Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001379808
Ethics application status
Approved
Date submitted
10/08/2021
Date registered
11/10/2021
Date last updated
17/04/2024
Date data sharing statement initially provided
11/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Why does pain spread? Using touch to treat the spread of pain
Scientific title
Why does pain spread? An investigation of inhibition in the human brain in adults with chronic back pain
Secondary ID [1] 303339 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic non-specific low back pain 320590 0
Condition category
Condition code
Musculoskeletal 318447 318447 0 0
Other muscular and skeletal disorders
Anaesthesiology 318448 318448 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Scan sessions (Electroencephalography, EEG, and Magnetic Resonance Imaging, MRI, and Magnetic Resonance Spectroscopy, MRS) will be conducted before and after the intervention in participants who are eligible and safe for neuroimaging. The scan sessions, where possible, will be conducted within a short time frame (or at least the second scanning session will, where possible, be conducted within approximately a week of training completion), in order to maximise chances of a positive training effect on pain (and detection of its effects with neuroimaging).
The scan sessions will be used to explore brain activity (EEG and functional MRI) and neurochemistry (MRS) - and their relationship - before and after the intervention.
EEG sessions will last a duration of approximately 45 minutes. The EEG sessions will occur at a University research laboratory at Curtin University, in a dedicated quiet room and will be conducted by a trained Research Assistant.
MRI/S sessions will last a duration of approximately 1 hour and will be conducted at Perth Radiological Clinic, a private radiological clinic.
The neuroimaging assessment provides an insight into the neural mechanisms that might be responsible for the hypothesised reduction in pain with our intervention - a tactile training program.
The tactile training program is a two point discrimination (TPD) training program, consisting of stages, that has been designed specifically for this study.
Participants will be randomly assigned to either the intervention group or the control group. In all instances the training will be completed by either the trial CI or the trained Research Assistant (both are registered physiotherapists). The location will be a quiet area - mutually convenient for the researcher and the participant. The training sessions will be of a duration of approximately one hour. Participants will attend up to 3 training sessions per week. They will attend a minimum of 2 sessions in a 'stage' (below). A maximum of 8 TPD training sessions will be conducted (10 total, when including the TPD training in the Scan Sessions).
The intervention involves TPD training at locations remote from the participant's pain, or locations adjacent to their pain, or at the site of pain. TPD is defined as the shortest distance between two points on the skin that someone can recognise as two points, not one, touching the skin. That is, this is a measure of tactile acuity. This task relies heavily on inhibition in the nervous system. Precise callipers will be placed on the skin at the aforementioned sites, and the distance between the callipers will be increased and decreased repeatedly. The participant will state whether one or two points has touched the skin. They will be informed of correct and incorrect responses immediately (i.e. feedback is given). To make the training more motivating and engaging, training will delivered in stages: i.e. participants may also be asked to judge the relative differences between two-point distances as they are placed on the skin, or asked to visually identify and show the researcher the two-point distance they believed they received. All participant responses/judgements will be met with feedback from the researcher.
Adherence to the intervention will be monitored by recording the participants’ attendance and intervention results on a data collection form.
A pilot study of up to 10 participants will be conducted within three months of commencement of the main RCT. Participants in the pilot study will receive either the intervention or control training programs. The purpose of the pilot study is to familiarise the Research Assistant with procedures and fine-tune the protocols. The data from the pilot study will not be included for analysis. It is not anticipated any changes to the intervention described herein will be made prior to commencing the main RCT.
Intervention code [1] 319651 0
Treatment: Other
Comparator / control treatment
The control stimulation group will undergo a single-point training program which has been designed specifically for this study. At the same body sites, probes of different sizes will be used - from small (approximately 1-5 mm) to large (approximately 6-50 mm) diameter. The probes will be gently placed in contact with the skin with consistent timings of stimulation as the training program above. The probes of differing diameters will ensure that the stimuli are novel and changing, and therefore engaging and holding the participants’ attention. In the control program there is also the equivalent of the 'stages' as per the training program - i.e. participants may be visually shown the probes that are being placed on their skin. Importantly however no responses will be sought from them. Prior to placing any probes on the skin a brief instruction will be given to the participants. Participants will be told the broad concept that the processing of sensory information occurs both at a conscious and a sub-conscious level; and that they are in the 'subconscious processing' arm of the study. The researcher will notify the participants that as the objects are placed on their skin they need to focus their attention on the objects as they touch their skin, even though in this condition the participants are not asked to discriminate or make any judgments, and they will therefore receive no feedback. This brief instruction is intended to increase the credibility of the control arm and make it more engaging for the participants in this group.
Training sessions will take place a maximum of three times per week, with a maximum of eight training sessions conducted. The number of sessions has been chosen to align with that of the intervention group.
Adherence to the control treatment will be monitored by recording attendance on a data collection form.
Control group
Active

