Please be advised that due to the high volume of submissions, the ANZCTR is currently experiencing delays in processing submissions from those outside of Australia and New Zealand. As the ANZCTR is funded by Australia and New Zealand, we must prioritise submissions from these countries first. International submissions should allow additional time for registration. Apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12616001495415
Ethics application status
Approved
Date submitted
21/10/2016
Date registered
28/10/2016
Date last updated
16/04/2019
Date data sharing statement initially provided
16/04/2019
Date results information initially provided
16/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Exploratory and safety study: Modulation of the cough reflex using ultrasonically nebulised distilled water (UNDW)
Scientific title
Exploratory and safety study: Modulation of the cough reflex using ultrasonically nebulised distilled water (UNDW) in healthy participants.
Secondary ID [1] 290362 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dysphagia 300661 0
Dystussia 300692 0
Condition category
Condition code
Respiratory 300513 300513 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will be conducted over 5 days. On day one, participants’ citric acid cough thresholds will be obtained. Citric acid cough threshold will be obtained by exposing participants to incrementally increasing concentrations of citric acid (0.01 to 3.2 mol/l). Citric acid will be administered using a breath activated dosimeter and a jet nebuliser (De Vilbiss 646). Participants will take three single inhalations of the citric acid until they produce a C2 cough response at a given concentration. Their cough threshold will be confirmed by re-administering the same concentration. Cough threshold is defined as the lowest concentration of citric acid capable of eliciting a C2 cough response, on the same concentration of citric acid twice Participants will also rate their urge to cough (UTC) following each citric acid inhalation.

Following phase one, participants will be randomly assigned to a supra-threshold group or a sub-threshold group. A no-treatment control group will also be included, in which participants receive inhalations of saline in place of distilled water. The supra-threshold group will receive the maximum nebulising output from the nebuliser 1.6 ml/min and the sub-threshold group will receive 0.5 ml/min. Participants will inhale UNDW once a day for 4 days (Tuesday - Friday).

Repeated rapid stimulation of UNDW, in cycles of 5 breaths + 10 sec break x 5 times (totalling approx. 1 minute of direct UNDW stimulation per cycle), will be used to stimulate and modulate the cough reflex. These cycles will be repeated 12 times per session. Between each cycle, there will be a minimum of a 1-minute break. Spirometry will be taken at regular intervals throughout the cycles. Total sensory stimulation session will be 1 hour 30 mins.

Comparisons between these groups will determine the optimal and safest stimulation parameters to enhance cough sensitivity. Outcome measures will include pre-treatment, mid-treatment (3 days) and post-treatment (5 days) citric acid cough reflex threshold testing. Respiratory measures (forced expiratory volume in 1 second) will be taken throughout and in between stimulation to ensure the safety of the protocol.
Intervention code [1] 296184 0
Rehabilitation
Intervention code [2] 296208 0
Treatment: Other
Comparator / control treatment
The control group will inhale 0.9% saline inhalations under the same inhalation parameters as the distilled water inhalation groups.
Control group
Active

Outcomes
Primary outcome [1] 299937 0
Primary outcome measure will be citric acid cough threshold. Participants will inhale increasing concentrations of citric acid (0.01 - 3.2 mol/L) until their cough threshold is reached. Cough threshold is defined as the concentration of citric acid that evoked 2 or more consecutive coughs. Saline aerosols will be randomly interspersed to increase the challenge blindness.
Timepoint [1] 299937 0
Pre intervention, day 3 and day 5.
Primary outcome [2] 305185 0
Urge-to cough will be measured during the citric acid cough threshold testing. Participants will rate their urge-to-cough using a modified Borg rating scale from 1-10 after each citric acid inhalation.
Timepoint [2] 305185 0
Baseline (day 1), day 3 day 5.
Primary outcome [3] 305186 0
Throughout the treatment protocol, spirometry will be performed to monitor the safety of the protocol and the presence of bronchoconstriction. (This is a composite outcome measure for both safety and the presence of bronchoconstriction), Spirometry will be performed every at baseline and every 3-4 cycles of distilled water inhalation (or more regularly if needed). This will be guided by the respiratory physiologist.
Timepoint [3] 305186 0
This will be completed throughout the intervention at regular intervals - baseline and after every 100 inhalations of distilled water.
Secondary outcome [1] 344448 0
Cough frequency of citric acid cough threshold: We will record the number of coughing events to citric acid at baseline, day 3 and day 5. This will be recorded on an audio recording application during citric acid cough threshold testing.
Timepoint [1] 344448 0
Baseline, day 3 and day 5.

