Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000151831
Ethics application status
Approved
Date submitted
15/01/2021
Date registered
15/02/2021
Date last updated
2/05/2022
Date data sharing statement initially provided
15/02/2021
Date results provided
2/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Exploring a novel brain stimulation protocol for treatment of tinnitus
Scientific title
Exploring the effects of transcranial infraslow pink noise stimulation on NZ adults suffering from chronic tinnitus – A feasibility and safety trial
Secondary ID [1] 303183 0
Nil known
Universal Trial Number (UTN)
U1111-1261-6945
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tinnitus 320318 0
Condition category
Condition code
Neurological 318233 318233 0 0
Other neurological disorders
Ear 318234 318234 0 0
Other ear disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
high definition transcranial infraslow pink noise stimulation (HD-tIPNS) will be administered by a researcher experienced in administering neuromodulation techniques. HD-tIPNS will be administered face-to-face, three times a week for four weeks (i.e. total of 12 intervention sessions) in the Department of surgical sciences laboratory at the Dunedin School of Medicine, University of Otago. Each intervention session will have a duration of ~1hr (30min set-up and 30min of stimulation). For the active treatment group (HD-tIPNS), the stimulation will be delivered at a current strength of maximum of 2mA for 30min, with 60s ramp up and ramp down at the beginning and end of each stimulation session, with continuous stimulation in between. The pink noise stimulation at a current strength of maximum of 0.6mA will be superimposed on the infraslow stimulation waveform of a current intensity of 1mA, such that the current strength of the waveform never exceeds the maximum of 2mA. For the sham stimulation group, to create an identical skin sensation to the active stimulation, the current will be applied for a 60s ramp up (0-2mA) and 60s ramp down (2-0mA), at the beginning and the end of each stimulation session, without any current for the remainder of the stimulation period. A battery-driven wireless 32 channel transcranial current stimulation (Starstim32 TES®, Neuroelectrics, Spain, http://www.neuroelectrics.com) will be used to deliver stimulation while the participants are comfortably and quietly seated. The Starstim32 is a high definition system with small electrode size (1 cm radius) that can focally target deeper brain regions. Thirty-two circular Ag/AgCl stimulation electrodes will be placed on a neoprene head cap following the International 10-20 EEG system to target the AC, PCC, and PHC. The optimal montages to target the network activity of these areas were created using the Stimweaver optimization software by the Neuroelectrics company. The placement of the electrodes will be identical for both the intervention groups. Using the Neuroelectrics software, intervention protocols will be administered to participants without the researcher being aware of the specific intervention group the participant has been randomly allocated to. Adherence to the intervention will be monitored by recording the number of sessions attended by each participant and will be represented as a percentage of the total number of sessions.
Intervention code [1] 319491 0
Treatment: Devices
Comparator / control treatment
To create identical skin sensation to the active treatment group, current will be applied for a 60s ramp up (0-2mA) and a 60s ramp down (2-0mA) at the beginning and end of each stimulation session, without any current for the remainder of the stimulation period.
Control group
Placebo

