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Trial registered on ANZCTR


Registration number
ACTRN12619000002189
Ethics application status
Approved
Date submitted
14/12/2018
Date registered
8/01/2019
Date last updated
8/08/2019
Date data sharing statement initially provided
8/01/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Does sensorimotor cortex plasticity predict the development of chronic low back pain: a protocol for a prospective, longitudinal, cohort study
Scientific title
Do sensorimotor cortex activity, an individual’s capacity for neuroplasticity, and psychological features during an episode of acute low back pain predict outcome at 6-months: a protocol for a prospective, longitudinal cohort study
Secondary ID [1] 296860 0
Nil Known
Universal Trial Number (UTN)
Nil known
Trial acronym
UPWaRD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute low back pain 310774 0
Chronic low back pain 310775 0
Condition category
Condition code
Musculoskeletal 309456 309456 0 0
Normal musculoskeletal and cartilage development and function
Neurological 309517 309517 0 0
Other neurological disorders

Intervention/exposure
Study type
Observational
Patient registry
True
Target follow-up duration
6
Target follow-up type
Months
Description of intervention(s) / exposure
Participants experiencing an acute episode of low back pain (less than 6 weeks duration) will be included and followed for 6 months. Eligible participants will complete tests that assess characteristics of the sensory and motor cortex, individual capacity for neuroplasticity and psychological status at baseline. Fifteen candidate predictors are selected a priori based on a theoretical association with the development of chronic LBP. Methods for obtaining measures of candidate predictors are outlined below.

Sensory and anterior cingulate cortex activity:
Sensory evoked potentials will be recorded in response to electrical stimulation of the paraspinal muscles through surface electrodes positioned ipsilateral to the side of worst low back pain. Primary sensory cortex activity (S1) is recorded using electroencephalography via gold plated cup electrodes (Digitimer, Reusable Au and Ag EEG Cup Electrodes) positioned over S1 (3 cm lateral and 2 cm posterior to Cz) on the side contralateral to worst low back pain and referenced to Fz according to the International 10/20 EEG placement system. Two blocks of 500 stimuli are recorded for each participant.

Motor cortex activity:
Single-pulse, monophasic transcranial magnetic stimulation (TMS) is delivered to the primary motor cortex (M1) contralateral to the side of worst LBP (Magstim 200 stimulator/7 cm figure-of-eight coil; Magstim Co. Ltd. Dyfed, UK). During testing the coil is positioned tangential to the skull and moved lateral to the midline. Using a stimulator intensity of 100%, with an inter-stimulus interval of ~5s, 5 stimuli are delivered over pre-marked scalp sites on a 6x7cm grid, commencing at the vertex. Surface electromyography (EMG) is recorded from the paraspinal muscles throughout. As paraspinal motor evoked potentials (MEPs) are difficult to elicit at rest, M1 stimulation is conducted during sub-maximal paraspinal muscle contractions. Target muscle activation is achieved by leaning backward into resistance provided from a pillow, whilst keeping the back straight. TMS map data are exported and analysed using MATLAB 7 (The MathWorks, USA). MEP responses are superimposed over the respective scalp sites to construct a topographical representation of the target paraspinal muscle and normalized to the peak response for each participant.

Capacity for neuroplasticity:
Brain derived neurotrophic factor (BDNF) genotyping: Cheek swabs taken on the day of baseline testing are used to prepare genomic DNA (Isohelix DNA Isolation Kit). Samples taken at T1 are immediately frozen at -80 oC and stored until analyses.
Brain derived neurotrophic factor (BDNF) serum concentration: Peripheral venous blood is drawn into serum tubes (BD Vacutainer, SST II Advance) and clotted (30 min, room temperature) at T1. Serum is then separated by centrifugation (2500 rpm, 15 min) and stored separately at -80°C until measurement. BDNF serum concentration is measured using an enzyme-linked immunosorbent assay (ELISA).

