Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001158954
Ethics application status
Approved
Date submitted
16/08/2020
Date registered
4/11/2020
Date last updated
4/11/2020
Date data sharing statement initially provided
4/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigation of sensory nerve fibre alterations in people with sciatica
Scientific title
Investigation of altered sensory nerve fibre structure and function using quantitative sensory testing and skin biopsy in patients with lumbar radiculopathy and radicular leg pain
Secondary ID [1] 302031 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lumbar radiculopathy with radicular pain 318608 0
Condition category
Condition code
Neurological 316628 316628 0 0
Other neurological disorders
Surgery 316652 316652 0 0
Other surgery

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Symptomatic participants will undergo a baseline assessment which includes a clinical examination, quantitative sensory testing, and completion of questionnaires. Skin biopsies will be taken at the time of surgery (in theatre). The initial assessment will be performed in the week prior to surgery and will take approximately 2.5 hours.

Healthy control participants will only undergo a baseline assessment including quantitative sensory testing, completion of questionnaires and the taking of skin biopsies. The total visit will take approximately 2.5 hours.

a) Clinical examination
The participant’s pain history, including pain distribution and pain behaviour will be recorded and a clinical examination for determination of neurological deficits will be conducted (reflex, strength and sensation testing). The clinical examination will be performed by the PI or a research assistant. The time required for the clinical examination: 15 minutes

b) Questionnaires
Consistent with our previous study (ANZCTR Trial 366797) patients will complete various questionnaires to capture their clinical profile, including:

Assessment of pain
• Pain intensity of back and leg pain (11- point numerical rating scale (NRS))
• Health care utilisation
• Bothersomeness of back and leg pain (NRS)
• #Sciatica Bothersomeness Index
• #Brief pain Inventory (BPI) 7-item pain interference sub-scale

Assessment of functional deficits
• Oswestry Disability Index

Assessment of neuropathic pain symptoms
• painDETECT Questionnaire
• #Neuropathic Pain Symptoms Inventory

Assessment of psychological factors
• *Hospital Anxiety and Depression Scale
• *Pain Catastrophizing Scale
• Fear avoidance behaviour (Tampa Scale for Kinesiophobia)
• Confidence in recovery (‘great deal’, ‘moderate’, ‘no confidence’, ‘do not know’)

Assessement of quality of life
• *SF-36
• *#EQ-5D-5L

Assessment of sleep interference
• *Sleep quality (Visual analogue scale)

*Questionnaires will also be completed by healthy participants.
#Questionnaires will allow comparison to data collected by our collaborator in non-surgical patients with lumbar referred leg pain.

The questionnaires will be collected by the PI or a research assistant.

c) Quantitative Sensory testing
Standardised quantitative sensory testing (QST) will be performed according to the standardised and well validated QST protocol of the German Research Network on Neuropathic Pain (DFNS). The protocol includes the following assessments: cold and warm detection thresholds; the number of paradoxical heat sensations during the procedure of alternating warm and cold stimuli; cold and heat pain thresholds; mechanical detection threshold; mechanical pain threshold; stimulus-response functions: mechanical pain sensitivity and dynamic mechanical allodynia; wind-up ratio; vibration detection threshold; pressure pain threshold. The full test battery will be applied to the lower back and main pain area in the leg on the symptomatic side. Testing of the full test battery will take approximately 25-30 minutes. In the L5/S1 foot dermatomes only thermal, mechanical and vibration detection thresholds will be measured which will take approximately 10 minutes. Prior to testing, participants will be familiarised with the testing methods in a body region which will not be assessed afterwards. The familiarisation will take approximately 10 minutes. The methodology is consistent with our methods in previous studies (ANZCTR trials 366797, 365980). The total time required for the QST will be approximately 1.5 hours.

Healthy controls will undergo exactly the same QST procedures as patients. Each healthy control is matched to a specific patient, i.e. the same body regions will be assessed as in the respective patient.

c) Skin samples
The determination of intraepidermal nerve fibre density (IENFD) in skin biopsies is the gold standard to determine structural integrity of small fibres. Measurement of IENFD is a relatively simple assay which can be performed in relatively innocuous 3mm punch biopsies of skin, a routine dermatological investigation

Skin biopsies will be taken by the surgeon at the time of surgery (in theatre) in the lower back and in the leg on the symptomatic side in the same area where the full QST battery had been performed. In each body region (lower back and leg), one skin biopsy will be taken. For healthy controls the skin samples will be taken by a doctor after QST measures have been taken. The skin biopsies will be taken in the same body region where the full QST battery had been performed (lower back and leg).

The skin areas will be anaesthetised (1-2ml of 2% lidocaine) prior to the biopsy. Skin punch biopsies will be fresh frozen or fixed with 2% paraformaldehyde-lysine-periodate, as instructed by our AI Schmid (Oxford University), coded with the participant’s ID number and stored in a locked freezer.

