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Trial registered on ANZCTR


Registration number
ACTRN12623000244606p
Ethics application status
Submitted, not yet approved
Date submitted
21/02/2023
Date registered
7/03/2023
Date last updated
7/03/2023
Date data sharing statement initially provided
7/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Neurofeedback for Fibromyalgia.
Scientific title
Exploring the safety and feasibility of functional connectivity neurofeedback training for treatment of fibromyalgia- A pilot double blinded randomised placebo-controlled study.
Secondary ID [1] 309035 0
None
Universal Trial Number (UTN)
U1111-1288-7113
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Fibromyalgia 329088 0
Condition category
Condition code
Neurological 326065 326065 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Electroencephalogram based Neurofeedback (EEG NF) will be administered three times a week (30 min/session) for a total of four weeks (i.e., 12 sessions) by the researcher experienced in delivering neuromodulation techniques, using a 21 channel DC coupled amplifier produced by Brainmaster Inc. During each session, participants will be asked to sit on a chair with back supported and relaxed for 10 minutes, which allows the trainer to prepare the participant for NF training. 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 EEG.

Active-NF treatment group: Participants will be instructed to close their eyes, relax, and listen to the sound being played. The system delivers sound feedback (reward) each time the participant's brain activity meets the desired threshold at the targeted brain regions: pregenual anterior cingulate cortex (pgACC) and the primary somatosensory cortex (S1). For the current study, we have developed NF program to reinforce and train the real-time EEG functional connectivity from pgACC to the S1 in the alpha band. For all the active-NF treatment groups, the reward threshold will be adjusted in real-time between 60-80%, i.e., for 60-80% of the time, sound feedback (reward) will be delivered by the system when the participant's functional connectivity at the targeted regions meets the desired alpha magnitude (threshold).

The intervention will be delivered individually to participants by a researcher trained in delivery of EEG NF. This will be delivered face-to-face in a hospital-based setting.

The researcher will monitor adherence to the intervention by recording sessions attended with a checklist.
Intervention code [1] 325470 0
Treatment: Other
Comparator / control treatment
Conditions for the placebo-neurofeedback group will be the same as the active-neurofeedback treatment groups except that the participants will not receive a sound feedback based on their real-time functional connectivity, but according to someone else’s pre-recorded NF session. The pre-recorded files will be chosen randomly, using an open-access randomization software program, from a database of files of healthy participants who underwent NF training using the concurrent up-train pgACC and down-train dorsal anterior cingulate cortex (dACC) + S1 protocol. The sound feedback from the healthy participant’s training files has been recorded using the Audacity software, which is a free and open-source digital audio editor and recording application. Participants in the placebo-NF will be prepared as same as active-NF group, and they will receive these pre-recorded feedback sound.
Control group
Placebo

Outcomes
Primary outcome [1] 333918 0
Brief pain inventory-short form
Timepoint [1] 333918 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Primary outcome [2] 333921 0
Arthritis Impact Questionnaire
Timepoint [2] 333921 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Primary outcome [3] 333938 0
Fibromyalgia Impact Questionnaire
Timepoint [3] 333938 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Secondary outcome [1] 418750 0
Resting state EEG (Primary outcome measure)

Effective connectivity between pgACC and S1 calculated using the standardized low-resolution brain electromagnetic tomography (sLOERTA) program
Timepoint [1] 418750 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Secondary outcome [2] 418793 0
Depression, Anxiety, and Stress Scale (DASS)
Timepoint [2] 418793 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Secondary outcome [3] 418794 0
European Quality of Life–5 Dimensions (EQ-5D) scale
Timepoint [3] 418794 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Secondary outcome [4] 418795 0
Medical Outcomes Study-Sleep Scale (MOS-Sleep)
Timepoint [4] 418795 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Secondary outcome [5] 418796 0
Pain Catastrophizing scale
Timepoint [5] 418796 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Secondary outcome [6] 418797 0
Pain Vigilance and Awareness questionnaire
Timepoint [6] 418797 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Secondary outcome [7] 418798 0
World Health Organization-Five Well-being index
Timepoint [7] 418798 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Secondary outcome [8] 418799 0
Pressure Pain threshold- defined as the minimum force applied, which induces pain, will be measured at the non-dominant wrist using a digital handheld algometer.
Timepoint [8] 418799 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Secondary outcome [9] 418800 0
Temporal Summation (TS), an increased pain perception to repetitive mechanical stimuli, will be assessed using a nylon monofilament (Touchtest Sensory Evaluator 300g) at the non-dominant wrist region. Participants will report the perceived pain intensity immediately after first contact with monofilament and then following ten contacts over the same testing site. The TS index will be defined as the ratio the of "follow-up" pain rating divided by "baseline" pain rating.
Timepoint [9] 418800 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Secondary outcome [10] 418801 0
Feasibility (Primary outcome measure)

• Recruitment rate, i.e., number of participants recruited per month, until the proposed sample size is reached. This will be assessed by audit of study records.
Timepoint [10] 418801 0
The recruitment rate will be recorded by PI on a weekly basis, since the release of the advertisements, and the number of advertisements will also be recorded.
Secondary outcome [11] 418802 0
Safety (Primary Outcome measure): Any adverse effects (e.g., headache, pain flare-ups) that likely have a causal relationship with the intervention will be recorded by the treating researcher at each session before and after the treatment session.