Eligibility
Key inclusion criteria
Participants must be healthy and capable of providing informed, written consent to participate.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
History of asthma, neurological disorders, respiratory diseases or gastro-esophageal reflux.
Any participants ACE inhibitor drugs, codeine, smoking, or have had a upper respiratory chest infection in the past 2 weeks..

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 concealled
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Citric acid cough thresholds were re-coded from 1-7, one representing 0.05 mol/L and seven representing 3.2 mol/L. No participants’ cough threshold was 0.01 mol/L. Participants who did not respond at the highest concentration of citric acid were coded as missing data, so that variability was not skewed by assigning a false value. Linear mixed effects models were used to estimate the interaction effect between day and group on NCT and SCT. In the linear mixed-effects analysis, the interaction between day and group was entered as a fixed effect into the model and intercepts for each participant were included as a random effect. The inclusion of the interaction effect was firstly evaluated by comparing the model with and without the interaction effect using a likelihood ratio test. If the likelihood ratio test was significant (i.e. p-value <0.05) the analysis was continued and the coefficient estimates, 95% confidence intervals and p-values of the model coefficients are reported. If the likelihood ratio test was non-significant (i.e. p-value >0.05) no further analyses were completed.

For UTC data, linear mixed effects models were used to estimate the interaction effect between day and group on UTC at NCT, SCT and subthreshold citric acid concentration (i.e. 0.05 mol/L). The interaction between day and group was entered as a fixed effect into the model, and intercepts for each participant were included as a random effect. As above, the inclusion of the interaction effect was firstly evaluated by comparing the model with and without the interaction effect using a likelihood ratio test. If the likelihood ratio test was significant (i.e. p-value <0.05) the analysis was continued and the coefficient estimates, 95% confidence intervals and p-values of the model coefficients are reported. If the likelihood ratio test was non-significant (i.e. p-value >0.05) no further analyses were completed. Data were analysed using R statistical package (R Core Team, 2017) and a linear mixed effects models statistical package, lme4 (Bates et al., 2015). A p-value of 0.05, or less, was considered statistically significant.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 8340 0
New Zealand
State/province [1] 8340 0
Canterbury

Funding & Sponsors
Funding source category [1] 294753 0
University
Name [1] 294753 0
University of Canterbury Rose Centre for Stroke Recovery and Research
Address [1] 294753 0
University of Canterbury, Rose Centre for Stroke Recovery and Research,
Level 1, Leinster Chambers,
St Georges Medical Centre,
249 Papanui Road.
Christchurch, 8014
New Zealand.
Country [1] 294753 0
New Zealand
Funding source category [2] 295129 0
Government body
Name [2] 295129 0
Health Research Council of New Zealand
Address [2] 295129 0
PO Box 5541, Wellesley Street, Auckland 1141
Country [2] 295129 0
New Zealand
Primary sponsor type
University
Name
University of Canterbury
Address
University of Canterbury, Rose Centre for Stroke Recovery and Research,
Level 1, Leinster Chambers,
St Georges Medical Centre,
249 Papanui Road.
Christchurch, 8014
New Zealand.
Country
New Zealand
Secondary sponsor category [1] 293603 0
None
Name [1] 293603 0
Address [1] 293603 0
Country [1] 293603 0
Other collaborator category [1] 279271 0
Individual
Name [1] 279271 0
Dr Phoebe Macrae
Address [1] 279271 0
University of Canterbury, Rose Centre for Stroke Recovery and Research,
Level 1, Leinster Chambers,
St Georges Medical Centre,
249 Papanui Road.
Christchurch, 8014
New Zealand.
Country [1] 279271 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296168 0
Health and Disability Ethics Committees (HDEC)
Ethics committee address [1] 296168 0
Health and Disability Ethics Committees
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington, 6011
Ethics committee country [1] 296168 0
New Zealand
Date submitted for ethics approval [1] 296168 0
01/11/2016
Approval date [1] 296168 0
21/04/2017
Ethics approval number [1] 296168 0

