Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000300774
Ethics application status
Approved
Date submitted
8/02/2022
Date registered
16/02/2022
Date last updated
11/01/2023
Date data sharing statement initially provided
16/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Characterisation of voice and swallowing in individuals with chronic cough
Scientific title
Characterisation of upper aerodigestive tract dysfunction in individuals with chronic cough
Secondary ID [1] 306075 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic cough 324724 0
Condition category
Condition code
Respiratory 322174 322174 0 0
Other respiratory disorders / diseases
Musculoskeletal 322402 322402 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Please note that this study does not involve an intervention as such. However, because the study protocol (i.e., assessments used) goes beyond a typical medical investigation of patients with chronic cough, it cannot be classed as purely observational.

All participants will undergo the following assessment protocol:
- Questionnaire completed
- Respiratory and respiratory-swallowing measures including
a) assessment of breathing at rest (i.e., while seated in a chair, not talking or eating)
b) spirometry (lung function testing)
- Swallowing measures including
a) Timed Water Swallow Test (TWST; drinking 150mL water as quickly as possible)
b) Test of Masticating and Swallowing Solids (TOMASS; eating a cracker as quickly as possible)
c) Videofluoroscopic Swallowing Study (VFSS), a video x-ray of participants whilst eating/drinking various amounts of water, and a cracker. Water will be mixed with a barium contrast powder to allow visualisation of the bolus on VFSS (69 g to every 150mL water). Barium contrast paste will be spread on cracker to thinly coat.
- Voice assessment tasks including
a) endoscopic voice imaging (using a flexible camera in the throat to assess gross anatomy)
b) stroboscopic voice imaging (using the same flexible camera in the throat to assess vocal fold movement and vibration)
c) audio recording of the voice, for offline analysis. Participants will do the following during the voice assessment:
1) humming
2) sustained vowel sounds "eee" and "aaa"
3) pitch glide (i.e., from lowest note to highest note, and back down, like a siren)
4) counting from 1-5 with increasing volume (i.e., from lowest non-whispering volume to
shouting)
5) repetition of the sentence "how hard did he hit him"
6) conversation, prompted by asking the participant "tell me about your weekend"
- Laryngeal sensitivity measures including:
a) Presence or absence of the laryngeal adductor reflex i.e., whether a cough response
occurs when the larynx (voice box) is touched with a flexible camera
b) cough sensitivity threshold to an inhaled citric acid mist

Most participants will undergo the above assessment once. This will be completed during one assessment session which will take up to four hours. A subset of patients will undergo the assessment twice, eight weeks apart, to monitor progress over time with usual treatment. This subset will be comprised of participants in the chronic cough group who are currently undergoing treatment for their coughing. In this subset, the treatment will not be completed as part of the study i.e., the group are being assessed prior to and after eight weeks of treatment; change over time is being assessed rather than a specific therapeutic protocol. The assessments will be conducted by a Speech-Language Therapist (SLT)/PhD student. The individual is trained and competent to conduct all assessments, and is certified to practice First Aid. Assessment will be conducted face-to-face, with a single participant per each session. The study will be completed at the University of Canterbury Rose Centre for Stroke Recovery and Research, a laboratory dedicated to investigation of swallowing and voice.
Intervention code [1] 322489 0
Diagnosis / Prognosis
Comparator / control treatment
There is a control group in this study, comprised of healthy individuals without a chronic cough. The control group will undergo an identical assessment protocol to the chronic cough group.
Control group
Active

