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Trial registered on ANZCTR


Registration number
ACTRN12616001410448
Ethics application status
Approved
Date submitted
22/09/2016
Date registered
10/10/2016
Date last updated
13/07/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of short-term exposure to sound at very high and ultrasonic frequencies at subthreshold levels; a double-blind provocation study.
Scientific title
Effects on sensitive and non-sensitive adults of short-term exposure to sound at very high and ultrasonic frequencies at subthreshold levels; a double-blind provocation study.
Secondary ID [1] 290169 0
none
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pain or sensation of pressure in the ears 300304 0
Tinnitus 300439 0
Dizziness or light-headedness 300440 0
Nausea 300441 0
Headache or pain or pressure other than in the ears 300442 0
Anxiety 300443 0
Inability to concentrate 300444 0
Condition category
Condition code
Ear 300171 300171 0 0
Other ear disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study comprises an initial screening session, a hearing threshold measurement session, and four test conditions.
== Asymptomatic participants ==
The following procedure applies to asymptomatic participants, as identified by questionnaire in the screening session
== Hearing threshold level measurement session ==
In the hearing-threshold measurement session, the hearing threshold level (HTL) of the participant at 20 kHz will be measured using standard psychoacoustic methods with very short bursts of ultrasound (<0.5 sec per presentation). The HTL is required in order to ensure that an inaudible sound can be presented to the participant during the exposure conditions. The maximum sound pressure level used in this measurement will be 105 dB (re 20 microPa). The measurement will be performed in a sound-treated booth using earphones. The level of the sound is that measured at the reference microphone of the appropriate ear simulator according to IEC 60318. The HTL will be re-measured after the test condition to ensure that it has not altered (for example due to changes in earphone placement). If the HTL has reduced by 10 dB or more, then the test session will be deemed invalid, and will be repeated on another day.
== Test conditions ==
Four test conditions will be carried out.
Condition A, the “Ultrasound ON” condition: Ultrasound will be presented to the participant; the participant will be told that ultrasound may or may not be present.
Condition B, the “Ultrasound OFF” condition: Sham ultrasound (silence) will be presented to the participant; the participant will be told that ultrasound may or may not be present.
Condition X and Y; additional information will be displayed to the participant.
The comparison of conditions A and B will be used to estimate any genuine effect of ultrasound presence. The details of the four conditions are given below.
Condition A, the “Ultrasound ON” condition.
The participant will be seated in a sound proof booth with the earphones placed by the tester, and not removed for the duration of the test session (unless requested by the participant). High-frequency sound will be presented to the participant at a frequency of 20 kHz and at a sound-pressure level that is either 88 dB (re 20 microPa) or is 15 dB below the participant's hearing threshold level at 20 kHz, whichever is the lower level. The participant will be exposed for a period of 20 minutes, during which time they will be asked to perform a computer-based visual recognition task, displayed to them via a small screen. Galvanic skin responses will be recorded from electrodes attached to the fingers. After the 20-minutes of exposure, the participant will asked to remain seated for a further 5-minute recovery period.
The participant will be asked to complete subjective ratings of the severity of their symptoms relating to the health conditions stated previously. Ratings are performed at three time points: pre-exposure (baseline), immediately following exposure, and at the end of the recovery period. Testing will be postponed if the participant scores higher than “0” (=”no symptoms”) on any of the health conditions in the baseline condition.

Condition B, the “Ultrasound OFF” condition.
This condition is identical to condition A in all respects except that silence is presented from the loudspeaker.
Condition X and Y: These conditions are identical to conditions A and/or B in all respects except that additional information will be displayed to the participant.
== Sequence and timing of test conditions ==
Participants will be randomly allocated to one of four arms, which determines the order in which the four conditions will be conducted:
Arm 1: A X B Y
Arm 2: A Y B X
Arm 3: B X A Y
Arm 4: B Y A X
Allocation will be by random selection without replacement in blocks of four participants to achieve a counterbalanced design.
There will be a maximum of two conditions per day, such that A and B will be separated by approximately 24 hours (at least), and X and Y will also be separated by approximately 24 hours. If two conditions are conducted on one day, there will be a minimum of 2 hours between the end of the first condition and the start of the second. A test condition will be postponed if the participant scores higher than “0” (=”no symptoms”) on any of the health conditions in the baseline condition.
== Conducting the test ==
For all conditions, the sound will be presented from a computer in an observation room adjacent to thesound-treated both. The tester has no influence on the sounds being presented, and no way of telling whether ultrasound is being presented or not in conditions A and B. After starting the software run, the tester inputs the participant number only. The software uses a random number generator to determine which arm the participant is allocated to, and thus whether genuine ultrasound or sham exposure (silence) is presented in any session. The key indicating which participant was allocated to which arm is stored in a coded computer file that is not opened until after the experimental phase of the study has finished, and the statistical analysis has been completed. Conditions X and Y are not blind to the tester as they are able to see the same display as the participant.

