Mechanisms of Neurodynamic Treatments

Carpal Tunnel Syndrome Clinical Trial

— MONET  

Official title:

Mechanisms of Neurodynamic Treatments (MONET)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05859412
• Other study ID #: 313200
• Status: Recruiting
• Phase: N/A
• Start date: May 17, 2023
• Est. completion date: April 1, 2026

Study information

• Verified date: January 2024
• Source: University of Oxford
• Contact: Annina Schmid, PhD
• Phone: +44 (0) 1865 223254
• Email: annina.schmid[@]ndcn.ox.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

INTRODUCTION: Carpal tunnel syndrome (CTS) is a relatively common condition caused by compression of one of the main nerves at the wrist, the median nerve. Non-surgical treatments, like steroid injections and physiotherapy, are the first line of treatment for patients with carpal tunnel syndrome. The investigators have previously shown that specific physiotherapeutic exercises (neurodynamic exercises) can reduce the need for carpal tunnel surgery in some patients. Experimental studies in animal models demonstrate that these exercises have an anti-inflammatory effect and can help the nerve to regenerate. However, the exact mechanisms of action of these exercises are not well understood in patients. A better understanding of the mechanisms of action of physiotherapeutic exercises would help clinicians to better target these treatments to those patients who may benefit from them.

AIM: To investigate the mechanisms of action of 6 weeks' neurodynamic treatments on nerve function and structure as well as patient-reported outcome measures in patients with CTS compared to a positive control intervention (routine care steroid injection) and a negative control intervention (advice).

METHODS AND ANALYSIS: In this single-blind randomised mechanistic trial, patients with confirmed mild to moderate CTS (n=78) and age and gender-matched healthy controls (n=30) will be included. Patients will be randomly allocated to a 6-week neurodynamic exercise group, steroid injection, or advice group. Outcome measures will be explored at baseline (patients and controls), post-intervention (patients), and 6-month follow-up (patients). Outcomes include diffusion-weighted and anatomical MRI of the median nerve at the wrist, quantitative sensory testing, nerve conduction studies, inflammatory markers in blood and skin biopsies, and validated questionnaires for pain, function, and psychological factors. Two-way repeated measures ANCOVAs (factors time and intervention, adjusted for baseline measurements as a continuous covariate) will be performed to identify differences in MRI parameters, clinical assessment, and inflammatory markers between patients in different groups and healthy controls.

Description:

Follow-up at 6 months will only include outcome measures from questionnaires.

Details on enrollment:

Pilot testing of healthy participants who consented to our ethics but will not be included in the study was on 13-April-2023.

• First healthy participant enrolled: 17-May-2023.

• First patient participant enrolled: 1-June-2023.

Details on amendment:

• Amendment SA2_BPOR on 3/Aug/2023 to expand recruitment through registries of patients

• Amendment SA3_REC on 22/Aug/2023 to add Thames Valley Primary Care Research Partnership, musculoskeletal clinics, and media advertisement to help with recruitment of participants.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 108
• Est. completion date: April 1, 2026
• Est. primary completion date: February 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria

Patients:

1. Patients who have a diagnosis of mild to moderate carpal tunnel syndrome based on a clinical assessment and confirmed with nerve conduction studies.

2. Male or Female, aged 18 years or above.

3. Patient is willing and able to give informed consent for participation in the study.

Healthy participants:

1. Male or female aged 18 years or above.

2. Participant is willing and able to give informed consent for participation in the study.

3. No history of hand or arm symptoms

4. No history of neck pain in the past 3 months

5. No systemic medical condition

6. No strong anticoagulant medication or altered coagulation (e.g., hemophilia) preventing skin biopsies

7. Severe anxiety or depression

8. Participants are required to be age- & sex-matched to patient participants

9. No contraindications for magnetic resonance scanning at 3T

10. Sufficient command of the English language

Exclusion Criteria

Patients:

1. Patients who already had surgery for their carpal tunnel syndrome (CTS) or are planning to undergo surgery in the next 6 weeks (patients with unilateral surgery who have unoperated CTS on the other hand are eligible to participate)

2. Patients who had a steroid injection for their CTS in the 6 months prior to the study enrolment or who had already more than 1 steroid injection into the study wrist.

