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Trial registered on ANZCTR


Registration number
ACTRN12620000273987
Ethics application status
Approved
Date submitted
7/02/2020
Date registered
2/03/2020
Date last updated
2/03/2020
Date data sharing statement initially provided
2/03/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
Neurofeedback for Osteoarthritic Knee Pain
Scientific title
A pilot randomised sham-controlled clinical trial evaluating the feasibility, safety, and acceptability of Infraslow electroencephalography neurofeedback training on experimental and clinical pain outcomes in people with chronic painful knee osteoarthritis.
Secondary ID [1] 299514 0
Nil Known
Universal Trial Number (UTN)
U1111-1241-2310
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Osteoarthitic Knee Pain
314763 0
Condition category
Condition code
Musculoskeletal 313094 313094 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants allocated to the intervention group will required to attend nine sessions (30 minutes; three sessions/week) of Infraslow Fluctuation-Neurofeedback (ISF-NF) treatment at the school of physiotherapy and two 90-minute sessions for undergoing baseline (S1) and post-intervention assessments (S11).

During each session, participants will be asked to sit on a chair with back supported, and relaxed for 10 minutes, that allows the trainer (University research student) to prepare the participant for NF training. Both ISF-NF and sham ISF-NF will be administered using a 21 channel DC coupled amplifier produced by Brainmaster Inc. The Comby EEG lead cap with sensors (Ag/AgCl) will be fixed to the individual’s scalp, with reference electrodes placed at the mastoids. The impedance of the active electrodes will be monitored through the Mitsar amplifier and will be kept below 5 kilo-ohms. The participants will also be emphasized to minimize the eyeball movement, head and neck movements, swallowing, and clenching of teeth to minimize motion artifact in electroencephalogram (EEG).
Participants will be instructed to close their eyes, relax and listen to the sound being played. A distinct tone will be played when the participant’s brain activity meets ISF (0.0 to 0.1 Hz) magnitude (threshold) at the following cortical areas of the brain: somatosensory cortex (SSC), dorsal anterior cingulate cortex (dACC) and pregenual anterior cingulate cortex (pgACC). The brain regions are chosen based on brain imaging studies on KOA and previous NF studies. Training will be intended to down-train SSC and dACC activity, simultaneously with up-training of pgACC. Efforts will be made to keep the reward threshold in real-time between 60-80%. In other words, for 60-80% of the time, a sound will be played (reward) when the participant's brain activity meets the infraslow magnitude (threshold).
Intervention code [1] 315771 0
Treatment: Other
Comparator / control treatment
Conditions for the sham ISF-NF group will be the same as ISF-NF group except the participants will receive feedback according to someone else pre-recorded session. To ensure this, we have trained healthy participants with an active NF program for nine sessions and we captured the feedback sound using Audacity software, which is a free and open-source digital audio editor and recording application
Participants in the sham ISF-NF will be prepared as same as ISF-NF group, and they will receive these pre-recorded feedback sound. This process has been incorporated in order to record the real-time EEG of the participants undergoing NF training in the sham group.
The pre-recorded signals will be selected randomly by the chit method form a set of nine files.
Control group
Placebo