The skin biopsies will be sent via WorldCourier to our AI in Oxford/UK. Intra-epidermal nerve fibre density reflecting structural small fibre integrity will be established immunohistochemically using protein gene product 9.5 (PGP9.5, panaxonal marker) as previously performed by our collaborator (AI Schmid).

Symptomatic participants will be observed up to 12 months after surgery. The 3
months post-surgery assessment will include the same QST procedures as pre-surgery, i.e. the full QST protocol in the participants' lower back, in the pre-surgical main pain area in the leg and the reassessment of detection thresholds in the relevant dermatome. The duration of the QST will be approximately 1.5 hours. In addition participants will have to complete questionnaires to assess pain, functional deficits and neuropathic pain symptoms (see baseline measures). The anticipated duration for the 3 months post-surgery visit is 2 hours. The 12 months follow up will only include the questionnaires as at 3 months. The questionnaires will be sent to the participants. The completion of questionnaires will take approximately 30-40 minutes.
Intervention code [1] 318345 0
Diagnosis / Prognosis
Comparator / control treatment
For each patient an age (+/-5 years)- and gender matched healthy control participant will be recruited and assessed. Healthy controls will complete questionnaires and undergo QST as outlined under "Description of interventions".
Control group
Active

Outcomes
Primary outcome [1] 324776 0
Intra-epidermal nerve fibre density (IENFD) will be determined by microscopic examination of skin biopsies. Intra-epidermal nerve fibre density will be established immunohistochemically usign protein gene product 9.5 (PGP9.5, panaxonal marker), as previously performed by our collaborator (AI Schmid).
Timepoint [1] 324776 0
Baseline
Primary outcome [2] 324777 0
Cold detection threshold; Thermal detection thresholds will be measured according to the standardised QST protocol of the German Research Network on Neuropathic pain. Thermal detection thresholds will be measured using the TSA NeuroSensory Analyzer (Medoc, Israel) with a 12.5cm2 probe. The baseline temperature will be set at 32°C; cut-off temperatures are at 5°C and 50°C. Thresholds will be obtained with ramped stimuli (1°C/s) which will be terminated when the subject presses a button. For cold detection thresholds, the subject is asked to press a button as soon as they feel the first temperature change to cooler. The mean threshold temperature of three consecutive measurements will be calculated.
Timepoint [2] 324777 0
baseline, 3 months
Primary outcome [3] 325177 0
warm detection threshold; . Thermal detection thresholds will be measured according to the standardised QST protocol of the German Research Network on Neuropathic pain. Thermal detection thresholds will be measured using the TSA NeuroSensory Analyzer (Medoc, Israel) with a 12.5cm2 probe. The baseline temperature will be set at 32°C; cut-off temperatures are at 5°C and 50°C. Thresholds will be obtained with ramped stimuli (1°C/s) which will be terminated when the subject presses a button. For warm detection thresholds, the subject is asked to press a button as soon as they feel the first temperature change to warmer. The mean threshold temperature of three consecutive measurements will be calculated.
Timepoint [3] 325177 0
baseline, 3 months
Secondary outcome [1] 385715 0
Oswestry Disability Index
Timepoint [1] 385715 0
baseline, 3 months, 12 months
Secondary outcome [2] 387091 0
Pain intensity of back and leg pain (11-point numerical rating scale (NRS)
Timepoint [2] 387091 0
baseline, 3 months, 12 months
Secondary outcome [3] 387092 0
Bothersomeness of back and leg pain (NRS)
Timepoint [3] 387092 0
baseline, 3 and 12 months
Secondary outcome [4] 387093 0
Sciatica Bothersomeness Index
Timepoint [4] 387093 0
baseline, 3 months, 12 months
Secondary outcome [5] 387094 0
Brief Pain Inventory 7-item pain interference sub-scale
Timepoint [5] 387094 0
baseline, 3 months, 12 months
Secondary outcome [6] 387095 0
painDETECT questionnaire
Timepoint [6] 387095 0
baseline, 3 months, 12 months
Secondary outcome [7] 387096 0
Neuropathic Pain Symptoms Inventory
Timepoint [7] 387096 0
baseline, 3 months, 12 months
Secondary outcome [8] 387097 0
EQ-5D-5L to assess quality of life
Timepoint [8] 387097 0
baseline, 3 months, 12 months
Secondary outcome [9] 387098 0
SF-36 for the assessment of quality of life
Timepoint [9] 387098 0
baseline, 3 months, 12 months
Secondary outcome [10] 387099 0
Sleep quality (Visual Analogue Scale)
Timepoint [10] 387099 0
baseline, 3 months, 12 months
Secondary outcome [11] 387100 0
Health Care Utilisation will be assessed with a study-specific questionnaire
Timepoint [11] 387100 0
baseline, 3 months, 12 months

Eligibility
Key inclusion criteria
Inclusion criteria for symptomatic participants: symptom duration of > 3 months; clinical diagnosis of L5 or S1 lumbar sensory radiculopathy (defined as conduction block along a spinal nerve or nerve root, manifesting clinically with dermatomal sensory loss) with lower back and radicular leg pain; demonstrable clinically relevant abnormality on imaging studies indicating nerve root compromise at the relevant spinal level. Waitlisted for surgery.