Summary
Brief summary
Background: This project seeks to answer the clinical question of whether it is possible to rehabilitate the cough reflex. Dysphagia refers to disordered swallowing, the nature of which can be neurological, structural (due to injury or cancer), or developmental. Patients with dysphagia are at high risk of dystussia (impairment of the cough reflex), which is unsurprising given the close association of the neural, anatomical and physiological mechanisms involved in both reflexes. Coughing serves as a vital airway protective mechanism, and is of particular importance for patients with dysphagia, for which
aspiration (when food/liquid enters the airway below the vocal cords) frequently occurs. In the absence of an intact cough reflex, these patients are at risk of silent aspiration (aspiration in the absence of triggering a cough reflex) and aspiration pneumonia (lung infection from inhalation of food/liquids) and are generally considered unsafe for oral intake. Both the sensory and motor components of the cough reflex can be impaired. The citric acid cough reflex test (CRT) is a reliable, objective, clinically applicable assessment of cough sensitivity that enables clinicians to identify patients at risk of silent aspiration with high sensitivity and specificity (Miles et al, 2013; Miles & Huckabee, 2013, Miles et al, 2014). The introduction of a CRT protocol for acute stroke patients in Christchurch Hospital alone reduced the prevalence of aspiration pneumonia from 26% to 11%, with estimated savings of $1.4 million [press release - Retrieved from
http://www.cdhb.health.nz/News/Media-Releases/Pages/Outstanding-Quality-Improvement-
Innovation-Awards.aspx)]. While clinicians can now identify patients with an absent or impaired cough reflex at bedside, there are currently no treatments available for them. Many patients are placed on non-oral methods of feeding and are not prescribed swallowing rehabilitation exercises to promote their recovery, due to their high risk of aspiration and pulmonary system compromise. Successful rehabilitation of the cough reflex would offer patients the opportunity to engage in swallowing rehabilitation while maintaining adequate airway protection. It would also offer clinicians the opportunity to assume an active rehabilitation role.
Objectives: This aim of this study is to determine the optimal parameters to safely enhance cough reflex sensitivity (as measured by citric acid cough reflex threshold) in healthy individuals, using ultrasonically nebulised distilled water (UNDW), which is a known tussigenic agent currently used in cough challenge tests.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69814 0
Miss Emma Wallace
Address 69814 0
University of Canterbury Rose Centre for Stroke Recovery and Research,
Level 1, Leinster Chambers,
St Georges Medical Centre,
249 Papanui Road,
Christchurch, 8014,
New Zealand.
Country 69814 0
New Zealand
Phone 69814 0
+64 027 456 21 69
Fax 69814 0
Email 69814 0
emma.wallace@pg.canterbury.ac.nz
Contact person for public queries
Name 69815 0
Miss Emma Wallace
Address 69815 0
University of Canterbury Rose Centre for Stroke Recovery and Research,
Level 1, Leinster Chambers,
St Georges Medical Centre,
249 Papanui Road,
Christchurch, 8014,
New Zealand.
Country 69815 0
New Zealand
Phone 69815 0
+64 027 456 21 69
Fax 69815 0
Email 69815 0
emma.wallace@pg.canterbury.ac.nz
Contact person for scientific queries
Name 69816 0
Miss Emma Wallace
Address 69816 0
University of Canterbury Rose Centre for Stroke Recovery and Research,
Level 1, Leinster Chambers,
St Georges Medical Centre,
249 Papanui Road,
Christchurch, 8014,
New Zealand.
Country 69816 0
New Zealand
Phone 69816 0
+64 027 456 21 69
Fax 69816 0
Email 69816 0
emma.wallace@pg.cantebruy.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
No, as participants did not sign consent to have their individual data shared for this trial. Secondly, the ethics application for the current study did not specify that this data would be shared.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Yes
Other publication details
Citation type [1] 1634 0
Thesis/dissertation
Citation/DOI/link/details [1] 1634 0
Not currently available online. As soon as the thesis is available on the university library I will update this field.
Attachments [1] 1634 0
Results – basic reporting
Results – plain English summary
In this study, we wanted to know whether we could safely modulate and enhance cough sensitivity using inhalations of distilled water. The distilled water senosory stimulation protocol was designed as a potential treatment for silent aspiration, where individuals aspirate due to a lack of sensation in their throat. We wanted to determine if the sensory stimulation protocol was safe on pulmonary function and whether it could modulate cough sensitivity.

We recruited 28 healthy volunteers to undergo the distilled water sensory stimulation protocol. Four participants were excluded, as they were not suitable to participate in the study. A total of 24 individuals, 8 per group, were included in the final analysis.

The distilled water sensory stimulation protocol did not induce narrowing of the airways (i.e. bronchoconstriction) in any participant. Cough sensitivity changed differently across days in the high and low-intensity sensory stimulation groups, compared to the control group. In the control group, cough sensitivity increased across days. This is what we expect when we repeat the citric acid cough reflex test across days. In contrast, an absence of habituation to citric acid CRT was observed following both of the sensory stimulation protocols, suggesting an increase in cough sensitivity.