Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000128695
Ethics application status
Approved
Date submitted
12/01/2023
Date registered
7/02/2023
Date last updated
4/04/2024
Date data sharing statement initially provided
7/02/2023
Date results information initially provided
7/02/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
Using electrical stimulation of the ear to change cough reflex sensitivity
Scientific title
Identifying optimal auricular stimulation parameters for modulating cough sensitivity in healthy human adults
Secondary ID [1] 308721 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stroke 328673 0
Dystussia 328674 0
Condition category
Condition code
Physical Medicine / Rehabilitation 325668 325668 0 0
Speech therapy
Stroke 325679 325679 0 0
Ischaemic
Neurological 325752 325752 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Non-invasive auricular stimulation was delivered to the seated participant for 10 minutes of continuous stimulation using a CE-approved home-use transcutaneous electrical nerve stimulation device. Single-use flexible hydrogel electrodes (RELI-Stick, Soterix Medical, New York, NY, USA) were placed on the concha and external auditory canal of the ear, with electrode gel applied on the electrodes. Stimulation intensity was adjusted at the beginning of each stimulation block as above the participant’s detection threshold and below their pain threshold. Delivery of intervention was performed by a research speech-language therapist, face-to-face and individually with each participant.

Each participant had 8 sessions of intervention, spaced at least 2 days apart, at a research laboratory. Stimulation parameters varied by stimulation side (right ear, left ear), stimulation zone (ear canal, concha), and stimulation frequency (25 Hz, 80 Hz), for a total of eight conditions. Each participant received 1 condition per visit, for a total of eight 1-hour visits. Order of visits were incompletely counterbalanced between participants. Two balanced Latin squares were used to generate 16 different visit sequences (https://cs.uwaterloo.ca/~dmasson/tools/latin_square/) and participants were randomly assigned to a sequence.
Intervention code [1] 325186 0
Rehabilitation
Intervention code [2] 325196 0
Treatment: Devices
Comparator / control treatment
This is a within-subjects study on healthy volunteers. Each participant will complete all 8 conditions., The active control condition is the 25 Hz, left ear concha stimulation condition. This is the standard stimulation parameter used in stroke rehabilitation currently.
Control group
Active

Outcomes
Primary outcome [1] 333534 0
Change in natural cough threshold, as assessed using a citric acid cough reflex test
Timepoint [1] 333534 0
Before and after 10 minutes of non-invasive auricular stimulation
Secondary outcome [1] 417455 0
Change in Suppressed cough threshold, as assessed using a citric acid cough reflex test
Timepoint [1] 417455 0
Before and after 10 minutes of non-invasive auricular stimulation

Eligibility
Key inclusion criteria
Healthy adult humans
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- History of swallowing, psychiatric, neurological, gastro-esophageal reflux, or cardio-respiratory disorders (e.g., chronic obstructive pulmonary disease or asthma);
- History of recent (< 2 weeks) acute upper respiratory tract infection;
- Current or previous smoker;
- Currently taking opioid or angiotensin-converting enzyme (ACE) inhibiting drugs;
- Currently pregnant;
- Presence of an implanted device (e.g., pacemaker).

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)
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
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
A previous sensory rehabilitation study completed in our lab indicated a cough threshold reduction of 1.2 mol/L after treatment, and standard deviation of .79 mol/L (Wallace, 2020). We have powered this study to detect a difference of 1.2 mol/L. Sample size calculations, using Lehr’s equation (van Belle, 2008) with a power of .95 and a Type I error rate of .05, indicates that 12 participants will need to be enrolled to detect a difference of 1.2 mol/L. To allow for 20% drop out and a balanced design, 16 participants will be recruited.