Outcomes
Primary outcome [1] 326217 0
change in resting-state electroencephalography (EEG) activity as assessed by standard low-resolution brain electromagnetic tomography (sLORETA)
Timepoint [1] 326217 0
Baseline, immediately post-intervention [3-days post-intervention], and 10-days post-intervention
Primary outcome [2] 326218 0
Change in participant perception of tinnitus' impact on their daily lives, measured using the mini tinnitus questionnaire (mTQ),
Timepoint [2] 326218 0
Baseline, immediately post-intervention [3-days post-intervention], and 10-days post-intervention
Primary outcome [3] 326219 0
Safety is a composite primary outcome, measured by the occurrence of any adverse event or reaction will be recorded on a case report form detailing a verbatim description of the event, intensity of each symptom using a likert scale ranging from 0 (none) to 10 (extreme), relation of the symptom to the treatment using a scale ranging from 1 (unrelated) to 5 (strongly related), duration of each symptom and time taken for each symptom to resolve (expressed in min), and any drop-outs due to adverse effects.
Timepoint [3] 326219 0
At each session before the intervention, during the intervention (at 5min intervals), and after completion of the day’s intervention session
Secondary outcome [1] 390556 0
Number of participants recruited per month until sample size of 20 is reached, determined by an audit of the study database. This is one facet of feasibility assessment, which is an additional primary outcome measure.
Timepoint [1] 390556 0
This will be assessed once recruitment has ended.
Secondary outcome [2] 390557 0
Proportion of participants recruited from the total number screened will be determined by an audit of the study database. This is one facet of feasibility assessment, which is an additional primary outcome measure.
Timepoint [2] 390557 0
This will be assessed once recruitment has ended
Secondary outcome [3] 390558 0
Percentage of treatment sessions attended (i.e. adherence rate) will be determined by an audit of the study database. This is one facet of feasibility assessment, which is an additional primary outcome measure.
Timepoint [3] 390558 0
Adherence rate will be calculated once the 4-week treatment phase is complete.
Secondary outcome [4] 390559 0
Percentage of participants that drop-out of the study will be determined by an audit of the study database. This is one facet of feasibility assessment, which is an additional primary outcome measure.
Timepoint [4] 390559 0
Drop-out rates will be calculated once the 1-week follow-up phase is completed (i.e. 5 weeks post-intervention commencement).
Secondary outcome [5] 390561 0
Participant satisfaction level with the intervention will be assessed using an 11-point numeric rating scale (0-Not at all satisfied to 10-Very satisfied). This is one facet of feasibility assessment, which is an additional primary outcome measure.
Timepoint [5] 390561 0
Participant satisfaction of the intervention will be assessed in the post-intervention phase at each follow-up [3-days and 10-days post-treatment].
Secondary outcome [6] 391713 0
Change in tinnitus functional index (TFI) score will be used to assess tinnitus associated distress.
Timepoint [6] 391713 0
Baseline, immediately post-intervention [3-days post-intervention], and 10-days post-intervention
Secondary outcome [7] 391714 0
An 11-point numeric rating scale designed specifically for this study by the primary and coordinating investigators will be used to measure tinnitus loudness, suffering, unpleasantness, fear, frustration, anger, and association with self-perception.
Timepoint [7] 391714 0
Baseline, immediately post-intervention [3-days post-intervention], and 10-days post-intervention
Secondary outcome [8] 391715 0
Depression, anxiety, and stress scale (DASS-21) is a 21-item questionnaire that will be used to assess changes in participant depression, anxiety and stress levels.
Timepoint [8] 391715 0
Baseline, immediately post-intervention [3-days post-intervention], and 10-days post-intervention
Secondary outcome [9] 391716 0
The tinnitus catastrophizing scale (TCS) will be used to assess excessively negative misinterpretations of tinnitus.
Timepoint [9] 391716 0
Baseline, immediately post-intervention [3-days post-intervention], and 10-days post-intervention
Secondary outcome [10] 391717 0
The European Quality of Life-5 Dimensions (EQ-5D) scale will be used to assess the health related quality of life for all participants.
Timepoint [10] 391717 0
Baseline, immediately post-intervention [3-days post-intervention], and 10-days post-intervention
Secondary outcome [11] 391718 0
The World health Organisation-5 Well-being Index (WHO-5) consists of self-reported 5-items and will be used to assess current mental well-being of all participants.
Timepoint [11] 391718 0
Baseline, immediately post-intervention [3-days post-intervention], and 10-days post-intervention
Secondary outcome [12] 391719 0
The TrackYourTinnitus (TYT) app will be suggested to participants to record changes in their tinnitus outside of their sessions.
Timepoint [12] 391719 0
If the TYT app is used by participants, data will be collected from it after the final post-intervention follow-up [10-days post-intervention].

