Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000268640
Ethics application status
Approved
Date submitted
20/02/2023
Date registered
13/03/2023
Date last updated
25/09/2023
Date data sharing statement initially provided
13/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of electrical stimulation of the ear on cough reflex after stroke
Scientific title
Modulation of cough sensitivity using auricular stimulation in stroke: a randomised pilot trial
Secondary ID [1] 308943 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dystussia 328952 0
Stroke 328953 0
Condition category
Condition code
Stroke 325940 325940 0 0
Haemorrhagic
Physical Medicine / Rehabilitation 325941 325941 0 0
Speech therapy
Stroke 325942 325942 0 0
Ischaemic

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

There will be three conditions: A) standard active stimulation (10 min of 20Hz concha stimulation), B) experimental active stimulation (10 min of 80Hz canal stimulation), and C) sham stimulation (no stimulation). Each participant will be randomly allocated to receive 1 of the 3 conditions. For the two active stimulation groups, the stimulation intensity will be determined for each participant with the electrodes in place, and then stimulation will be delivered at that intensity for 10 minutes.

Participants will take part in the baseline outcome measurements (1 session of approximately 15 minutes). After 2-4 hours (on the same day), they will take part in a second session comprising intervention and post-intervention outcome measures, for approximately 30 minutes.
Intervention code [1] 325392 0
Rehabilitation
Comparator / control treatment
For sham stimulation, the stimulator and electrodes will be applied to the ear, and the participant's perceptual threshold of stimulation intensity will be determined, similar to the other active conditions. However, during the "stimulation period," the stimulator will not be turned on and the participant will remain seated for the 10 minute period.
Control group
Active

Outcomes
Primary outcome [1] 333792 0
Citric acid cough test response, as assessed using a citric acid cough reflex test
Timepoint [1] 333792 0
Change between 2-4 hours before stimulation, to immediately after stimulation
Secondary outcome [1] 418312 0
Urge-to-cough change at cough threshold, as assessed using modified Borg scale
Timepoint [1] 418312 0
Change between 2-4 hours before stimulation, to immediately after stimulation
Secondary outcome [2] 426313 0
completion rate (percentage of recruited participants that completed the study), as measured by an audit of study logs.
Timepoint [2] 426313 0
At the end of session 2
Secondary outcome [3] 426314 0
completion time (number of minutes for a participant to complete outcome measures and intervention), measured using a stopwatch.
Timepoint [3] 426314 0
At the beginning and end of session 1, and beginning and end of session 2

Eligibility
Key inclusion criteria
Inclusion criteria are as follows: (1) diagnosis of cerebrovascular accident; (2) reduced cough reflex sensitivity (defined as absence of two consecutive strong coughs within 15 seconds of initiating 0.6 mol/L citric acid delivery during clinical natural cough reflex test, on 2/3 trials); and (3) ability to follow study directions and provide informed consent given supported decision-making.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Due to possible effects on cough sensitivity, participants will be excluded if they have history of other neurological or respiratory diseases that might impact cough function; have poorly-controlled reflux; are currently taking opioid pain or angiotensin-converting enzyme (ACE) inhibiting drugs; had a recent (< 2 weeks) acute upper respiratory tract infection; or are a current or previous smoker.
Due to safety considerations when receiving auricular stimulation, participants will be excluded if they are pregnant or trying to get pregnant; or have an implanted electrical device (e.g., pacemaker).
Due to possible risk of bronchoconstriction during citric acid cough reflex test, participants will be excluded if they have asthma; history of respiratory disease; or intolerance/insensitivity to citric acid or citrus fruits.

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)
Block randomisation will be used, ensuring that random assignment into groups results in equal sample sizes across groups over time. This was completed using www.randomizer.org.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size calculation: In a previous (unpublished) study using healthy participants and cough threshold testing, the estimated effect size of the mean standardised difference between left concha 25 Hz (standard) and left canal 80 Hz stimulation (experimental) was 0.8, indicating a large effect size. For an 80% powered main trial where the standardised effect size is medium to large, the rule of thumb for pilot trial sample sizes per treatment arm is 10 (Whitehead et al., 2016). Therefore, we planned that a pilot trial sample size of 10 participants per group (30 participants total) would be recruited.

Proposed statistical analysis plan: Descriptive statistics will be reported for baseline and post-stimulation. This will include frequencies and percentages of present/absent cough response and mean and SD for urge-to-cough rating, at baseline and post-stimulation.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
24/07/2023
Actual
14/08/2023
Date of last participant enrolment
Anticipated
30/09/2024
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
3
Final
Recruitment outside Australia
Country [1] 25251 0
New Zealand
State/province [1] 25251 0

Funding & Sponsors
Funding source category [1] 313155 0
Government body
Name [1] 313155 0
Health Research Council of New Zealand
Country [1] 313155 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] 314965 0
None
Name [1] 314965 0
Address [1] 314965 0
Country [1] 314965 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312395 0
Northern A Health and Disability Ethics Committee, New Zealand
Ethics committee address [1] 312395 0
Ministry of Health
PO Box 5013, Wellington 6140
Ethics committee country [1] 312395 0
New Zealand
Date submitted for ethics approval [1] 312395 0
20/02/2023
Approval date [1] 312395 0
01/05/2023
Ethics approval number [1] 312395 0

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. There are currently limited rehabilitation options available for improving cough sensitivity. Interestingly, probing the ear canal during a medical examination or having impacted ear wax can cause coughing. Non-invasive auricular stimulation has been found to improve upper limb and swallowing function after stroke, however the effect of auricular stimulation on cough sensitivity is unknown. In a study with a non-patient population, we found that 80 Hz ear canal stimulation resulted in a greater increase in cough sensitivity compared to the standard 25 Hz concha stimulation parameter most commonly used in the literature.

The goal of this pilot study is to determine the feasibility of a future definitive randomised controlled trial, by quantifying recruitment and completion rate, completion time, and treatment effect size of auricular stimulation on cough function. A parallel study design will be used where stroke patients will receive 1 of 3 types of stimulation: standard active stimulation (25 Hz, left concha), experimental active stimulation (80 Hz, left canal), and sham stimulation. This research can provide important information for developing a future randomised controlled trial investigating taVNS as a potential rehabilitation approach for reducing silent aspiration and risk of chest infection.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124514 0
A/Prof Yusuf Ozgur Cakmak
Address 124514 0
Department of Anatomy
School of Biomedical Sciences
University of Otago
PO BOX 913, DUNEDIN 9054
Country 124514 0
New Zealand
Phone 124514 0
+64 34794030
Fax 124514 0
Email 124514 0
yusuf.cakmak@otago.ac.nz
Contact person for public queries
Name 124515 0
A/Prof Yusuf Ozgur Cakmak
Address 124515 0
Department of Anatomy
School of Biomedical Sciences
University of Otago
PO BOX 913, DUNEDIN 9054
Country 124515 0
New Zealand
Phone 124515 0
+64 34794030
Fax 124515 0
Email 124515 0
yusuf.cakmak@otago.ac.nz
Contact person for scientific queries
Name 124516 0
Dr Karen Ng
Address 124516 0
University of Canterbury Rose Centre for Stroke Recovery and Research
Leinster Chambers, Level 1
249 Papanui Road, Christchurch 8140
Country 124516 0
New Zealand
Phone 124516 0
+64 3 369 1786
Fax 124516 0
Email 124516 0
karen.ng@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


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.