Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000454875
Ethics application status
Approved
Date submitted
22/03/2021
Date registered
19/04/2021
Date last updated
7/03/2024
Date data sharing statement initially provided
19/04/2021
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 pulmonary afferents (sub-study 2)
Secondary ID [1] 303743 0
none
Universal Trial Number (UTN)
U1111-1247-2800
Trial acronym
Linked study record
The current study is one of three sub-studies. Sub-study 1 is ACTRN12621000049875. Sub-study 3 is ACTRN12620001018909.

Health condition
Health condition(s) or problem(s) studied:
Interstitial Lung disease 321218 0
Condition category
Condition code
Respiratory 318996 318996 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 two:

Brief name: Effect of pulmonary afferents on dyspnoea and exercise capacity

All sessions (familiarisation 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) Familiarisation 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. This consists of:
-all measuring instruments will be attached to the participant
-participant will be shown the nebuliser. The participant will have brief exposure (i.e nebuliser mask attached to face or use of mouthpiece) to nebulisation of 0.9% saline for the purpose of familiarisation with the mask/mouthpiece, sound of the nebuliser and sensation of mist generated by the nebuliser.
-participant will peddle briefly on the exercise ergometer (less than 5 minutes)
-the investigator will explain the experiment process

2) Experimental visits (~60min): Participants will attend two visits separated by ~ 7 days. Participants will be given either nebulisation of 100 mcg of fentanyl citrate or nebulisation of control (0.9% saline). The order will be randomised and single blinded. Following treatment venous blood samples for fentanyl will be taken. Samples taken following nebulisation of control will be discarded. Samples taken following nebulisation of fentanyl will be stored in a secure location and only to be analysed if there is a positive result and/or a need to exclude systemic effect. Exactly 10 minutes following nebulisation participants will then perform a symptom-limited incremental cycle exercise test on a cycle ergometer in accordance with international guidelines (ACC/AHA 2002).

During the 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.

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] 320066 0
Treatment: Drugs
Comparator / control treatment
The control will consist of nebulisation of 0.9% saline as described above.
Control group
Placebo

Outcomes
Primary outcome [1] 326919 0
Dyspnoea intensity as assessed using Modified Borg Scale
Timepoint [1] 326919 0
At the end of exercise (estimated to be <12 minutes)
Primary outcome [2] 326920 0
Exercise endurance time measured using a timer on the cardiopulmonary exercise software
Timepoint [2] 326920 0
At the end of the exercise (estimated to be <12 minutes)
Primary outcome [3] 326921 0
Minute ventilation measured using an oronasal mask (Hans Rudolph) attached to a heated pneumotachograph
Timepoint [3] 326921 0
breath-by-breath measurements during the cycle exercise (estimated to be <12 minutes)
Secondary outcome [1] 393140 0
Perceived rating of exertion using the Borg CR10 Rating of perceived exertion scale
Timepoint [1] 393140 0
At the end of the exercise (estimated to be <12 minutes)
Secondary outcome [2] 393141 0
Heart rate measured using an electrocardiogram (12-lead)
Timepoint [2] 393141 0
beat-by-beat measurements during exercise (estimated to be <12 minutes)
Secondary outcome [3] 393142 0
oxyhaemoglobin saturation using finger oximeter
Timepoint [3] 393142 0
continuous measurements during exercise (estimated to be <12 minutes)
Secondary outcome [4] 393143 0
Blood pressure using an automated sphygmomanometer (cuff wrapped around upper arm) validated for use during exercise (SunTech)
Timepoint [4] 393143 0
During last 45s of each 2 minute stage during exercise.
Secondary outcome [5] 393144 0
Oxygen consumption measured through gas analyser line attached to oronasal mask
Timepoint [5] 393144 0
Breath by breath measurement during exercise (estimated to be <12 minutes)
Secondary outcome [6] 393145 0
CO2 production measured through gas analyser line attached to oronasal mask
Timepoint [6] 393145 0
Breath-by-breath measurement during exercise (estimated to be <12 minutes)

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)
• 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
• More than 10 pack year smoking history
• Evidence of significant 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
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
• Allergy or intolerance to fentanyl
• Use of anti-depressants (i.e monoamine oxidase inhibitors, serotonin reuptake inhibitors, serotonin norephinephrine re-uptake inhibitors) in the last 14 days
• Use of opioid medications (eg morphine, fentanyl, oxycodone, hydromorphone, methadone, codeine) in the previous 4 weeks.
• 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
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 the paucity of relevant data in ILD, sample size estimate is based on a study of COPD patients by Gagnon et al. (Gagnon et al 2012). This study (n=8) the authors observed that spinal anaesthesia, administered to inhibit central feedback of lower limb muscle afferents, increased endurance time, reduced ventilation and respiratory rate. It is estimated that a sample size of 15 patients will provide the power (80%) needed to detect meaningful differences of Borg dyspnoea ratings (20) of ±1.5 units, 86 s in exercise capacity, and 0.5 L/min peak minute ventilation between the control and intervention 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 fentanyl and control 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
Recruiting
Date of first participant enrolment
Anticipated
3/07/2023
Actual
26/07/2023
Date of last participant enrolment
Anticipated
29/03/2024
Actual
Date of last data collection
Anticipated
29/03/2024
Actual
Sample size
Target
15
Accrual to date
8
Final
Recruitment outside Australia
Country [1] 23556 0
New Zealand
State/province [1] 23556 0

Funding & Sponsors
Funding source category [1] 308149 0
Government body
Name [1] 308149 0
Health research council of NZ
Country [1] 308149 0
New Zealand
Funding source category [2] 308159 0
Hospital
Name [2] 308159 0
Greenlane Research and Educational Fund, Auckland District Health Board.
Country [2] 308159 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] 308914 0
None
Name [1] 308914 0
Address [1] 308914 0
Country [1] 308914 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308134 0
Northern A Health and Disability Ethics Committee, Ministry of Health New Zealand
Ethics committee address [1] 308134 0
Ethics committee country [1] 308134 0
New Zealand
Date submitted for ethics approval [1] 308134 0
17/04/2020
Approval date [1] 308134 0
29/07/2020
Ethics approval number [1] 308134 0
20/NTA/68

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

Contacts
Principal investigator
Name 109658 0
Dr Charlotte Chen
Address 109658 0
Faculty of health and medical sciences University of Auckland 85 Park Road Grafton Auckland 1023
Country 109658 0
New Zealand
Phone 109658 0
+64 093737599
Fax 109658 0
Email 109658 0
[email protected]
Contact person for public queries
Name 109659 0
Charlotte Chen
Address 109659 0
Faculty of health and medical sciences University of Auckland 85 Park Road Grafton Auckland 1023
Country 109659 0
New Zealand
Phone 109659 0
+64 093737599
Fax 109659 0
Email 109659 0
[email protected]
Contact person for scientific queries
Name 109660 0
Charlotte Chen
Address 109660 0
Faculty of health and medical sciences University of Auckland 85 Park Road Grafton Auckland 1023
Country 109660 0
New Zealand
Phone 109660 0
+64 093737599
Fax 109660 0
Email 109660 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.