Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000422628
Ethics application status
Approved
Date submitted
23/03/2023
Date registered
28/04/2023
Date last updated
10/05/2023
Date data sharing statement initially provided
28/04/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Altering the cough response after stroke
Scientific title
Altering cough thresholds in stroke patients with use of ultrasonically distilled water in a sensory stimulation protocol
Secondary ID [1] 302337 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dysphagia 319106 0
Dystussia 319107 0
Condition category
Condition code
Stroke 317065 317065 0 0
Ischaemic
Stroke 317066 317066 0 0
Haemorrhagic
Respiratory 317067 317067 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will be a prospective study with participants allocated to a treatment or a sham group if they meet the inclusion criteria for the study in session one. The intervention arm is ultrasonically nebulized distilled water and the comparator sham arm is physiologic saline (0.9% sodium chloride). The group allocation will be counterbalanced. The primary outcome measure is cough sensitivity. Participants are required to attend 12 sessions at the research centre. Participant checklists will be used to document session attendance.

Fully trained personnel will administer all aspects of the research. Researchers conducting spirometry will be certified by the Respiratory Physiology Laboratory at Christchurch Hospital. A respiratory physician will be available for all sessions to assist with the management of any bronchoconstriction.

The study will take place over a three-week period. The duration of the sessions varies through the study as detailed below.
- Week 1 comprises of two sessions. Session 1 is a screening session, to ensure participants meet the criteria for the study. The session will take up to 1 hr. Session 2 consists of a cough test and will take up to 40mins.
- Weeks 2 and 3 (sessions 3 - 12) are the most intensive with participants required to attend the Rose Centre for daily sessions (excluding weekends) for a two week period. Six of the sessions will take up to 1hr, and four of the sessions will take up to 1hr 30mins (total 12hrs).

PROCEDURES
Prior to the screening session, a phone call will occur to answer any questions the participant has and to ensure no exclusion criteria are met.

Week 1 - Session 1
Participants will be required to attend the research centre and give written consent to participate in the study. Participants will complete lung function testing (see below). If their lung function is within normal limits, they will then complete a cough test (see below). This concludes the initial screening session. If they exhibit exclusionary patterns of respiratory function (see below) or cough in response to the 0.4mol/L concentration of citric acid during the cough response test, they will be excluded from further participation. They will be given a $10 MTA voucher to reimburse them for their travel expenses.

Lung function testing (spirometry)
Baseline spirometry will be taken in the initial session to ensure that the participant meets the inclusion criteria for the study. Spirometry will be performed on all participants by qualified clinicians certified in spirometry assessment. Age, height and weight (wearing indoor clothes without shoes) will be recorded to enable calculation of reference values. The test will be explained and they will be given instructions and a demonstration of what is required to perform the test.

If their spirometry results are within the reference range the participant will be invited to continue with the study. If an obstructive pattern of respiratory function is indicated, the participant will not meet the inclusion criteria for the study. If a restrictive pattern is suggested by the results, and this has not been previously investigated, the participants GP will be informed with their consent. The GP will be required to approve their ongoing participation before they can continue with the study.

Cough threshold testing
Citric acid will be delivered through a mouthpiece attached to a jet nebuliser using a breath activated dosimeter and driven by an air compressor. Participants will be given instructions and a demonstration of what is required to perform the test. Nebulised citric acid will be given in ascending order from 0.4 - 3.2 mol/L (in increments of 0.4 mol/L), alongside interspersed placebo doses of physiologic saline (0.9% sodium chloride). The placebo doses will be given at identified points and this will be consistent across participants. Physiologic saline is isotonic, and therefore, is frequently used as a control condition in respiratory studies (Khan & O'Driscoll, 2004). Three inhalations of 1.2 s doses of citric acid (or saline) will be inhaled through a mouthpiece, for each trial. Tachyphylaxis is recognised to occur with repeated inhalations of citric acid (Morice et al., 2007). There will be up to a three minute break between each trial to minimize the effects of tachyphylaxis. Participants will be blinded to what they are inhaling.

A cough threshold will be defined as two consecutive coughs (C2 response), on the same concentration of citric acid for two successive trials with an interspersed trial of saline. The natural cough threshold (NCT) will be identified with the instruction for participants to “inhale and exhale three times, and cough if you need to”.

After each inhaled concentration of citric acid or physiologic saline trialled, participants will be asked to “rate their urge to cough” on a visual analogue scale (VAS) presented on a tablet device. One end of the scale will be marked as ‘no urge’ and the other marked ‘maximum urge’. They will be told to focus on the strength of their urge to cough, and to ignore any sensations unrelated to coughing (such as irritation or the taste of the citric acid).

Week 1 (Session 2)
Participants will be required to attend the research centre for a cough test. Cough threshold testing will be conducting as described previously (in session 1).

Week 2 and 3 (Sessions 3 – 12)
For this part of the study participants will be required to attend the research centre daily. Every session will include the stimulation protocol and lung function testing to ensure the safety of the protocol (see below). Additionally, for four of the sessions (3, 7, 8, and 12) they will have a cough threshold test to monitor changes in cough sensitivity.

Cough threshold testing
As described previously.

Lung function testing (spirometry)
Spirometry will be completed on four occasions in each session. Each test will take approximately five minutes. It will be completed once before, twice during and once after completion of the stimulation. Spirometry will be performed on all participants by researchers certified in spirometry assessment. A respiratory physician will be aware of each session, and available on the medical centre grounds at all times to address any concerns or any instances of bronchoconstriction.

If a participant was to show signs of bronchoconstriction (lung inflammation) at any time during the study, they will be treated with a bronchodilator (inhaler) under the guidance of a respiratory physician until their lung function returns to normal. They will be excluded from further participation in the study.