Outcomes
Primary outcome [1] 328422 0
Spread or spatial extent/location of pain, according to a body diagram/photo of participant, on which they mark their pain area/s.
Timepoint [1] 328422 0
On completion of the tactile training program.
Primary outcome [2] 328423 0
Level of pain intensity measured using a visual analog scale.
Timepoint [2] 328423 0
On completion of the tactile training program.
Primary outcome [3] 328848 0
Level of pain unpleasantness measured using a visual analog scale.
Timepoint [3] 328848 0
On completion of the tactile training program.
Secondary outcome [1] 398970 0
Pain-related disability assessed using the Roland-Morris Disability Questionnaire.
Timepoint [1] 398970 0
On completion of the tactile training program.
Secondary outcome [2] 398971 0
Back perceptions assessed using the FreBAQ Questionnaire.
Timepoint [2] 398971 0
On completion of the tactile training program.
Secondary outcome [3] 399064 0
Two point discrimination threshold assessed using precise callipers with pre-determined spacing 5mm apart, The distance between callipers will be increased and decreased in 5mm increments repeatedly until the participant identifies two points touching the skin. The shortest distance correctly identified as two points will be used as the discrimination threshold.
Timepoint [3] 399064 0
On completion of the tactile training program.
Secondary outcome [4] 399489 0
EEG power will be determined across the scalp, including the primary sensory areas.
Timepoint [4] 399489 0
EEG measures will be compared before and after the training program, in those eligible for the neuroimaging procedures, in an effort to elucidate the brain mechanisms associated with the hypothesised reduction in pain (spread, intensity) with the tactile training program.
Secondary outcome [5] 400635 0
EEG frequency will be determined across the scalp, including the primary sensory areas.
Timepoint [5] 400635 0
EEG measures will be compared before and after the training program, in those eligible for the neuroimaging procedures, in an effort to elucidate the brain mechanisms associated with the hypothesised reduction in pain (spread, intensity) with the tactile training program.
Secondary outcome [6] 400636 0
MRS - neurochemistry in the thalamus of the brain will be determined, including glutamate (or Glx) our main excitatory chemical.
Timepoint [6] 400636 0
MRS measures will be compared before and after the training program, in those eligible for the neuroimaging procedures, in an effort to elucidate the brain mechanisms associated with the hypothesised reduction in pain (spread, intensity) with the tactile training program.
Secondary outcome [7] 421048 0
fMRI measures, ie brain activity.
Timepoint [7] 421048 0
Pre- and post- tactile training program/intervention.

Eligibility
Key inclusion criteria
Participants will be included if they are adults, have chronic non-specific back pain, i.e pain duration of 3 months or more, are fluent in written and verbal English and under the regular care of a General Practitioner (GP).
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Potential participants will be excluded if their back pain is not non-specific: i.e. if their pain is primarily visceral in origin; they demonstrate signs or symptoms of nerve root pain; or there is evidence of current specific spinal pathology (eg malignancy, fracture, infection, inflammatory joint or bone disease). We will also exclude potential participants if they are pregnant or less than 6 months post-partum, if they have undergone recent spinal surgery, or if they have a significant mental health disorder or a health impairment that would interfere with their safe participation and adherence to study requirements.
Each participant will complete safety screening questionnaires prior to the MRS and the EEG assessments. Participants will be excluded from these assessments if they do not meet the required safety criteria for each.

