Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001329651
Ethics application status
Approved
Date submitted
13/09/2023
Date registered
19/12/2023
Date last updated
19/12/2023
Date data sharing statement initially provided
19/12/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
UNderstanding CONSciousness Connectedness and Intraoperative Unresponsiveness Study-3: a randomised, double-blind, cross-over trial in healthy volunteers
Scientific title
UNderstanding CONSciousness Connectedness and Intraoperative Unresponsiveness Study-3: a randomised, double-blind cross-over trial in healthy volunteers undergoing sedation with dexmedetomidine
Secondary ID [1] 311199 0
None
Universal Trial Number (UTN)
Trial acronym
UN-ConsCIOUS-3
Linked study record
NCT03284307, this trial is a follow up study to the Unconscious 1 study completed in the United States of America

Health condition
Health condition(s) or problem(s) studied:
Sedation 330055 0
Unconsciousness 330056 0
Condition category
Condition code
Anaesthesiology 326958 326958 0 0
Anaesthetics
Neurological 326959 326959 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Transcranial alternating current stimulation (TACS) will occur using an Soterix MxN 33 channel transcranial alternating current stimulation device that is designed for non-invasive stimulation of brain function which has a long history of safety. Notably the stimulation currents are significantly lower than current stimulation techniques used in the operating theatre (e.g. 50mA is typically used for somatosensory evoked potentials and tetanic stimulation with up to 200mA used to drive motor evoked potentials).
TACS (or sham dependent on randomisation) will be performed 5 minutes prior to the wakeup protocol stage 3 (see protocol section 6.1.3- attached at bottom of this form) being performed. The total amperes will not exceed 2 mA, and each stimulation period will be brief across different periods throughout the experience. Stimulation will be performed using five electrodes, four centred around Cz/Fz and one placed around Pz/Oz. These are located at the back and central area of the head. The placement of the electrodes makes a focal ‘closed’ circuit for stimulation around the given area.. Stimulation will be targeted to electrodes Oz/Cz/Fz using a five electrode montage that has previously been shown to modulate default mode network activity and connectivity and we have shown these regions are important for consciousness under dexmedetomidine sedation. Stimulation will occur for 5 minutes at a time with a total of 1:15 stimulation time).
The intervention will be administered by the Anaesthetic consultant and Dr Jordan Wehrman (post doctorate associate researcher).
The intervention is monitored via computer linked to the tACS machine and checked throughout the study by Dr. Wehrman, Dr. Wehrman is unblinded in the study and in charge of administering the intervention.

The study will occur in 4 stages.
Stage 1- resting state EEG data with 10X blocks of data collection for periods of 5-7 minutes. Participants will be randomised live to resting (no stimualtion - patient rests with eyes closed) or auditory stimulation (a series of sounds played on speaker to patient). There will be a total of 3 auditory, 7 resting stages. This will take around 1-1.5 hours and the following stage commences immediately after.

Stage 2- Sedation -Professor Robert Sanders or an anaesthetic fellow will administer the dexmedetomidine via intravenous cannula. Dexmedetomidine will be titrated at a starting of 0.5 mcg/kg/hr until the patient falls asleep. The sedation, monitoring and safety interventions such as fluid administration and oxygen therapy will be managed by the two anaesthetic doctors present.

There will be a series of 10 wake ups during this stage. Prior to each stage live randomisation to resting or auditory stimulation will occur. The resting stage is just relaxing with eyes closed. The auditory stimulation involves playing a series of sounds via a small speaker to the patient. This will take around 1-1.5 hours and the following stage commences immediately after.

Stage 3- TACs/Sham - Live randomisation to TACS or sham will occur prior to each block of data. There will be 30 wake ups in total in a random order following the stimulation period of 5 minutes before each wake up. This will take around 3 hours and the next stage will commence immediately.

Stage 4- Live randomisation to 15 minutes of TACs or sham and then after 3 minutes the participant will be allowed to naturally wake up. This will take around 1 hour and the patient will be recovered following this stage.