Outcomes
Primary outcome [1] 330187 0
Cepstral Peak Prominence (CPP), as recorded during endoscopic/audio voice assessment. CPP will be measured using Praat (a software for speech analysis), to analyse the audio voice recording.
Timepoint [1] 330187 0
Measures made during endoscopic and audio voice assessment. Measures will be made at baseline (all participants), and 8 weeks post-baseline (treatment follow-up subset).
Primary outcome [2] 330188 0
Cough reflex threshold, i.e., concentration of citric acid mist (mol/L) to cause two coughs in immediate succession within 15 seconds of inhalation
Timepoint [2] 330188 0
As determined during citric acid cough testing procedure at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Primary outcome [3] 330189 0
Total pharyngeal transit time (B1 [onset of bolus transit time] - BP2 [bolus passes through upper esophageal sphincter]) i.e., time from swallow initiation until bolus (food or liquid) passes from the pharynx (throat) into the esophagus, determined during the videofluoroscopic swallowing study (VFSS).
Timepoint [3] 330189 0
As measured during the videofluoroscopic swallowing study (VFSS), at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [1] 405195 0
Respiratory-swallowing co-ordination pattern (i.e., exhale-swallow-exhale, inhale-swallow-exhale, exhale-swallow-inhale or inhale-swallow-inhale), as measured using a dual-port (oral and nasal) face mask and spirometer
Timepoint [1] 405195 0
During initial breathing measurements, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [2] 405196 0
Oro-nasal respiratory pattern (i.e., primarily nasal OR primarily oro-nasal), as measured using a dual-port (oral and nasal) face mask and spirometry
Timepoint [2] 405196 0
During initial breathing measurements, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [3] 405197 0
Forced vital capacity (FVC) as measured using spirometry
Timepoint [3] 405197 0
During initial breathing measurements (spirometry assessment), at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [4] 405199 0
Forced expiratory volume during the first second of exhalation/forced vital capacity (FEV1/FVC), as measured using spirometry
Timepoint [4] 405199 0
During initial breathing assessment (spirometry), at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [5] 405200 0
Average volume per swallow (mL/swallow) while drinking water, measured using a digital stopwatch and calculated offline post-assessment
Timepoint [5] 405200 0
Measured during the Timed Water Swallow Test (TWST), at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [6] 405201 0
Average time per swallow (seconds/swallow) while drinking 150mL water continuously, measured using a digital stopwatch
Timepoint [6] 405201 0
Measured during the Timed Water Swallow Test (TWST), at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [7] 405202 0
Mean swallowing capacity (mL/s) while drinking 150mL water continuously, measured using a digital stopwatch
Timepoint [7] 405202 0
Measured during the Timed Water Swallow Test (TWST) at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [8] 405205 0
Number of swallows per cracker whilst eating one Arnott's Salada cracker as quickly as is comfortably possible
Timepoint [8] 405205 0
Measured during the Test of Masticating and Swallowing Solids (TOMASS), at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [9] 405206 0
Total time taken (per one cracker) whilst eating one Arnott's Salada cracker as quickly as is comfortably possible, measured using a digital stopwatch
Timepoint [9] 405206 0
Measured during the Test of Masticating and Swallowing Solids (TOMASS), at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [10] 405209 0
Timing of airway closure between AEstart (beginning of epiglottic closure) and AEclose (completion of supraglottic closure), using SwallowTail to objectively measure data from videofluoroscopic swallowing study (VFSS)
Timepoint [10] 405209 0
Measures made during VFSS, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [11] 405210 0
Stage transition duration i.e., time taken from bolus entrance into pharynx to beginning of hyoid movement, using SwallowTail to objectively measure data from videofluoroscopic swallowing study (VFSS)
Timepoint [11] 405210 0
Measures made during VFSS, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [12] 405211 0
Laryngeal vestibule closure (LVC) reaction time i.e., time taken to close the laryngeal vestibule, using SwallowTail to objectively measure data from videofluoroscopic swallowing study (VFSS)
Timepoint [12] 405211 0
Measures made during VFSS, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [13] 405212 0
Laryngeal closure duration (LCD) i.e., duration of contact between the arytenoids and epiglottis, using SwallowTail to objectively measure data from videofluoroscopic swallowing study (VFSS)
Timepoint [13] 405212 0
Measures made during VFSS, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [14] 405213 0
Instances of penetration of the bolus to the level of the vocal folds, measured on observation
Timepoint [14] 405213 0
During videofluoroscopic swallowing study (VFSS), at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [15] 405214 0
Instances of aspiration of the bolus below the level of the vocal folds, measured on observation
Timepoint [15] 405214 0
During videofluoroscopic swallowing study (VFSS), at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [16] 405215 0
Ratio of visible vocal folds during phonation and at rest (phonation:rest), measured in pixels, taken from endoscopic images
Timepoint [16] 405215 0
Data collected during endoscopic voice assessment, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [17] 405216 0
Mean fundamental frequency, measured using Praat to analyse audio voice recordings
Timepoint [17] 405216 0
Data collected during voice assessment, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [18] 405217 0
Overall sound pressure level, measured using Praat to analyse audio voice recordings
Timepoint [18] 405217 0
Data collected during voice assessment, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [19] 405218 0
Harmonic-to-noise ratio, measured using Praat to analyse audio voice recordings
Timepoint [19] 405218 0
Data collected during voice assessment, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [20] 405219 0
Pitch range (lowest to highest, Hz), measured using Praat to analyse audio voice recordings
Timepoint [20] 405219 0
Data collected during voice assessment, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [21] 405220 0
Dynamic range (lowest to highest, dB), measured using Praat to analyse audio voice recordings
Timepoint [21] 405220 0
Data collected during voice assessment, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [22] 405221 0
Frequency (pitch) variability, in Hz, measured using Praat to analyse audio voice recordings
Timepoint [22] 405221 0
Data collected during voice assessment, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [23] 405222 0
Amplitude (volume) variability, in dB, measured using Praat to analyse audio voice recordings
Timepoint [23] 405222 0
Data collected during voice assessment, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [24] 405223 0
Presence or absence of organic vocal fold pathology or lesions, measured observationally by Ear, Nose and Throat surgeon
Timepoint [24] 405223 0
As observed during endoscopic voice assessment, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [25] 405225 0
Presence or absence of laryngeal adductor reflex, as measured during flexible endoscopic evaluation of swallowing with sensory testing (FEES-ST)
Timepoint [25] 405225 0
Measured at the end of the endoscopic voice assessment, at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).
Secondary outcome [26] 405241 0
Questionnaire about participants' perceptions of their coughing, voice, swallowing and breathing. Possible answers are:
- never
- sometimes
- often
- always
The questionnaire has been designed specifically for this study and has not been validated.
Timepoint [26] 405241 0
Measured at baseline (all participants) and 8 weeks post-baseline (treatment follow-up subset).