== Symptomatic participants ==
For symptomatic participants, the above procedure will be adapted as follows. They will be asked about the time course of the symptoms they have previously experienced. If the estimated onset and recovery time of these allows, then the exposure time and time between test conditions will be reduced. Additional repeats of the set of four conditions will also be conducted.
Intervention code [1] 295927 0
Other interventions
Comparator / control treatment
For the primary research question, which is to determine whether the presence of ultrasound has an effect on health conditions, the comparator condition is the silent condition described above under "interventions" (condition B).

The participant will be seated in a sound-treated booth with the earphones in place. No sound will be presented but the participant will not know whether ultrasound is being presented or not. The participant will be exposed for a period of 20 minutes to this sham ultrasound, during which time they will be asked to perform a computer-based visual recognition task, displayed to them via a small screen. Galvanic skin responses will be recorded from electrodes attached to the fingers. After the 20-minutes of exposure, the participant will asked to remain seated for a further 5-minute recovery period.
Control group
Placebo

Outcomes
Primary outcome [1] 299700 0
The primary outcome measure will be a composite obtained by summing the scores on a 7-item subjective rating scale. The seven items are tinnitus, pain or fullness in the ear, Headache or pain or pressure somewhere other than my ears, nausea, dizziness or light headedness, anxiety, and inability to concentrate. For each item, the participant will be asked to rate the severity of their symptoms on an 11-point scale running from “0” (No symptoms) to “10” Extreme severity. The scale is administered via computer and does not allow fractional selections.
Timepoint [1] 299700 0
Immediately following each exposure condition (i.e. true or sham exposure)
Secondary outcome [1] 327886 0
Performance on a sustained attention task carried out during each of the four test conditions. The task is the Conjunctive Continuous Performance Task (Kelip, J.G., Herrera, J., Stritzke, P., Cornblatt, B.A. [2003]. The continuous performance test, identical pairs version [CPT-IP]. III. Brain functioning during performance of numbers and shapes subtasks. Psychiatry Research, 74:35-45.)
Timepoint [1] 327886 0
Performance is measured at the end of exposure condition (i.e. true or sham exposure)
Secondary outcome [2] 327887 0
Change in mean galvanic skin response measured on the finger relative to the baseline reading. This is a measure related to emotional stress or arousal.
Timepoint [2] 327887 0
Average is measured across the duration of exposure condition and compared to the value at baseline.
Secondary outcome [3] 327888 0
Ability to correctly state that ultrasound is present after prolonged exposure, despite the level of ultrasound being presenented below the hearing threshold of the participant at that frequency, as measured using detection of short stimuli (< 0,5 sec).
Timepoint [3] 327888 0
Immediately after exposure condition (i.e. true or sham exposure).
Secondary outcome [4] 328115 0
Same as for the primary outcome measure, but with a different timepoint.
Timepoint [4] 328115 0
End of the 5-minute recovery period which immediately follows the exposure period.

Eligibility
Key inclusion criteria
For participants deemed "sensitive or symptomatic", the participant must have reported adverse reactions which they attribute to ultrasound exposure in the past.
For aysmptomatic participants, they must have hearing within normal limits at conventional audiometric frequencies (0,25 - 8 kHz).
Minimum age
18 Years
Maximum age
69 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Severe tinnitus as identified by screening questionnaire
2. Abnormality detected on otoscopy, such as discharge, inflammation, infection, or excessive wax.
3. Contraindications in screening questionnaire such as recent ear infection, current ear pain, or exposure to very loud sounds in the last 24-hours.
4. Excessive intake of caffine in the two hours before the study (e.g. 2 cups of strong coffee)
5. Excessive intake of alcholol withing 24 hours of the study (e.g. more than 2 pints of beer, or two glasses of wine)
6. Colour blindness effecting participants ability to distinguish red, green and blue (which could affect outcomes on the sustained attention task used)
7. Epilepsy (which might be agrivated by the sustained attention task, which has flashing images)
8. Use of recreational drugs in the last week.
9. Strenuous physical or mental activity on the day of the experiment.
10 Hyperacusis experienced for sounds at "conventional" frequencies (< 10 kHz).

