-by-breath measurements during both control and intervention trials (8 minutes each)
Secondary outcome [3] 383636 0
Heart rate measured using an electrocardiogram (3-lead)
Timepoint [3] 383636 0
beat-by-beat measurements during both control and intervention trials (8 minutes each)
Secondary outcome [4] 383637 0
oxyhaemoglobin saturation using finger oximeter
Timepoint [4] 383637 0
Continuous measurements during both control and intervention trials (8 minutes each)
Secondary outcome [5] 383638 0
Diaphragm surface electromyography using surface electrodes
Timepoint [5] 383638 0
Continuous measurements during both control and intervention trials (8 minutes each)
Secondary outcome [6] 386808 0
Tidal volume measured using an oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
Timepoint [6] 386808 0
Breath-by-breath measurements during both control and intervention trials (8 minutes each)
Secondary outcome [7] 386809 0
Blood pressure using finger photoplethysmography
Timepoint [7] 386809 0
Continuous measurements during both control and intervention trials (8 minutes each)
Secondary outcome [8] 386810 0
Partial pressure of end-tidal carbon dioxide through gas analyser line attached to oronasal mask
Timepoint [8] 386810 0
Continuous measurements during both control and intervention trials (8 minutes each)
Secondary outcome [9] 386811 0
Partial pressure of end-tidal oxygen through gas analyser line attached to oronasal mask
Timepoint [9] 386811 0
Continuous measurements during both control and intervention trials (8 minutes each)

Eligibility
Key inclusion criteria
• Patients with fibrotic ILD (total lung capacity <80% predicted; FEV1/FVC > 0.7 and standard HRCT criteria (British Thoracic Society guidelines, 2008)
• Control participants free from fibrotic ILD
• 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
• More than 10 pack year smoking history
• Evidence of emphysema on CT scan
• Pulmonary Sarcoidosis
• Currently taking regular inhaled therapy for airways disease
• Serious co-morbidities that may contribute to dyspnoea and/or reduce exercise capacity including:
o Severe respiratory disease other than ILD (e.g., chronic obstructive pulmonary disease)
o Pulmonary hypertension
o Severe obesity (Body mass index > 35 kg/m2)
o Severe orthopaedic impairment or rheumatologic disease
o Significant neurological disease
o Infection or pyrexial illness

• Presence of any contraindications to cardiopulmonary exercise testing (as per American Thoracic Society/American College of Chest Physicians Statement on Cardiopulmonary Exercise Testing, 2003)
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

• 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 the paucity of relevant data in ILD, sample size estimate is based on a study of COPD patients by Bruce et al 2016 ("Ventilatory responses to muscle metaboreflex activation in chronic obstructive pulmonary disease"). It is estimated that a sample size of 15 patients and 15 controls will provide the power (80%) needed to detect meaningful differences of Borg dyspnoea ratings of ±1.5 units and 2.3 L/min minute ventilation between post exercise circulation occlusion and control recovery conditions (at 5% alpha).

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 patients and healthy controls. 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
21/10/2020
Actual
19/10/2020
Date of last participant enrolment
Anticipated
30/06/2021
Actual
21/07/2021
Date of last data collection
Anticipated
30/07/2021
Actual
2/08/2021
Sample size
Target
30
Accrual to date
Final
32
Recruitment outside Australia
Country [1] 22662 0
New Zealand
State/province [1] 22662 0
Auckland

Funding & Sponsors
Funding source category [1] 305897 0
Government body
Name [1] 305897 0
Health research council of NZ
Country [1] 305897 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
85 Park Road Grafton Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 306352 0
None
Name [1] 306352 0
Address [1] 306352 0
Country [1] 306352 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306155 0
Northern A Health and Disability Ethics Committee, Ministry of Health New Zealand
Ethics committee address [1] 306155 0
Ethics committee country [1] 306155 0
New Zealand
Date submitted for ethics approval [1] 306155 0
17/04/2020
Approval date [1] 306155 0
29/07/2020
Ethics approval number [1] 306155 0
20/NTA/68

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

Contacts
Principal investigator
Name 102902 0
Dr Charlotte Chen
Address 102902 0
Faculty of health and medical sciences
University of Auckland
85 Park Road Grafton Auckland 1023
Country 102902 0
New Zealand
Phone 102902 0
+64093737599
Fax 102902 0
Email 102902 0
[email protected]
Contact person for public queries
Name 102903 0
Charlotte Chen
Address 102903 0
Faculty of health and medical sciences
University of Auckland
85 Park Road Grafton Auckland 1023
Country 102903 0
New Zealand
Phone 102903 0
+64093737599
Fax 102903 0
Email 102903 0
[email protected]
Contact person for scientific queries
Name 102904 0
Charlotte Chen
Address 102904 0
Faculty of health and medical sciences
University of Auckland
85 Park Road Grafton Auckland 1023
Country 102904 0
New Zealand
Phone 102904 0
+64093737599
Fax 102904 0
Email 102904 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
EmbaseCardiorespiratory responses to muscle metaboreflex activation in fibrosing interstitial lung disease.2022https://dx.doi.org/10.1113/EP090252
N.B. These documents automatically identified may not have been verified by the study sponsor.