Psychological status:
Pain catastrophising scale: The Pain Catastrophising Scale (PCS) is included to assess catastrophizing thoughts about pain. The PCS includes 13 items, scored on a 5-point scale.
Depression, anxiety and stress scale: A 21-item version of the depression, anxiety and stress scales questionnaire (DASS-21) will be administered. The questionnaire includes three 7-item subscales: DASS-depression, DASS-anxiety, DASS-stress. A total score is obtained for the DASS-21 with higher scores indicating greater depression, anxiety and/or stress
Pain self-efficacy questionnaire: The pain self-efficacy questionnaire consists of 10 items, each scored on a 7-point scale. The questionnaire evaluates the confidence of an individual in their ability to perform a range of functional activities whilst in pain. A total score between 0 to 60 is calculated, with higher scores representing greater self-efficacy beliefs

Demographics and baseline pain intensity;
Age, sex and previous history of low back pain data will be collected from all participants at baseline. Baseline pain intensity will be drawn from the Brief Pain Inventory administered at T1 (as described under primary outcome measure 1) where participants score their pain intensity on average over the previous week using the NRS.
Intervention code [1] 313138 0
Diagnosis / Prognosis
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 308415 0
Pain intensity: Participants complete the Brief Pain Inventory (BPI) at where they are asked to score their pain intensity on average over the previous week using an eleven-point numerical rating scale (NRS: 0 = “no pain”, 10 = “worst pain imaginable”). At T2 a NRS score less than or equal to 1 will be classified as recovered low back pain and a NRS score greater than or equal to 2 will be classified as chronic low back pain.

Timepoint [1] 308415 0
Basline - T1
6 month follow up - T2
Secondary outcome [1] 354899 0
Disability: Participants complete the 24-point Roland Morris Disability Questionnaire (RMDQ). This questionnaire aims to detect the level of disability experienced as a result of low back pain. At T2 a RMDQ score less than or equal to 6 will be classified as recovered low back pain and a RMDQ score greater than or equal to 7 will be classified as chronic low back pain.
Timepoint [1] 354899 0
Basline - T1
6 month follow up - T2

Eligibility
Key inclusion criteria
Eligible participants must be 18 years or older and currently experiencing acute non-specific low back pain - defined as pain in the region of the lower back, superiorly bound by the thoracolumbar junction and inferiorly by the gluteal fold. Participants remain eligible if they have pain referred beyond this region that is not suspected radicular pain from neural tissue involvement. Pain must have been present for more than 24 hours and less than 6 weeks duration following a period of at least 1-month pain-free. As we aim to determine which variables predict low back pain outcome, regardless of whether this is the first episode of pain, participants need not be experiencing their first low back pain episode. Previous history of low back pain will be included as a candidate predictor in the statistical model. Participants must provide written informed consent to participate and be able to speak and read English.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Known or suspected serious spinal pathology (fracture; malignancy, inflammatory or infective diseases of the spine; cauda equina syndrome or widespread neurological disorder); suspected or confirmed pregnancy or less than six months’ post-partum; suspected radicular pain (dominant leg pain, positive neural tissue provocation tests and/or any two of altered strength, reflexes, or sensation for the same nerve root, assessed clinically); previous lumbar spinal surgery (e.g. spinal fusion, intervertebral disc replacement); presence of another painful condition (e.g. fibromyalgia, neuropathy, rheumatoid arthritis); comorbidities affecting sensorimotor function or causing neurological deficit (e.g. multiple sclerosis, spinal cord injury); history of psychological disorders requiring medication for symptom control (e.g. major depressive disorder, bipolar disorder, schizophrenia) and/or contraindications to transcranial magnetic stimulation.

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Candidate predictors assessed at baseline are listed below:
Sensory and anterior cingulate cortex activity:
- SEP N80 component area
- SEP N150 component area
- SEP P260 component area

Motor cortex activity
- L3 map volume
- L5 map volume
- L3/L5 centre of gravity overlap

Capacity for neuroplasticity
- BDNF genotype
- BDNF serum concentration

Psychological status
- PCS
- DASS-21
- PSEQ

Demographics
- Age
- Sex
- Previous history of low back pain

Baseline pain intensity
- NRS score at T1

SEP – sensory evoked potential, L3 – electrode recording site 3cm lateral to the L3 spinous process, L5 - electrode recording site 1cm lateral to the L3 spinous process, BDNF – brain derived neurotrophic factor, PCS – Pain catastrophising scale, DASS-21 - Depression, anxiety and stress scale, PSEQ - Pain self-efficacy questionnaire, NRS – 11-point numerical rating scale, T1 – within 6-weeks of acute low back pain onset.

Sample size:
- Ten subjects will be ensured per variable (SPV) in the linear regression model to assess whether baseline variables are associated with pain intensity at T2.
- We will seek a minimum of five events per variable (EPV) for logistic regression analysis.