Eligibility
Key inclusion criteria
For the chronic cough group:
- 18 years and over
- Able to consent to study
- Frequent coughing lasting longer than eight weeks (Morice et al., 2020)
- Optimal management of chronic cough without resolution, prompting referring
respiratory physician to consider behavioural cough control therapy

For the healthy group:
- 18 years and over
- Able to consent to the study
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
For the chronic cough group:
- Patient has not received sufficient prior assessment and/or treatment of chronic cough on respiratory physician's review of health information
- Structural abnormalities of the lower airways including emphysema, bronchiectasis, pulmonary fibrosis, or sarcoidosis
- Chronic obstructive pulmonary disease
- Smoking or vaping in the last 6 months
- Upper respiratory tract infection in the last two weeks
- Uncontrolled reflux
- Use of opioids in the last six months
- Use of ACE inhibitors in the last six months
- Current use of neuromodulatory medicines
- Use of spirometry is contraindicated
- Previous or current behavioural treatment for chronic cough by a Speech-Language Therapist or physiotherapist
- Arrived from overseas in the last 14 days
- Displaying symptoms of Covid-19 in the last 14 days
- Been in close physical contact with someone with a suspected or confirmed case of Covid-19 in the last 14 days
- Lack of full vaccination against Covid-19, or unable to prove full vaccination using My Vaccine Pass
- Allergy or intolerance to wheat or gluten