All participants will be provided with contact details of a designated respiratory physician and will be encouraged to contact the physician if they feel wheezy or short of breath in the 24 hours following the session. If required, another researcher who is not blinded to the sensory stimulation allocation will liaise with the respiratory physician and will discuss the parameters of the participants stimulation with them.

Stimulation
Participants will receive 3,000 high flow rate inhalations (1.6 ml/min) of either (1) distilled water or (2) physiologic saline (0.9% sodium chloride) over a period of ten sessions across ten days (i.e. 300 inhalations per session). Stimulation will not occur over the weekend, as a respiratory physician is not available. Each session is made up of 12 cycles and in each cycle the participant will receive 25 inhalations. Participants will have a ten second break after each five inhalations, and a one minute break between cycles. Spirometry will be performed four times within each session as described above.
Intervention code [1] 318629 0
Rehabilitation
Comparator / control treatment
The sham group will receive inhalations of physiologic saline (0.9% sodium chloride)
Control group
Placebo

Outcomes
Primary outcome [1] 334217 0
Cough thresholds assessed using citric acid cough threshold testing
Timepoint [1] 334217 0
Baseline thresholds: session 1
Threshold testing (no stimulation): session 2
Threshold testing (stimulation): sessions 3, 7, 8, 12
Secondary outcome [1] 419866 0
Lung function testing (spirometry)
For baseline testing, forced vital capacity (FVC), forced expired volume in one second (FEV1) and FEV1/FVC (%) will be measured. For ongoing lung monitoring during the study, only FEV1 will be reported to monitor for signs of bronchoconstriction (defined by a greater than or equal to 15% drop in FEV1).
Timepoint [1] 419866 0
Baseline spirometry: session 1
During stimulation: sessions 3-12

Eligibility
Key inclusion criteria
Participants will be/have:
- Over the age of 18 years
- Able to give informed consent
- A diagnosed stroke
- Intact volitional cough (indicating that motor innervation of the cough response is intact)
- An absent cough response to a 0.4 mol/L concentration of citric acid (completed in Session 1 after giving consent)
- Spirometry results that do not demonstrate an obstructive pattern (a lung function ratio that is below the lower limit of the normal range – (completed in Session 1 after giving consent)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will not be/have:
- A communication or cognitive impairment
- A diagnosed progressive neurological disease (eg Multiple Sclerosis, Motor Neurone Disease, Parkinson’s Disease)
- A history of cancer of the head, neck or lungs
- Any history of respiratory conditions including COPD and asthma (or any prior use of an inhaler)
- A current smoker / vaper or have ceased smoking within last 6 months
- Poorly controlled reflux
- Currently taking or have taken any opioid pain medications in the last 6 months
- Currently taking or have taken any ACE inhibitor medications in the last 3 months
- Currently taking or have taken any antipsychotic medications in the last 6 months
- A current or recent respiratory tract infection in the last 2 weeks including displaying symptoms of a cold, flu or COVID-19
- A myocardial infarction in the last 4 weeks
- Eye surgery in the last 2 weeks
- Previous bad reaction to any inhaled therapies in the past (e.g. allergic type reaction)

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/05/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment outside Australia
Country [1] 25339 0
New Zealand
State/province [1] 25339 0

Funding & Sponsors
Funding source category [1] 306766 0
Other
Name [1] 306766 0
Health Research Council of New Zealand - Explorer Grant awarded to Phoebe Macrae
Country [1] 306766 0
New Zealand
Primary sponsor type
University
Name
University of Canterbury
Address
University of Canterbury Rose Centre for Stroke Recovery and Research
St Georges Medical Centre
249 Papanui Road
Christchurch 8014
Country
New Zealand
Secondary sponsor category [1] 315248 0
None
Name [1] 315248 0
Address [1] 315248 0
Country [1] 315248 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306931 0
Northern B Health and Disability Ethics Committee (HDEC)
Ethics committee address [1] 306931 0
Ethics committee country [1] 306931 0
New Zealand
Date submitted for ethics approval [1] 306931 0
Approval date [1] 306931 0
27/05/2021
Ethics approval number [1] 306931 0

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

Contacts
Principal investigator
Name 105490 0
Dr Phoebe Macrae
Address 105490 0
The University of Canterbury Rose Centre for Stroke Recovery and Research,
St Georges Medical Centre, Leinster Chambers, Level 1,
Private Bag 4737,
249 Papanui Road,
Christchurch, 8014
Country 105490 0
New Zealand
Phone 105490 0
+64 33692385
Fax 105490 0
Email 105490 0
[email protected]
Contact person for public queries
Name 105491 0
Phoebe Macrae
Address 105491 0
The University of Canterbury Rose Centre for Stroke Recovery and Research,
St Georges Medical Centre, Leinster Chambers, Level 1,
Private Bag 4737,
249 Papanui Road,
Christchurch, 8014
Country 105491 0
New Zealand
Phone 105491 0
+64 33692385
Fax 105491 0
Email 105491 0
[email protected]
Contact person for scientific queries
Name 105492 0
Phoebe Macrae
Address 105492 0
The University of Canterbury Rose Centre for Stroke Recovery and Research,
St Georges Medical Centre, Leinster Chambers, Level 1,
Private Bag 4737,
249 Papanui Road,
Christchurch, 8014
Country 105492 0
New Zealand
Phone 105492 0
+64 33692385
Fax 105492 0
Email 105492 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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
18667Study protocol    380608-(Uploaded-05-05-2023-09-54-02)-Study-related document.docx
18668Informed consent form    380608-(Uploaded-05-05-2023-09-54-50)-Study-related document.docx



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.