Inclusion criteria for healthy controls: age 18 to 65 years; participants are required to be age- & sex-matched to symptomatic participants; participant is willing and able to give informed consent for participation in the study.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion criteria for symptomatic participants: Diabetes and vascular disease; other neurological or psychiatric disorder; pregnancy, central nervous lesions; previous lumbar surgery; an insufficient level of English to understand and fill out questionnaires and to understand the instructions/requirements for the QST procedures
Healthy control subjects with a history of current pain or a chronic pain condition or any of the exclusion criteria described for the symptomatic participant group will be excluded, including taking medications that influence pain perception (e.g. analgesics, non-steroidals, antidepressants).

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
This is a pilot/feasibility study on 10 symptomatic participants and 10 healthy controls. Should our methods prove to be feasible, we anticipate to conduct a study with a larger sample size (n=25). Data obtained in patients with carpal tunnel syndrome revealed a 50% reduction in IENFD in patients compared to healthy control . Using these data but assuming a smaller difference in IENFD between patients and healthy controls (25%), 25 patients will be required in each group to detect significant differences in IENFD (80% power, p=0.05, d=0.82).

Data of symptomatic participants and healthy controls will be compared using parametric or non-parametric statistics as appropriate (a < 0.05).
Spearmann correlation analysis will be performed to explore any associations between histological data and QST findings.
Differences in outcome measures pre- and post-surgery will be compared using paired t-tests.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/12/2020
Actual
Date of last participant enrolment
Anticipated
30/07/2021
Actual
Date of last data collection
Anticipated
30/09/2022
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 17260 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 17261 0
St John of God Hospital, Subiaco - Subiaco
Recruitment postcode(s) [1] 30973 0
6009 - Nedlands
Recruitment postcode(s) [2] 30974 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 306453 0
Hospital
Name [1] 306453 0
Sir Charles Gairdner and Osborne Park Health Care Group Research Advisory Committee
Country [1] 306453 0
Australia
Primary sponsor type
Individual
Name
Brigitte Tampin
Address
Sir Charles Gardner Hospital, Department of Physiotherapy
Hospital Ave, Nedlands, Western Australia 6009
Country
Australia
Secondary sponsor category [1] 306971 0
None
Name [1] 306971 0
Address [1] 306971 0
Country [1] 306971 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306660 0
Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee
Ethics committee address [1] 306660 0
Ethics committee country [1] 306660 0
Australia
Date submitted for ethics approval [1] 306660 0
17/01/2019
Approval date [1] 306660 0
03/04/2019
Ethics approval number [1] 306660 0
RGS0000001296
Ethics committee name [2] 306674 0
St John of God Health Care Human Research Ethics Committee
Ethics committee address [2] 306674 0
Ethics committee country [2] 306674 0
Australia
Date submitted for ethics approval [2] 306674 0
21/04/2020
Approval date [2] 306674 0
18/05/2020
Ethics approval number [2] 306674 0
1669

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

Contacts
Principal investigator
Name 104590 0
Prof Brigitte Tampin
Address 104590 0
Sir Charles Gairdner Hospital, Neurosurgery Spinal Clinic, Department of Physiotherapy, Hospital Avenue Nedlands WA
6009
Country 104590 0
Australia
Phone 104590 0
+61 8 6457 7964
Fax 104590 0
+61 8 6457 3481
Email 104590 0
Brigitte.Tampin@health.wa.gov.au
Contact person for public queries
Name 104591 0
Brigitte Tampin
Address 104591 0
Sir Charles Gairdner Hospital, Neurosurgery Spinal Clinic, Department of Physiotherapy, Hospital Avenue Nedlands WA
6009
Country 104591 0
Australia
Phone 104591 0
+61 8 6457 7964
Fax 104591 0
+61 8 6457 3481
Email 104591 0
Brigitte.Tampin@health.wa.gov.au
Contact person for scientific queries
Name 104592 0
Brigitte Tampin
Address 104592 0
Sir Charles Gairdner Hospital, Neurosurgery Spinal Clinic, Department of Physiotherapy, Hospital Avenue Nedlands WA
6009
Country 104592 0
Australia
Phone 104592 0
+61 8 6457 7964
Fax 104592 0
+61 8 6457 3481
Email 104592 0
Brigitte.Tampin@health.wa.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?

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.