Outcomes
Primary outcome [1] 321635 0
Recruitment rate: The number of participants attending screening assessment will be assessed using participant data from the study records.
Timepoint [1] 321635 0
Monthly for the first three months of the recruitment period (February, March and April, 2020)
Primary outcome [2] 321636 0
Randomization rate: a ratio of the number of participants willing to be randomized into the trial from amongst those eligible. This will be assessed using the participant data from the study records.
Timepoint [2] 321636 0
Monthly for the first three months of the recruitment period (February, March and April, 2020)
Primary outcome [3] 321637 0
Retention rate: The number of sessions attended by the participant will be assessed from the individual participant data from the study records.
Timepoint [3] 321637 0
Monthly for the first four months of the intervention period (February, March, April, & May 2020)
Secondary outcome [1] 375685 0
Pain intensity and interference (composite item)
Timepoint [1] 375685 0
Brief Pain Inventory tool will be used at baseline (S1) & two days following the last NF session (S11).
Prior to every NF session- Pain intensity and single-item pain interference (same tool).
Secondary outcome [2] 375686 0
Pain unpleasantness will be measured using a VAS-unpleasantness scale.
Timepoint [2] 375686 0
Baseline (S1), prior to every NF session, and two days following the last NF session (S11)
Secondary outcome [3] 375687 0
Pain bothersomeness: Participants will be asked about the bothersomeness (24 Hrs) of their knee pain with a categorical question (not at all, slightly, moderately, very much, extremely)
Timepoint [3] 375687 0
Baseline (S1), prior to every NF session, and two days following the last NF session (S11)
Secondary outcome [4] 375693 0
Knee injury and Osteoarthritis Outcome Score (KOOS)
Timepoint [4] 375693 0
Baseline (S1) and two days following the last NF session (S11)
Secondary outcome [5] 375703 0
Pressure Pain Threshold (PPT) - Experimental pain measure
Timepoint [5] 375703 0
Baseline (S1) and two days following the last NF session (S11)
Secondary outcome [6] 375704 0
Mechanical Temporal Summation (MTS)- Experimental pain measure
Timepoint [6] 375704 0
Baseline (S1) and two days following the last NF session (S11)
Secondary outcome [7] 375705 0
Conditioned Pain Modulation (CPM)- Experimental pain measure
Timepoint [7] 375705 0
Baseline (S1) and two days following the last NF session (S11)
Secondary outcome [8] 379728 0
Cold hyperalgesia- an experimental pain measure assessed using timed-ice protocol (30 sec.).
Timepoint [8] 379728 0
Baseline (S1) and two days following the last NF session (S11)
Secondary outcome [9] 379729 0
Vibration detection threshold (VDT)
Timepoint [9] 379729 0
Baseline (S1) and two days following the last NF session (S11)
Secondary outcome [10] 379730 0
Two-point discrimination threshold (TPD), a measure of- Tactile acuity will be measured.
Timepoint [10] 379730 0
Baseline (S1) and two days following the last NF session (S11)
Secondary outcome [11] 379731 0
Left/right judgement task (LRJT), an implicit measure of motor imagery will be measured.
Timepoint [11] 379731 0
Baseline (S1) and two days following the last NF session (S11)
Secondary outcome [12] 379732 0
Six-minute walk test, assessing the sub-maximal exercise capacity as well as sensitivity to Physical Activity (SPA) index (composite item).
Timepoint [12] 379732 0
Baseline (S1) and two days following the last NF session (S11)
Secondary outcome [13] 379733 0
Physical performance measure: 30 seconds chair stand test
Timepoint [13] 379733 0
Baseline (S1) and two days following the last NF session (S11)
Secondary outcome [14] 380111 0
Dropout rate (Primary outcome): The number of dropouts in each group (Reasons for non-attendance or early withdraw from treatment will be noted) will be recorded using the individual participant data from the study records.
Timepoint [14] 380111 0
Monthly for the first four months of the intervention period (February, March, April, & May 2020)
Secondary outcome [15] 380112 0
Adverse effects/events (primary outcome):; Discontinuation-Emergent Sign and Symptom Scale will be used to measure potential adverse events (e.g.,: headaches, anxiety, trouble sleeping).
Timepoint [15] 380112 0
Before every NF session (from S3)
Secondary outcome [16] 380113 0
Acceptability of the NF intervention (primary)
Timepoint [16] 380113 0
Two days following the last NF session (S11); using a Likert scale

Eligibility
Key inclusion criteria
Adults aged 44-75 years, with a clinical diagnosis of knee OA; with pain (at least = four on an 11-point numerical rating scale) for a minimum duration of three months will be eligible to participate in the study.
Minimum age
44 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Underwent surgery or other invasive procedures in the last six months and any surgical procedures scheduled within 8 weeks after screening.
• Undertaken any steroid injections to the knee joint in the past three months or on oral steroids in the previous month.
• Current intake of centrally acting medications (e.g. antidepressants, anticonvulsants, neuropathic pain drugs) or intention of taking new medications in the next 8 weeks.
• Neurological conditions/diseases (brain, spinal cord or peripheral nerve injuries, radiculopathy and neuropathies).
• Soft tissue injuries of the knee (e.g. meniscus/muscle/tendon/ligament injury) in the last 3 months.
• Cognitive impairments (dementia, post-traumatic stress disorders, Alzheimer’s disease).
• Difficulty or inability to read or understand English.
• Hearing problems (hearing loss, tinnitus) and ear infections.
• Pregnancy or six months post-labour.