Linear mixed effects models will be used to investigate the effect of stimulation frequency, side, and zone on post-stimulation cough threshold. Separate models will be run for the two outcome measures of natural cough threshold and suppressed cough threshold. Fixed effects will be stimulation frequency (high, low), stimulation side (right, left), stimulation zone (ear canal, concha), and baseline cough sensitivity threshold. Random intercepts for participant and by-participant random slopes will be included to control for individual differences. Interactions between stimulation frequency, side, and zone will be analysed. If no significant interaction is found, the main effects of frequency, side, and zone will be analysed. If a main effect is found, post-hoc analyses will be completed using a t-test to determine significant differences between the two levels.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
1/03/2022
Date of last participant enrolment
Anticipated
Actual
30/08/2022
Date of last data collection
Anticipated
Actual
6/12/2022
Sample size
Target
16
Accrual to date
Final
16
Recruitment outside Australia
Country [1] 25206 0
New Zealand
State/province [1] 25206 0
Canterbury

Funding & Sponsors
Funding source category [1] 312945 0
Government body
Name [1] 312945 0
Health Research Council of New Zealand
Country [1] 312945 0
New Zealand
Primary sponsor type
Individual
Name
Yusuf Ozgur Cakmak
Address
Department of Anatomy
Otago School of Medical Sciences
University of Otago
PO Box 913, Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 314702 0
None
Name [1] 314702 0
Address [1] 314702 0
Country [1] 314702 0
Other collaborator category [1] 282524 0
University
Name [1] 282524 0
University of Canterbury Rose Centre for Stroke Recovery and Research
Address [1] 282524 0
Private Bag 4737
249 Papanui Rd
Christchurch 8140
Country [1] 282524 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312218 0
University of Otago, Human Ethics Committee (Health)
Ethics committee address [1] 312218 0
Room G22, Clocktower Building, Leith St,
University of Otago, Dunedin 9054
Ethics committee country [1] 312218 0
New Zealand
Date submitted for ethics approval [1] 312218 0
12/07/2021
Approval date [1] 312218 0
11/08/2021
Ethics approval number [1] 312218 0
H21/106

Summary
Brief summary
Neurological disease, such as stroke, has a devastating effect on sensation in the throat and the cough reflex. Without the ability to detect food or fluid from entering the lungs and eject it with a cough, stroke patients are at a high risk of developing chest infection. Chest infection is associated with prolonged hospitalisation, high death rate, and significant cost to the healthcare system. There are currently limited rehabilitation options available. Interestingly, probing the ear canal during a medical examination or having impacted ear wax can cause coughing. We propose to develop a protocol and explore the effect of using light electrical stimulation of the nerves within the outer ear (transcutaeneous auricular vagus nerve stimulation; taVNS) to improve cough sensitivity after stroke. Using a wearable device to stimulate the external ear has the potential of providing a portable, safe, non-invasive, and low-cost treatment for improving the cough reflex and boosting airway protection. The aim of this study is to find the optimal location and frequency of ear stimulation for improving cough reflex sensitivity in healthy participants. The effects of different stimulation frequencies (high vs. low), stimulation zone (ear canal vs. concha), and side of stimulation (right vs. left ear) on cough sensitivity will be investigated. The parameters in this study that result in the greatest decrease in citric acid cough threshold (i.e., greatest increase in cough sensitivity) will be used as the stimuluation parameters in a future randomised controlled trial investigating taVNS as a treatment for cough sensitivity in individuals with neurological disorders.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123886 0
A/Prof Yusuf Ozgur Cakmak
Address 123886 0
Department of Anatomy
School of Biomedical Sciences
University of Otago
PO BOX 913, DUNEDIN 9054
Country 123886 0
New Zealand
Phone 123886 0
+6434794030
Fax 123886 0
Email 123886 0
yusuf.cakmak@otago.ac.nz
Contact person for public queries
Name 123887 0
A/Prof Yusuf Ozgur Cakmak
Address 123887 0
Department of Anatomy
School of Biomedical Sciences
University of Otago
PO BOX 913, DUNEDIN 9054
Country 123887 0
New Zealand
Phone 123887 0
+6434794030
Fax 123887 0
Email 123887 0
yusuf.cakmak@otago.ac.nz
Contact person for scientific queries
Name 123888 0
A/Prof Yusuf Ozgur Cakmak
Address 123888 0
Department of Anatomy
School of Biomedical Sciences
University of Otago
PO BOX 913, DUNEDIN 9054
Country 123888 0
New Zealand
Phone 123888 0
+6434794030
Fax 123888 0
Email 123888 0
yusuf.cakmak@otago.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
Results will be published and the method/data/results/outcome will be open access.


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.