The following variables will be recorded and will be assessed as a composite outcome:
• Qualitative description of each symptom assessed by study-specific questionnaire.
• Intensity of each symptom, measured using a Likert scale ranging from 0 (none) to 10 (extreme)
Relation of the symptom to the NF treatment, measured on a scale ranging from 1 (unrelated) to 5 (strongly related).
• Duration of each symptom and the time taken for resolution of each symptom, expressed in minutes assessed by study-specific questionnaire.
• Worsening or improvement of symptoms: The Discontinuation-Emergent Sign and Symptom (DESS), a 43-item checklist, will be used to record worsening or improving of side effects compared to the status prior to the previous session. The DESS consisting of emotional, behavioral, cognitive, and physical conditions that can be considered possible side effects from NF training.
• Any drop-outs due to adverse effects will also be recorded. This will be assessed by audit of study records.
Timepoint [11] 418802 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Secondary outcome [12] 419049 0
Resting state EEG (Primary outcome measure)

Functional connectivity between pgACC and S1 calculated using the standardized low-resolution brain electromagnetic tomography (sLOERTA) program
Timepoint [12] 419049 0
Baseline, immediately post-completion of intervention, and at follow-up of 10 days and 1-month post-completion of intervention
Secondary outcome [13] 419050 0
Feasibility (Primary outcome measure)

• Proportion of participants recruited from the total number screened (with reasons for exclusion), expressed as a percentage. This will be assessed by audit of study records.
Timepoint [13] 419050 0
Proportion of participants recruited from the total number screened will be calculated once the treatment phase of the study is completed.
Secondary outcome [14] 419051 0
Feasibility (Primary outcome measure)

Adherence to intervention measured as number of treatment sessions attended by each participant and expressed as a percentage of the total number of sessions. This will be captured by study attendance checklists.
Timepoint [14] 419051 0
Adherence rates will be calculated once the treatment phase of the study is completed.
Secondary outcome [15] 419052 0
Feasibility (Primary outcome measure)

• 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. This will be assessed by audit of study records.
Timepoint [15] 419052 0
Drop-outs rates will be calculated once the follow-up phase of the study is completed.
Secondary outcome [16] 419053 0
Feasibility (Primary outcome measure)

Participant satisfaction levels regarding treatment and the acceptability of the NF will also be recorded on an 11-point numeric rating scale (0-Not at all satisfied/acceptable to 10-Very satisfied/acceptable). This will be assessed by patient questionnaires.
Timepoint [16] 419053 0
Participant satisfaction levels regarding treatment and the acceptability of the NF will be recorded immediately post-completion of treatment.


Eligibility
Key inclusion criteria
Participants with a diagnosis of fibromyalgia will be eligible to participate.

To be included in the study, participants must meet all of the following inclusion criteria:
• Capable of understanding and signing an informed consent form
• Age between 18 to 75 years on the day of the consent
• Satisfy the Modified American Collage of Rheumatology (ACR) 2011 Fibromyalgia Diagnostic Criteria
• A score greater than or equal to 4 on the 11-point numeric pain rating scale (NPRS, 0=No pain to 10=Worst pain) in the past 7 days
• A disability score of greater than or equal to 50 on Fibromyalgia Impact Questionnaire
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants who meet any of the following conditions will be excluded:
• Neurological conditions
• Cognitive and psychiatric disorders
• Epilepsy
• Seizures
• Substance abuse
• Pregnant or six-months post-partum

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)
Concealed in opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Open-access randomization software program
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
Sample size estimation has not been conducted as this is a pilot study. We aim to recruit a modest sample (15 per group). Effect sizes will be calculated based on this study estimates on outcomes, which will be used to calculate sample size for the future fully powered trial.

SPSS version 28.0 will be used for all statistical analyses. Descriptive statistics will be used to analyse feasibility and safety measures. Central tendency, variability/confidence intervals will be derived for all primary and secondary outcomes. Percentage change from baseline will be calculated for all outcomes and will be used to determine the intervention effects on outcome measures.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
20/03/2023
Actual
Date of last participant enrolment
Anticipated
27/10/2023
Actual
Date of last data collection
Anticipated
29/12/2023
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment outside Australia
Country [1] 25274 0
New Zealand
State/province [1] 25274 0
Dunedin

Funding & Sponsors
Funding source category [1] 313239 0
University
Name [1] 313239 0
University of Otago
Country [1] 313239 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
362 Leith Street, Dunedin North, Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 314966 0
None
Name [1] 314966 0
NA
Address [1] 314966 0
NA
Country [1] 314966 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 312471 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 312471 0
Ethics committee country [1] 312471 0
New Zealand
Date submitted for ethics approval [1] 312471 0
12/01/2023
Approval date [1] 312471 0
Ethics approval number [1] 312471 0

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

Contacts
Principal investigator
Name 124778 0
Dr Divya Adhia
Address 124778 0
201 Great King Street, Dunedin hospital, 6th floor, Room 607,
Department of Surgical Sciences, Otago Medical School, University of Otago.
Dunedin
9013
New Zealand
Country 124778 0
New Zealand
Phone 124778 0
+64 34709337
Fax 124778 0
Email 124778 0
divya.adhia@otago.ac.nz
Contact person for public queries
Name 124779 0
Divya Adhia
Address 124779 0
201 Great King Street, Dunedin hospital, 6th floor, Room 607,
Department of Surgical Sciences, Otago Medical School, University of Otago.
Dunedin
9013
New Zealand
Country 124779 0
New Zealand
Phone 124779 0
+64 34709337
Fax 124779 0
Email 124779 0
divya.adhia@otago.ac.nz
Contact person for scientific queries
Name 124780 0
Divya Adhia
Address 124780 0
201 Great King Street, Dunedin hospital, 6th floor, Room 607,
Department of Surgical Sciences, Otago Medical School, University of Otago.
Dunedin
9013
New Zealand
Country 124780 0
New Zealand
Phone 124780 0
+64 34709337
Fax 124780 0
Email 124780 0
divya.adhia@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
None


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
No additional documents have been identified.