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Trial registered on ANZCTR


Registration number
ACTRN12621000119897p
Ethics application status
Submitted, not yet approved
Date submitted
7/12/2020
Date registered
5/02/2021
Date last updated
5/02/2021
Date data sharing statement initially provided
5/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of ketamine and brain stimulation on tinnitus loudness and distress
Scientific title
Effect of ketamine and concomitant multi-target high definition transcranial electrical stimulation on tinnitus loudness and distress in adults- A feasibility and safety study
Secondary ID [1] 302899 0
None
Universal Trial Number (UTN)
U1111-1261-0817
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tinnitus 319907 0
Condition category
Condition code
Ear 317845 317845 0 0
Other ear disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Brief Name: Ketamine and High Definition, Trancranial Infraslow Pink Noise Stimulation (HD-tIPNS)

The intervention arm will receive a low dose of subcutaneous ketamine (0.5mg/kg) as a bolus, from a clinician experienced in administration. This will be followed by HD-tIPNS administered for a single session of 30 minutes duration, beginning ~25 minutes after ketamine delivery, by a researcher experienced in administering neuromodulation techniques. A battery-driven wireless 32 channel transcranial current stimulator (Starstim32 TCS®, Neuroelectrics, Spain, http://www.neuroelectrics.com) will be used to deliver stimulation while the participants are comfortably and quietly seated. Simulation is delivered by AgCl electrodes placed in the international 10-20 arrangement, secured in a neoprene cap (see Neuroelectrics website for headset image). For the active treatment group, 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. For sham stimulation, 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.

This Intervention will be delivered twice, spaced 10 days apart. Intervention duration will be a total of 2 hours in length to allow for safety monitoring. After a 20 day washout, both groups will transition to the intervention, delivered twice again, 10 days apart.

The delayed start occurs as follows: Participants can be allocated to start with Ketamine + Active Stimulation or Ketamine + Sham Stimulation. Both the sham stimulation and the active stimulation groups will receive active stimulation after the 20 day washout (the Ketamine + Sham stimulation is the active control). Therefore the Ketamine + Sham stimulation (Active control) receives a delay to the start of active intervention.

Participants will undergo treatment at the Department of Psychological medicine laboratory at the Dunedin School of Medicine, University of Otago.
Intervention code [1] 319185 0
Treatment: Drugs
Intervention code [2] 319186 0
Treatment: Devices
Comparator / control treatment
Participants in the control arm will receive a low dose of subcutaneous ketamine (0.5mg/kg) as a bolus, from a clinician experienced in administration. This will be followed by Sham stimulation, designed to create identical skin sensations to active stimulation. Participants will use identical equipment to that of the active group, and will receive a short dose of the treatment protocol, mimicking the initial tingling/prickling commonly experienced with Transcranial electrical stimulation.
Control group
Active