The total project time is 8 hours with approximately 5 hours sedated.
Intervention code [1] 326998 0
Treatment: Devices
Intervention code [2] 327575 0
Treatment: Drugs
Comparator / control treatment
Sham (electrodes placed, no current applied).
Control group
Placebo

Outcomes
Primary outcome [1] 336070 0
The incidence of conscious state between Transcranial Alternating Current Stimulation (TACS) and sham stimulation under steady state dexmedetomidine, through EEG analysis using linear mixed effect models.
Timepoint [1] 336070 0
As observed during the sedation visit (8-10 hours)
Secondary outcome [1] 426734 0
The incidence of disconnected conscious experience (dreaming) versus connected conscious experience (awareness of the external world) between TACS and sham stimulation as assessed by direct patient interviews following participant wake up.
Timepoint [1] 426734 0
As observed during the sedation visit (8-10 hours)
Secondary outcome [2] 426735 0
The neural correlates of consciousness in anterior and posterior cingulate as identified by source reconstruction of beta/delta EEG power
Timepoint [2] 426735 0
As observed during the sedation visit (8-10 hours)
Secondary outcome [3] 426736 0
EEG responses 15 minutes of TACS or sham.
Timepoint [3] 426736 0
As observed during last 15 minutes of sedation/wake up during sedation visit.
Secondary outcome [4] 426737 0
Differences in resting state power, evoked and induced responses between wakefulness as a composite analysis using EEG data
Timepoint [4] 426737 0
As observed during the sedation visit (8-10hours)
Secondary outcome [5] 426738 0
Differences in resting state power, evoked and induced responses in connected consciousness as a composite outcome using EEG data
Timepoint [5] 426738 0
Sedation visit
Secondary outcome [6] 426739 0
Differences in resting state power, evoked and induced responses in disconnected consciousness and unconsciousness as a composite outcome using EEG data
Timepoint [6] 426739 0
As observed during the sedation visit
Secondary outcome [7] 426740 0
Differences in resting state power, evoked and induced responses and unconsciousness as a composite using EEG data.
Timepoint [7] 426740 0
As observed during the sedation visit (8-10 hours).
Secondary outcome [8] 428801 0
The incidence of disconnected conscious experience (dreaming) versus connected conscious experience (awareness of the external world) between TACS and no stimulation as assessed by direct patient interviews following participant wake up.
Timepoint [8] 428801 0
As observed during the sedation visit
Secondary outcome [9] 428803 0
Time to emergence with 15 minutes of TACS or sham timed via Garmin watch with hours:minutes:seconds.
Timepoint [9] 428803 0
As observed during the last 15 minutes of stage 4 sedation visit

Eligibility
Key inclusion criteria
• Adults, ages greater than or equal to 18 and 40 years old
• In good health, determined by the PI on the basis of medical history and a standard assessment for anaesthesia to be documented as part of the study record
• English Language Proficiency (suitable to provide informed consent and participate in research activities).
Minimum age
18 Years
Maximum age
40 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Adults <18 years old or >40 years old
• Pregnancy confirmed on pregnancy test on day of sedation
• Use of recreational drugs
• Use of sedatives/sleeping medication within 24 hours prior to sedation visit
• Prescription for opioids (chronic or PRN) or other medications that cause sedation
• Contraindication to anaesthesia or allergy to study drug
• Difficult anaesthesia: American Society of Anesthesiologists Physical Status greater than 1, per the discretion of the PI. Examples of ASA>1 status includes, but are not limited to:
o Any systemic disease present, such as diabetes, cardiac, pulmonary, or other acute or chronic disorder, or history of smoking
o Narrow angle glaucoma
o Abnormal airway examination
o Any abnormality on physical examination that could increase anaesthetic risk
o Snoring or sleep disorders including apnea
o Antecedent pulmonary aspiration risk (e.g., history GI reflux, heartburn, hiatal hernia)
o Adverse reaction or allergy with anaesthesia or other sedatives
o Chronic medication use
o History of difficult anaesthesia, laryngoscopy or intubation
o Family history of difficulty with anaesthesia or sedation
o History of vertigo, nausea or vomiting after anaesthesia
• BMI > 35
• Contraindication to HD-EEG for relative parts of the procedures.
• Exclusion from Dexmedetomidine:
o Resting heart Rate<50 bpm
o Known dexmedetomidine allergy
• People working in anaesthesia (such as anaesthetic registrars)
• People who are occupationally exposed to the study drugs.