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)
Allocation will be concealed. Participants will be randomly allocated to the treatment or control group using a randomisation program such as Excel or an online random number generator.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using computerised sequence generation will be utilised.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Nil to report
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The sample size of n = 30 has been estimated based on (is larger than most) other pain and neuroimaging studies. The data collected in this exploration will form a proposal to investigate broader questions on sensory and motor systems in chronic pain, with a larger NHMRC grant. (Application for Category One funding with these data is a requirement of the Raine Grant funding of this current proposal).
Systematic reviews - including our own - of the literature on chronic pain and neuroimaging indicate that studies tend to recruit samples of approximately 20 participants in a clinical group [1,2].
Minimising neuroimaging type 1 error:
MRS - we are investigating specific neurochemistry - e.g. glutamate - existing on a chemical spectrum.
EEG - we are investigating specific frequencies/regions of the cortex, based on what is known about thalamocortical rhythm (including our own work [3]). We may also engage with a specialist in signal processing from biomedical engineering - who would assist with novel forms of analysis.
[1] Di Pietro F, et al. (2013) The Journal of Pain, 14(10) p 1001-1018.
[2] Di Pietro F, et al. (2013) The Journal of Pain, 14(11) p 1270-1288.
[3] Di Pietro F, et al. (2018) Human Brain Mapping, 39(5) p 1945-1956.

Data analysis plan:
Research outcomes are: spread/total body area of pain (as indicated on a photo or body diagram by participants); ratings of current pain intensity (/10) and unpleasantness (/10); ratings of pain-related disability and back perceptions; and TPD threshold measures.
Comparison of these measures pre- and post-training program will inform us on the efficacy of the tactile training program.
Statistical analysis will be conducted using SPSS, GraphPad or similar. All data will be checked for normality prior to data analysis; corrections for multiple comparisons will be made.
Advice on EEG data analysis may be sought. EEG data may be analysed using EEGLAB, a commonly used EEG analysis tool, run on the MATLAB platform. We may Fourier transform the resting state data to elucidate the relative contribution of different brain frequencies.
MRS data will be analysed using the Java-based Magnetic Resonance Users' Interface (jMRUI) - to quantify neurochemicals such glutamate.
Functional MRI data may be analysed using custom software and scripts, based on advice/collaboration with colleagues in engineering/neuroimaging (AI on the Raine grant finding the project).
The relationship between EEG and MRS/I measures will be explored - both before and after the training program.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/11/2021
Actual
13/04/2022
Date of last participant enrolment
Anticipated
Actual
3/04/2023
Date of last data collection
Anticipated
Actual
1/05/2023
Sample size
Target
30
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
WA
Recruitment postcode(s) [1] 34843 0
6102 - Bentley

Funding & Sponsors
Funding source category [1] 307756 0
Charities/Societies/Foundations
Name [1] 307756 0
Raine Medical Research Foundation
Country [1] 307756 0
Australia
Primary sponsor type
University
Name
Curtin University
Address
Kent St, Bentley,
WA 6102
Country
Australia
Secondary sponsor category [1] 310330 0
None
Name [1] 310330 0
Address [1] 310330 0
Country [1] 310330 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307777 0
Curtin University Human Research Ethics Committee
Ethics committee address [1] 307777 0
Ethics committee country [1] 307777 0
Australia
Date submitted for ethics approval [1] 307777 0
02/02/2021
Approval date [1] 307777 0
25/03/2021
Ethics approval number [1] 307777 0
HRE2021-0150

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

Contacts
Principal investigator
Name 108462 0
Dr Flavia Di Pietro
Address 108462 0
Curtin University of Technology
Bentley Campus
Kent St
Bentley 6102
Western Australia
Country 108462 0
Australia
Phone 108462 0
+61 8 92667516
Fax 108462 0
Email 108462 0
flavia.dipietro@curtin.edu.au
Contact person for public queries
Name 108463 0
Flavia Di Pietro
Address 108463 0
Curtin University of Technology
Bentley Campus
Kent St
Bentley 6102
Western Australia
Country 108463 0
Australia
Phone 108463 0
+61 8 92667516
Fax 108463 0
Email 108463 0
flavia.dipietro@curtin.edu.au
Contact person for scientific queries
Name 108464 0
Flavia Di Pietro
Address 108464 0
Curtin University of Technology
Bentley Campus
Kent St
Bentley 6102
Western Australia
Country 108464 0
Australia
Phone 108464 0
+61 8 92667516
Fax 108464 0
Email 108464 0
flavia.dipietro@curtin.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
We currently do not have Human Research Ethics approval to make individual participant data available.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
12771Study protocol    381351-(Uploaded-27-03-2023-17-16-22)-Study-related document.docx
12773Informed consent form    381351-(Uploaded-27-03-2023-17-19-12)-Study-related document.docx



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.