Outcomes
Primary outcome [1] 325862 0
Tinnitus Functional Index (TFI). The TFI has eight subscales that address the intrusiveness of tinnitus, the sense of control the patient has, cognitive interference, sleep disturbance, auditory issues, relaxation issues, quality of life, and emotional distress. This provides an overall measure of how much of a problem tinnitus is for participants (severity).
Timepoint [1] 325862 0
Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow-up.
Primary outcome [2] 325870 0
Feasibility outcomes: The following feasibility outcomes will be measured by the study’s research fellow using study records:
a) Recruitment rate, i.e., number of participants recruited per month, until the proposed sample size is reached. The recruitment rate will be recorded on a weekly basis, since the release of the advertisements, and the number of advertisements will also be recorded.
b) Proportion of participants recruited from the total number screened (with reasons for exclusion) and expressed as a percentage.
c) Adherence to intervention measured as number of treatment sessions attended by each participant and expressed as a percentage of the total number of sessions. Adherence rates will be calculated once the treatment phase is completed.
c) Drop-out rates, measured as the number of participants who dropped-out in each group, and expressed as a percentage of the total number of participants enrolled in the study. Drop-outs rates will be calculated once the follow-up phase is completed.
d) These feasibility measures will be assessed by ethnicity (Maori and non- Maori) to permit an understanding of how successful were measures to engage Maori participants and honour Te Tiriti.
e) Participant satisfaction levels and the acceptability of the treatment will also be recorded on an 11-point numeric rating scale (0-Not at all satisfied/acceptable to 10-Very satisfied/acceptable).
Timepoint [2] 325870 0
Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow-up.
Primary outcome [3] 325871 0
Saftey Measures, including:
a) Vital Signs (Heart rate [pulse oximeter], blood pressure [digital sphygmomanometer], blood O2 saturation [pulse oximeter]) will be measured before ketamine administration and then at 30-minute intervals until completion of the intervention sessions.
b) Any adverse effects that likely have a causal relationship with the intervention will be recorded by the study’s assistant research fellow at each session, before the intervention, during the intervention (at intervals of 10 min), and after completion of that day’s intervention session. This will help evaluate adverse events from both the previous session’s (delayed) effects and the same session’s (immediate) effects. The following variables will be recorded:
(i) Qualitative description of each symptom.
(ii) Intensity of each symptom measured using a Likert scale ranging from 0 (none) to 10 (extreme).
(iii) Relation of the symptom to the treatment, measured on a scale ranging from 1 (unrelated) to 5 (strongly related).
(iv)Duration of each symptom and the time taken for resolution of each symptom, expressed in minutes.
(v) Visual Analog Scales (VAS): The VAS will consist of a series of 19 horizontal 100-mm lines, each labelled with an adjective: Alert, Anxious, Bad Medication Effect, Confusion, Down, Friendly, Good Medication Effect, High, Hungry, Irritable, Liking, Miserable, On Edge, Sedated, Self-Conscience, Social, Stimulated, Talkative, and Tired. Participants will be instructed to place a mark on each line indicating how they feel now from ‘not at all’ to ‘extremely’.
(vi) Any drop-outs due to adverse effects will also be recorded
Timepoint [3] 325871 0
Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow-up.
Secondary outcome [1] 389374 0
The Tinnitus Questionnaire (TQ) will be used to assess tinnitus-related distress. The TQ is a 52-item questionnaire, covering 5 subscales of Emotional Distress, Auditory Perceptual Difficulties, Intrusiveness, Sleep Disturbance, and Somatic Complaints.
Timepoint [1] 389374 0
Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow-up.
Secondary outcome [2] 389376 0
Tinnitus loudness and distress will be measured using an 11-point Numeric Rating Scale (0=no tinnitus/not distressing, 10=very loud tinnitus/extreme levels of distress).
Timepoint [2] 389376 0
Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow-up.
Secondary outcome [3] 389381 0
Changes in resting state brain activity, via resting-state electroencephalography (EEG) and source localization, obtained in a quiet room while the participant is sitting upright in a comfortable chair by an independent researcher blinded to the treatment group. EEG data will be collected using the 32 channel neuroelectrics amplifier (Starstim32 TCS®, Neuroelectrics, Spain, http://www.neuroelectrics.com).
Timepoint [3] 389381 0
Baseline, 10,60, and 120 minutes after the Ketamine infusions in the first treatment period, Before the second treatment period, 10,60, and 120 minutes after Ketamine infusions of the second treatment period, and at One month follow-up.
Secondary outcome [4] 389382 0
The Depression, Anxiety, and Stress Scale (DASS)
Timepoint [4] 389382 0
Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow-up.
Secondary outcome [5] 389383 0
European Quality of Life–5 Dimensions 5 levels Questionnaire (EQ-5D-5L)
Timepoint [5] 389383 0
Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow-up.

Eligibility
Key inclusion criteria
Adults aged between 18-70 years with constant subjective tinnitus and a grade of 3 or above on the tinnitus questionnaire.
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Active inner/middle/external ear pathology as identified in audiological screening exam
-Past or current bipolar disorder, schizophrenia. Participants with current anxiety disorders or MDE may be eligible. Use of antidepressants or other anxiolytics at stable doses > 4 weeks is acceptable.
-Participants who have a positive urine test for drugs of abuse at screening or pre-administration
-Participants with a prior history of seizures; susceptibility to photosensitivity; or a history of allergic skin reactions
-Female participants who are or intend to become pregnant or are lactating.
-Participants with current active suicidal ideation, assessed using C-SSRS.
-Participants with a history of intolerance or allergic reaction to ketamine that may place them at increased risk
-Presence of any pacemaker or defibrillator
-Presence of any implant in head/neck
-Impaired liver/kidney function as identified by blood testing

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)
The randomisation schedule will be concealed in numbered, sealed, and opaque envelopes and effected after baseline measurements.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A research administrator, not involved in treatment or assessment procedures, will randomise eligible volunteers using an open-access randomization software program, to begin with one of the two study arms.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Other
Other design features
Delayed start.
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Sample size estimation has not been conducted as this is a pilot study. We aim to recruit a modest sample of up to 24 persons. Effect sizes will be calculated based on this study estimates on outcomes, which will be used to calculate sample size for any future fully powered trial.
The Evaluable Participant Population (EPP) will be defined as all participants who successfully complete the intervention phase. The primary population for the evaluation of study objectives in this trial will be the EPP.