Statistical analysis:
Data analysis will be carried out using SPSS for Windows (V.25; SPSS, Chicago, IL). Continuous variables will be presented through centrality measures (mean, median), and dispersion (SD and IQR) according to the distribution, and categorical variables through frequencies and percentages. A primary and secondary analysis will occur to interpret the collected data.

Primary analysis:
The primary analysis will use a multivariate linear regression model to determine the candidate predictors associated with pain intensity and disability at T2. All predictors with a p-value <0.20 in a univariate analysis will be considered for inclusion in the final linear regression multivariate model. Goodness of fit of the final linear regression model will be reported with adjusted R2 values.

Secondary Analysis:
The secondary analysis will use logistic regression to investigate the relationship between baseline candidate predictors and measures of chronic LBP (pain and disability at T2). Multivariable logistic regression with backward stepwise selection will be employed. We will examine the predictive performance of the prognostic model by analysing measures of calibration and discrimination. We will assess internal validity and any over-fitting of the final model using bootstrapping techniques.

Missing data:
Cases with missing values will be removed from the dataset if follow-up rates are higher than 95%. If missing data exceeds 5%, multiple imputation will be used in line with recommendations of the TRIPOD statement.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
14/04/2015
Date of last participant enrolment
Anticipated
31/01/2019
Actual
23/01/2019
Date of last data collection
Anticipated
31/07/2019
Actual
25/07/2019
Sample size
Target
120
Accrual to date
Final
120
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 12709 0
Campbelltown Hospital - Campbelltown
Recruitment postcode(s) [1] 25131 0
2560 - Campbelltown

Funding & Sponsors
Funding source category [1] 301433 0
Government body
Name [1] 301433 0
National Health and Medical Research Council (NHMRC) of Australia
Country [1] 301433 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Neuroscience Research Australia
Address
139 Barker Street
Randwick, NSW, 2031
Country
Australia
Secondary sponsor category [1] 301117 0
University
Name [1] 301117 0
Western Sydney University
Address [1] 301117 0
School of Science and Health, Western Sydney University, Locked bag 1797 Penrith, New South Wales 2751
Country [1] 301117 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302165 0
Western Sydney University Human Research Ethics Committee
Ethics committee address [1] 302165 0
Ethics committee country [1] 302165 0
Australia
Date submitted for ethics approval [1] 302165 0
20/11/2013
Approval date [1] 302165 0
11/03/2014
Ethics approval number [1] 302165 0
H10465

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

Contacts
Principal investigator
Name 89350 0
A/Prof Siobhan Schabrun
Address 89350 0
Neuroscience Research Australia (NeuRA),
139 Barker Street
Randwick, New South Wales, 2031
Country 89350 0
Australia
Phone 89350 0
+61 2 4620 3497
Fax 89350 0
+61 2 4620 3792
Email 89350 0
s.schabrun@neura.edu.au
Contact person for public queries
Name 89351 0
Luke Jenkins
Address 89351 0
Neuroscience Research Australia (NeuRA),
139 Barker Street
Randwick, New South Wales, 2031
Country 89351 0
Australia
Phone 89351 0
+61 2 4620 3497
Fax 89351 0
Email 89351 0
L.Jenkins@westernsydney.edu.au
Contact person for scientific queries
Name 89352 0
Luke Jenkins
Address 89352 0
Neuroscience Research Australia (NeuRA),
139 Barker Street
Randwick, New South Wales, 2031
Country 89352 0
Australia
Phone 89352 0
+61 2 4620 3497
Fax 89352 0
Email 89352 0
L.Jenkins@westernsydney.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
According to ethics no identifiable data will be made available or reported.


What supporting documents are/will be available?




Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseIs there a causal relationship between acute stage sensorimotor cortex activity and the development of chronic low back pain? a protocol and statistical analysis plan.2019https://dx.doi.org/10.1136/bmjopen-2019-035792
EmbaseLow Somatosensory Cortex Excitability in the Acute Stage of Low Back Pain Causes Chronic Pain.2022https://dx.doi.org/10.1016/j.jpain.2021.08.003
EmbaseHuman assumed central sensitization in people with acute non-specific low back pain: A cross-sectional study of the association with brain-derived neurotrophic factor, clinical, psychological and demographic factors.2023https://dx.doi.org/10.1002/ejp.2078
N.B. These documents automatically identified may not have been verified by the study sponsor.