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
computer with controls the stimulus generation (whether genuine or sham exposure) also randomly assigns participants to each arm (genuine or sham exposure first). Key to allocation is stored on computer file, visible only after completion of the analysis.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization using computer generated sequence, counterbalanced over blocks.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
As well as conditions of genuine and sham exposure, where the participant is told ultrasound may or may not be present, the effect of informing that the ultrasound is definitely present or absent will be tested in two addional conditions using a display. These conditions will not be double blind.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
sample size:
For asymtomatic participants, the primary outcome measure is the difference in adverse ratings between genuine and sham exposure conditions, taken at the end of the exposure phase. An increase in rating of 3 points would be considered important, as it represents an increase from no noticeable effect to a clearly noticeable adverse effect. A previous pilot study indicated that the measurement error (standard deviation of measurement in identical exposure conditions) to be typically <1 point in asymptomatic participants who typically scored at the bottom of the rating scale (“no symptoms”) throughout the test. However, this is likely to be an underestimate for cases where symptoms arise.

The sample-size calculation is based the directional alternative hypothesis that the genuine effect of ultrasound will be >= 3 points on the response scale. The standard deviation is assumed to be 6 points. For a type 1 error rate of 5%, and a power of 80%, for a paired t-test, the required sample size is 27. Allowing for a requirement of an additional 15% in the sample size where non-parametric tests are required leads to a target sample size of 32.
Recruitment will continue until 32 participants complete the study. If participants withdraw early from the study due to high adverse symptoms following exposure, they will be included in the analysis. Those withdrawing for other reasons will not be included in the analysis.

Statistical analysis.
The null hypothesis under test is that there will be no increase in subjective rating scores between conditions of genuine and sham exposure measured at the end of the exposure period. Based on pilot studies, it is expected that the rating scores will be heavily positively skewed, with a preponderance of low scores. Parametric statistical analysis using MANOVA is unlikely to be appropriate. Instead, generalized estimating equations using a gamma distribution will be used. If these tests are judged inappropriate, then non-parametric tests such as Wilcoxon tests, corrected for familywise error will be used.

Fewer symptomatic participants are available for testing, and these will be tested using experiments customised to measure their specific symtpoms, and with many more repeats of the genuine and sham conditions to allow analysis using a multiple repeated measures (n-of-1) design.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
15/02/2017
Actual
23/02/2017
Date of last participant enrolment
Anticipated
27/03/2017
Actual
2/06/2017
Date of last data collection
Anticipated
12/05/2017
Actual
2/06/2017
Sample size
Target
32
Accrual to date
Final
40
Recruitment outside Australia
Country [1] 8251 0
United Kingdom
State/province [1] 8251 0
Hampshire

Funding & Sponsors
Funding source category [1] 294558 0
Charities/Societies/Foundations
Name [1] 294558 0
Colt Foundation
Country [1] 294558 0
United Kingdom
Primary sponsor type
University
Name
University of Southampton
Address
University of Southampton,
Highfield
Hampshire
Southampton
SO17 1BJ
United Kingdom
Country
United Kingdom
Secondary sponsor category [1] 293426 0
None
Name [1] 293426 0
Address [1] 293426 0
Country [1] 293426 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295994 0
University of Southampton, Ethics Committee of the Faculty of Engineering and the Environment
Ethics committee address [1] 295994 0
Ethics committee country [1] 295994 0
United Kingdom
Date submitted for ethics approval [1] 295994 0
16/09/2016
Approval date [1] 295994 0
12/10/2016
Ethics approval number [1] 295994 0
23716

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

Contacts
Principal investigator
Name 69090 0
Dr Ben Lineton
Address 69090 0
University of Southampton,
Highfield
Hampshire
Southampton
SO17 1BJ
United Kingdom
Country 69090 0
United Kingdom
Phone 69090 0
+44 23 8059 3467
Fax 69090 0
Email 69090 0
B.Lineton@soton.ac.uk
Contact person for public queries
Name 69091 0
Mark Fletcher
Address 69091 0
University of Southampton,
Highfield
Hampshire
Southampton
SO17 1BJ
United Kingdom
Country 69091 0
United Kingdom
Phone 69091 0
+44 23 8059 3467
Fax 69091 0
Email 69091 0
M.D.Fletcher@soton.ac.uk
Contact person for scientific queries
Name 69092 0
Ben Lineton
Address 69092 0
University of Southampton,
Highfield
Hampshire
Southampton
SO17 1BJ
United Kingdom
Country 69092 0
United Kingdom
Phone 69092 0
+44 23 8059 3467
Fax 69092 0
Email 69092 0
B.Lineton@soton.ac.uk

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