Tinnitus and psychological variables: SPSS will be used for all statistical analyses. Linear mixed model regression analysis will be used to obtain estimates of the intervention effects on clinical outcomes. The administration (or not) of stimulation will be defined as the between-subjects variable and the time (pre vs. post stimulation) as within-subjects variables.

EEG: Resting state EEG data will be analysed using sLORETA software for source localisation, and lagged phase connectivity. Lempel–Ziv–Welch compression will also be used to assess algorithmic complexity of brain activity.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 23236 0
New Zealand
State/province [1] 23236 0

Funding & Sponsors
Funding source category [1] 307321 0
University
Name [1] 307321 0
University of Otago
Address [1] 307321 0
201 Great King Street
Dunedin
9016
Country [1] 307321 0
New Zealand
Primary sponsor type
Individual
Name
Dirk De Ridder
Address
Department of Surgical Sciences
University of Otago
201 Great King Street
Dunedin
9016
Country
New Zealand
Secondary sponsor category [1] 308009 0
None
Name [1] 308009 0
Address [1] 308009 0
Country [1] 308009 0
Other collaborator category [1] 281561 0
Individual
Name [1] 281561 0
Professor Paul Glue
Address [1] 281561 0
Department of Psychological Medicine
University of Otago
201 Great King Street
Dunedin
9016
Country [1] 281561 0
New Zealand
Other collaborator category [2] 281562 0
Individual
Name [2] 281562 0
Dr Divya Adhia
Address [2] 281562 0
Department of Surgical Sciences
University of Otago
201 Great King Street
Dunedin
9016
Country [2] 281562 0
New Zealand
Other collaborator category [3] 281563 0
Individual
Name [3] 281563 0
Mr William Pitts
Address [3] 281563 0
Department of Surgical Sciences
University of Otago
201 Great King Street
Dunedin
9016
Country [3] 281563 0
New Zealand

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307411 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 307411 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 307411 0
New Zealand
Date submitted for ethics approval [1] 307411 0
11/11/2020
Approval date [1] 307411 0
Ethics approval number [1] 307411 0

Summary
Brief summary
Tinnitus is a significant and growing health challenge globally, affecting individuals, their whanau, the wider community, and the healthcare system. Tinnitus, defined as the phantom perception of sound, is estimated to affect 6% of New Zealand’s total population aged 14 and over, with prevalence increasing alongside age. For 2-3% of individuals in the population, tinnitus leads to significant impairments in quality of life. Psychological comorbidities associated with tinnitus drive much of the morbidity, and result in significant loss of health and productivity. Commonly reported symptoms include cognitive dysfunction, annoyance, insomnia, anxiety, and depression. Additionally, tinnitus management is a significant financial burden: in New Zealand, the approximate annual costs of tinnitus are estimated to be $7.5 billion. This makes tinnitus an attractive target for improving health related quality of life. Bimodal approaches may offer significant value in treating tinnitus, by coupling plasticity generation to a means of directing the brain towards a more normal state.

Hypothesis: That low dose Ketamine, through effects on brain plasticity, may be able to catalyse transcranial electrical stimulation, to reduce tinnitus loudness, and/or distress.

The aim of the proposed study is to explore the effect over short term follow-up of ketamine and transcranial stimulation on tinnitus loudness and distress, in participants suffering from tinnitus, in a controlled trial.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 107142 0
Prof Dirk De Ridder
Address 107142 0
Department of Surgical Sciences
University of Otago
201 Great King Street
Dunedin
9016
Country 107142 0
New Zealand
Phone 107142 0
+6434709337
Fax 107142 0
Email 107142 0
dirk.deridder@otago.ac.nz
Contact person for public queries
Name 107143 0
Prof Dirk De Ridder
Address 107143 0
Department of Surgical Sciences
University of Otago
201 Great King Street
Dunedin
9016
Country 107143 0
New Zealand
Phone 107143 0
+6434709337
Fax 107143 0
Email 107143 0
dirk.deridder@otago.ac.nz
Contact person for scientific queries
Name 107144 0
Prof Dirk De Ridder
Address 107144 0
Department of Surgical Sciences
University of Otago
201 Great King Street
Dunedin
9016
Country 107144 0
New Zealand
Phone 107144 0
+6434709337
Fax 107144 0
Email 107144 0
dirk.deridder@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 other documents available
Summary results
No Results