Eligibility
Key inclusion criteria
Capable of understanding and signing an informed consent form

A diagnosis of chronic tinnitus

At Screening, have constant subjective tinnitus with a grade of 3-4 on the mTQ and a TFI score of 25 or greater (indicating moderate/severe presentation with significant problems associated with tinnitus)
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Metal or electronic implants in the head and neck region, and presence of any pacemaker or defibrillator
• Neurological conditions
• Previous brain surgery
• Active inner/middle/external ear pathology identified by diagnostic audiological exam.
• Cognitive or psychiatric disorders
• Recent or current pregnancy
• History of epilepsy, seizures, or substance abuse
• Hyperacusis
• Received treatment for their tinnitus within two months of this study (including undergoing any therapy e.g. sound therapy)
• Dyslipidaemia
• History of uncontrolled/untreated hypertension
• Participants who, in the opinion of the investigator, do not understand the information and procedures of the study, or would not be compliant with them (in particular the study restrictions and risks involved).
• Any participant for whom the investigator believes, for any reason, that participation would not be an acceptable risk.
• Participants will be permitted to continue their medications for the duration of the trial, with the type and dosage of medication being recorded throughout the duration of the trial. However, participants with the intention of taking new medications in the next 2 months, will be excluded.

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)
Central randomisation by a computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
simple randomisation using a randomisation table created by computer software
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
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
We will recruit a modest sample (10 per group, 20 in total) and will calculate effect sizes based on this study estimates on outcomes. The Evaluable Participant Population (EPP) will be defined as all participants who successfully complete the intervention phase. The EPP will be the primary population for evaluation of study objectives. SPSS version 22.0 will be used for all statistical analyses. Descriptive statistics will be used to analyse feasibility and safety measures. Linear mixed model regression analysis will be used to obtain estimates of the intervention effects on clinical, functional, psychological, and quality of life outcome measures. Source localisation and functional connectivity will be estimated using standardised low-resolution brain electromagnetic tomography (sLORETA).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
22/02/2021
Actual
8/06/2021
Date of last participant enrolment
Anticipated
1/04/2021
Actual
23/09/2021
Date of last data collection
Anticipated
Actual
12/11/2021
Sample size
Target
20
Accrual to date
Final
20
Recruitment outside Australia
Country [1] 23387 0
New Zealand
State/province [1] 23387 0
Otago

Funding & Sponsors
Funding source category [1] 307590 0
University
Name [1] 307590 0
University of Otago Research Grant 2021
Country [1] 307590 0
New Zealand
Primary sponsor type
University
Name
University of Otago Research office
Address
Health Research South
Deans Office, Dunedin School of Medicine
Level One
Dunedin Hospital
Great King St
Central Dunedin
Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 308281 0
None
Name [1] 308281 0
Address [1] 308281 0
Country [1] 308281 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307645 0
Northern A Health and Disabilities Ethics Committee
Ethics committee address [1] 307645 0
Ethics committee country [1] 307645 0
New Zealand
Date submitted for ethics approval [1] 307645 0
24/11/2020
Approval date [1] 307645 0
17/02/2021
Ethics approval number [1] 307645 0
20/NTA/181

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

Contacts
Principal investigator
Name 107986 0
Prof Dirk De Ridder
Address 107986 0
Department of Surgical sciences, University of Otago, 201 Great King Street, Dunedin Central, Dunedin 9016
Country 107986 0
New Zealand
Phone 107986 0
+64 03 470 9337
Fax 107986 0
Email 107986 0
[email protected]
Contact person for public queries
Name 107987 0
Dirk De Ridder
Address 107987 0
Department of Surgical sciences, University of Otago, 201 Great King Street, Dunedin Central, Dunedin 9016
Country 107987 0
New Zealand
Phone 107987 0
+64 03 470 9337
Fax 107987 0
Email 107987 0
[email protected]
Contact person for scientific queries
Name 107988 0
Dirk De Ridder
Address 107988 0
Department of Surgical sciences, University of Otago, 201 Great King Street, Dunedin Central, Dunedin 9016
Country 107988 0
New Zealand
Phone 107988 0
+64 03 470 9337
Fax 107988 0
Email 107988 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
SourceTitleYear of PublicationDOI
EmbaseFeasibility and Safety of High-Definition Infraslow Pink Noise Stimulation for Treating Chronic Tinnitus-A Randomized Placebo-Controlled Trial.2023https://dx.doi.org/10.1016/j.neurom.2022.10.049
N.B. These documents automatically identified may not have been verified by the study sponsor.