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)
On the day of eligibility confirmation, a research administrator will randomize eligible volunteers using an open-access randomization software program, to receive either ISF-NF or sham ISF-NF. In order to ascertain an equal number of participants in both groups and decrease allocation bias, concealed allocation will be done using block randomization. The administrator will prepare opaque sealed randomization envelopes containing the information for the participant regarding the allocation group and details. The envelope will be given to the participant by the assessor on the baseline assessment day.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization schedule will be computer-generated by a research administrator.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Feasibility, acceptability and adverse events over the NF will be summarized descriptively. Means and standard deviations (or medians) of the clinical (pain and function) and experimental pain/sensory outcome measures for each group will be derived.
Standardised low-resolution brain electromagnetic tomography (sLORETA) software will be used to perform a voxel-by-voxel analysis (comprising 6239 voxels) for the different frequency bands of the current density distribution to identify potential differences in brain electrical activity. Nonparametric statistical analyses of functional sLORETA images (statistical nonparametric mapping: SnPM) will be performed for each contrast using sLORETA’s built-in voxel-wise randomization tests (5000 permutations) and employing a log-F-ratio statistic for independent groups with a threshold P < 0.05 to compute the cortical three-dimensional distribution of current density. Current density, power to power nesting, whole brain analysis and functional connectivity will be established based on the data availability.

Recruitment
Recruitment status
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] 21915 0
New Zealand
State/province [1] 21915 0
Otago

Funding & Sponsors
Funding source category [1] 304008 0
University
Name [1] 304008 0
School of Physiotherapy, University of Otago
Address [1] 304008 0
325 Great King St., North Dunedin, 9016
Country [1] 304008 0
New Zealand
Funding source category [2] 304463 0
University
Name [2] 304463 0
Dunedin School of Medicine, Department of Surgical Sciences, University of Otago
Address [2] 304463 0
201 Great King Street, Dunedin 9016
Country [2] 304463 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
325 Great King St., North Dunedin, 9016
Country
New Zealand
Secondary sponsor category [1] 304181 0
None
Name [1] 304181 0
Address [1] 304181 0
Country [1] 304181 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304502 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 304502 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 304502 0
New Zealand
Date submitted for ethics approval [1] 304502 0
18/10/2019
Approval date [1] 304502 0
25/11/2019
Ethics approval number [1] 304502 0
19/CEN/182

Summary
Brief summary
This is a pilot RCT involving randomization, double-blinding (participant and assessor), two-arm, parallel, sham-controlled trial. The participant will be randomized to receive either ISF-NF or sham ISF-NF. All the participants are expected to undergo 9 treatment sessions and two assessment sessions during the entire course of the study.
The primary outcomes of the study is intended to look at the feasibility, safety and adverse effect measures for tailoring a future fully powered RCT.
Trial website
www.otago.ac.nz/braintraining
Trial related presentations / publications
Public notes
The protocol of the pilot/feasibility study was presented at the Postgraduate Symposium 2019 held at CHARR, School of Physiotherapy.

Contacts
Principal investigator
Name 97170 0
Dr Ramakrishnan Mani
Address 97170 0
Senior Lecturer
School of Physiotherapy, University of Otago
325 Great King St.
Dunedin - 9016
Country 97170 0
New Zealand
Phone 97170 0
+64 03 479 3485
Fax 97170 0
Email 97170 0
ramakrishnan.mani@otago.ac.nz
Contact person for public queries
Name 97171 0
Mr Jerin Mathew
Address 97171 0
Postgraduate Student (Co-ordinating investigator)
School of Physiotherapy, University of Otago
325 Great King St.
Dunedin - 9016
Country 97171 0
New Zealand
Phone 97171 0
+64 0291271413
Fax 97171 0
Email 97171 0
jerin.mathew@postgrad.otago.ac.nz
Contact person for scientific queries
Name 97172 0
Mr Jerin Mathew
Address 97172 0
Postgraduate Student
School of Physiotherapy, University of Otago
325 Great King St.
Dunedin - 9016
Country 97172 0
New Zealand
Phone 97172 0
+64 0291271413
Fax 97172 0
Email 97172 0
jerin.mathew@postgrad.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