For the healthy group:
- History of frequent coughing lasting longer than eight weeks
Structural abnormalities of the lower airways including emphysema, bronchiectasis, pulmonary fibrosis, or sarcoidosis
- Chronic obstructive pulmonary disease
- Smoking or vaping in the last 6 months
- Upper respiratory tract infection in the last two weeks
- Uncontrolled reflux
- Use of opioids in the last six months
- Use of ACE inhibitors in the last six months
- Current use of neuromodulatory medicines
- Use of spirometry is contraindicated
- Arrived from overseas in the last 14 days
- Displaying symptoms of Covid-19 in the last 14 days
- Been in close physical contact with someone with a suspected or confirmed case of Covid-19 in the last 14 days
- Lack of full vaccination against Covid-19, or unable to prove full vaccination using My Vaccine Pass
- Allergy or intolerance to wheat or gluten

Study design
Purpose of the study
Diagnosis
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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Two groups, including individuals with chronic cough and health control participants
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
80 full data sets will be collected (40 full data sets in the chronic cough group, 40 full data sets in the control group). A cluster analysis is planned to identify the variables that are most likely to predict the presence of a chronic cough. A conservative sample size estimate (Qiu and Joe, 2009) suggests the following calculation for required sample size in a cluster analysis: ((10x number of predictors) x number of clusters). Given an expected number of 4-5 predictors, the final sample size should be between 80-100 participants. A different method (Dalmaijer et al., 2020) suggested that for a study resulting in two approximately equally-sized clusters (as in this study), each cluster should have 40 participants. Therefore, a sample size of 80 is indicated using both calculation methods.

4-5 variables are predicted to be included in the cluster analysis. However, a larger number of variables will be examined in the study. All variables will be refined prior to running the cluster analysis, to determine which variables are most likely to predict a chronic cough (these will be included in the cluster analysis). Correlations will be made between related variables, to that similar variables that correlate highly with one another can be represented by just one variable in the cluster analysis. A principle component analysis (PCA) will also be run. This will reduce the number of variables in the data set whilst ensuring that useful data is preserved.

All variables that are not included in the cluster analysis will be analysed using an ANOVA, to determine normative values which will allow comparison between the two groups.

The questionnaire will be analysed descriptively to enhance objective findings.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/04/2022
Actual
27/06/2022
Date of last participant enrolment
Anticipated
31/10/2023
Actual
Date of last data collection
Anticipated
31/01/2024
Actual
Sample size
Target
80
Accrual to date
8
Final
Recruitment outside Australia
Country [1] 24512 0
New Zealand
State/province [1] 24512 0
Canterbury

Funding & Sponsors
Funding source category [1] 310409 0
University
Name [1] 310409 0
University of Canterbury
Country [1] 310409 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,
249 Papanui Rd,
Merivale,
Christchurch 8014
Country
New Zealand
Secondary sponsor category [1] 311779 0
None
Name [1] 311779 0
Address [1] 311779 0
Country [1] 311779 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310057 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 310057 0
Ethics committee country [1] 310057 0
New Zealand
Date submitted for ethics approval [1] 310057 0
21/01/2022
Approval date [1] 310057 0
03/03/2022
Ethics approval number [1] 310057 0
2022 EXP 11049

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

Contacts
Principal investigator
Name 116338 0
Miss Elizabeth Cross
Address 116338 0
UC Rose Centre for Stroke Recovery and Research,
Level 1, Leinster Chambers, St George's Hospital,
249 Papanui Rd,
Merivale,
Christchurch 8014
Country 116338 0
New Zealand
Phone 116338 0
+64 3 369 2385
Fax 116338 0
Email 116338 0
[email protected]
Contact person for public queries
Name 116339 0
Elizabeth Cross
Address 116339 0
UC Rose Centre for Stroke Recovery and Research,
Level 1, Leinster Chambers, St George's Hospital,
249 Papanui Rd,
Merivale,
Christchurch 8014
Country 116339 0
New Zealand
Phone 116339 0
+64 3 369 2385
Fax 116339 0
Email 116339 0
[email protected]
Contact person for scientific queries
Name 116340 0
Elizabeth Cross
Address 116340 0
UC Rose Centre for Stroke Recovery and Research,
Level 1, Leinster Chambers, St George's Hospital,
249 Papanui Rd,
Merivale,
Christchurch 8014
Country 116340 0
New Zealand
Phone 116340 0
+64 3 369 2385
Fax 116340 0
Email 116340 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?

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.