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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 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]

Nil

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Dysphagia

Dystussia

Condition category

Condition code

Respiratory

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]

Rehabilitation

Intervention code [2]

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]

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]

Pre intervention, day 3 and day 5.

Primary outcome [2]

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]

Baseline (day 1), day 3 day 5.

Primary outcome [3]

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]

This will be completed throughout the intervention at regular intervals - baseline and after every 100 inhalations of distilled water.

Secondary outcome [1]

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]

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

Sex

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

2/01/2017

Actual

22/01/2018

Date of last participant enrolment

Anticipated

30/11/2018

Actual

6/08/2018

Date of last data collection

Anticipated

7/12/2018

Actual

24/08/2018

Sample size

Target

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Canterbury

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Canterbury Rose Centre for Stroke Recovery and Research

Address [1]

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]

New Zealand

Funding source category [2]

Government body

Name [2]

Health Research Council of New Zealand

Address [2]

PO Box 5541, Wellesley Street, Auckland 1141

Country [2]

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]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

Individual

Name [1]

Dr Phoebe Macrae

Address [1]

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]

New Zealand

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Health and Disability Ethics Committees (HDEC)

Ethics committee address [1]

Health and Disability Ethics Committees
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington, 6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

01/11/2016

Approval date [1]

21/04/2017

Ethics approval number [1]

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

Miss Emma Wallace

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

Phone

+64 027 456 21 69

Fax

emma.wallace@pg.canterbury.ac.nz

Contact person for public queries

Name

Emma Wallace

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

Phone

+64 027 456 21 69

Fax

emma.wallace@pg.canterbury.ac.nz

Contact person for scientific queries

Name

Emma Wallace

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

Phone

+64 027 456 21 69

Fax

emma.wallace@pg.cantebruy.ac.nz

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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 Supporting Document Provided

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Thesis	No		Not currently available online. As soon as the the... [More Details]
Plain language summary	No		In this study, we wanted to know whether we could ... [More Details]

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