Additional exclusion criteria on the day of sedation:
• Anything to eat or drink for the preceding 6 hours (excluding clear fluids)
• Anything to drink for the preceding 2 hours
• Any use of over-the-counter or recreational drugs (including alcohol or tobacco) within the preceding 24 hours
• Any use of opioid, sedative or sleep agents within the preceding 24 hours
• Recent change in health, including cough, cold, or fever
• Exposure to anaesthesia or sedation in the last 6 days

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)
Randomisation module in REDCap
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
STATISTICAL ANALYSIS PLAN
Stage 1 consists of collecting baseline EEG response to auditory evoked data and resting state data. This will be compared to the EEG responses collected from the same conditions in Stage 2 while participants are under light sedation. This comparison will consist of planned contrasts between the correlation of evoked responses to auditory stimuli under no- and light-sedation, analysed using standard EEG processing and cluster-based statistics as implemented in Fieldtrip. Resting state data will be compared between Stages 1 and 2 in terms of prediction of state, as performed using machine learning classification techniques.
The first primary comparison of interest is between the incidence of dreaming and unconsciousness during baseline (Stage 2) to either sham stimulation or TACS. To analyse this, we will use linear mixed effects models with random effects for participants, and fixed effects for Stage (2 or 3) and Stimulation (Real or Sham). We hypothesize an interaction effect, in which stimulation will increase the rate of disconnection in Stage 3 and have no effect in Stage 2 (in which no stimulation is given and thus which condition the subject is randomised should have no effect).
The second primary analysis is of Stage 4 data. Stage 4 will be analysed using a linear mixed effects model which attempts to predict the time-to-awakening, with subjects as random effects, and whether the participant had been given real or sham stimulation as a fixed effect. This model may also include baseline rate of disconnection per subject, and whether they were given real or sham stimulation in Stage 3.
We will include all available data in the models (e.g. linear mixed effects models with random effect for participant) and conduct sensitivity analyses with just paired data.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
28/11/2023
Date of last participant enrolment
Anticipated
27/11/2024
Actual
Date of last data collection
Anticipated
28/01/2025
Actual
Sample size
Target
20
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 25514 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 41334 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 313767 0
Hospital
Name [1] 313767 0
Royal Prince Alfred Hospital
Country [1] 313767 0
Australia
Primary sponsor type
Government body
Name
Sydney Local Health District
Address
50 Missenden Road Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 315594 0
None
Name [1] 315594 0
Address [1] 315594 0
Country [1] 315594 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312935 0
Sydney Local Health District (SLHD) HREC (RPAH Zone)
Ethics committee address [1] 312935 0
50 Missenden Road Camperdown NSW 2050
Ethics committee country [1] 312935 0
Australia
Date submitted for ethics approval [1] 312935 0
18/05/2023
Approval date [1] 312935 0
08/08/2023
Ethics approval number [1] 312935 0
ETH00964

Summary
Brief summary
This study will be a single-site, randomized, controlled, blinded study at the Royal Prince Alfred Hospital to examine changes in High definition-electroencephalogram (HD-EEG) correlates of cognition and consciousness during waking and sedation. Our study will address the neural correlates of consciousness and modulate these neural correlates through low frequency Transcranial alternating current stimulation (tACS).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126398 0
Prof Robert Sanders
Address 126398 0
Royal Prince Alfred Hospital, 50 Missenden Road Camperdown NSW 2050
Country 126398 0
Australia
Phone 126398 0
+61 2 951508507
Fax 126398 0
Email 126398 0
robert.sanders@sydney.edu.au
Contact person for public queries
Name 126399 0
Miss Kaitlin Kramer
Address 126399 0
Royal Prince Alfred Hospital, 50 Missenden Road Camperdown NSW 2050
Country 126399 0
Australia
Phone 126399 0
+61 0410114737
Fax 126399 0
Email 126399 0
Kaitlin.Kramer@health.nsw.gov.au
Contact person for scientific queries
Name 126400 0
Miss Kaitlin Kramer
Address 126400 0
Royal Prince Alfred Hospital, 50 Missenden Road Camperdown NSW 2050
Country 126400 0
Australia
Phone 126400 0
+61 0410114737
Fax 126400 0
Email 126400 0
Kaitlin.Kramer@health.nsw.gov.au

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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
20323Study protocol    385835-(Uploaded-13-09-2023-13-33-36)-Study-related document.pdf
20324Informed consent form    385835-(Uploaded-13-09-2023-13-34-56)-Study-related document.docx
20325Ethical approval    385835-(Uploaded-13-09-2023-13-35-38)-Study-related document.pdf



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.