3. Patients who have a diagnosis of severe carpal tunnel syndrome based on a clinical assessment and confirmed with electrodiagnostic testing

4. Electrodiagnostic testing revealing abnormalities other than CTS

5. Any other upper limb or neck problem for which they have sought treatment in the past 3 months

6. History of significant trauma to the upper limb or neck

7. Diabetes

8. Hypothyroidism

9. Severe anxiety or depression

10. Patient who is pregnant, lactating, or planning pregnancy during the study.

11. Patients on strong anticoagulant medication or altered coagulation preventing skin biopsies.

12. Contraindications for magnetic resonance imaging (assessed with MRI safety screening questionnaire).

13. Contraindications for steroid injections

14. Insufficient command of the English language

Related Conditions & MeSH terms

• Carpal Tunnel Syndrome
• Physiotherapy

Intervention

Other:
• Neurodynamic exercises
The neurodynamic exercises will consist of a home-based exercise programme performed over a period of 6 weeks. Patients will attend a single session with an investigator who will instruct them the home exercise programme consisting of nerve and tendon gliding exercises which will be adjusted with pre-specified progressions over the 6 weeks intervention period. Patients will receive a leaflet and a video link detailing these exercises.

Drug:
• Steroid injection (Depomedrone 40mg)
Steroid injection (Depomedrone 40mg) into the carpal tunnel as per standard practice in patients with carpal tunnel syndrome

Other:
• Advice
Group receiving advice but no additional treatment

Locations

Country	Name	City	State
United Kingdom	Nuffield Department of Clinical Neurosciences, University of Oxford	Oxford	Oxfordshire

Sponsors (2)

Lead Sponsor	Collaborator
University of Oxford	Wellcome Trust

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Blood samples - DNA	Blood samples coupled with detailed phenotype data will investigate potential gene associations in CTS and recovery	Baseline
Other	Change in blood samples - DNA	Change in blood samples coupled with detailed phenotype data will investigate potential gene associations in CTS and recovery	From baseline to post-intervention (after 6-weeks)
Other	Concentration of serum inflammatory markers - metabolomics	Concentrations of inflammatory markers in serum	Baseline
Other	Change in the concentration of serum inflammatory markers - metabolomics	Change in the concentrations of inflammatory markers in serum	From baseline to post-intervention (after 6-weeks)
Other	Pro-inflammatory cytokine levels	Proinflammatory cytokine assay (pg/ml); continuous data	Baseline
Other	Change in pro-inflammatory cytokine levels	Change in proinflammatory cytokine assay (pg/ml); continuous data	From baseline to post-intervention (after 6-weeks)
Other	Concentration of inflammatory markers in serial skin biopsies	Concentration of inflammatory markers in skin biopsies. Baseline biopsy will be performed in the most distal part of the ventrolateral side of the proximal phalanx of the index finger. The 6-weeks biopsy will be performed proximally, avoiding the primary biopsy site	Baseline
Other	Change in concentration of inflammatory markers in serial skin biopsies	Change in concentration of inflammatory markers in skin biopsies. Baseline biopsy will be performed in the most distal part of the ventrolateral side of the proximal phalanx of the index finger. The 6-weeks biopsy will be performed proximally, avoiding the primary biopsy site	From baseline to post-intervention (after 6-weeks)
Primary	Median nerve fractional anisotropy as determined on diffusion weighted imaging	Fractional anisotropy will be extracted from regions-of-interest in the median nerve and compared to healthy control group	Baseline
Primary	Change in median nerve fractional anisotropy as determined on diffusion weighted imaging	Change in fractional anisotropy extracted from regions-of-interest in the median nerve at post-intervention (after 6-weeks) compared to baseline	From baseline to post-intervention (after 6-weeks)
Secondary	Nerve markers on diffusion weighted imaging: water diffusivity (mm2/s)	Measured at the median nerve and cervical dorsal root ganglia. mm2/s; continuous data	Baseline
Secondary	Change to nerve markers on diffusion weighted imaging: water diffusivity (mm2/s)	Measured at the median nerve and cervical dorsal root ganglia. mm2/s; continuous data	From baseline to post-intervention (after 6-weeks)
Secondary	Nerve markers on anatomical MRI	Measured at the median nerve and cervical dorsal root ganglia. ratio/mm2; continuous data	Baseline
Secondary	Change in nerve markers on anatomical MRI	Measured at the median nerve and cervical dorsal root ganglia. ratio/mm2; continuous data	From baseline to post-intervention (after 6-weeks)
Secondary	Median nerve MRI T2 mapping	ms; continuous data	Baseline
Secondary	Changes in median nerve MRI T2 mapping	ms; continuous data	From baseline to post-intervention (after 6-weeks)
Secondary	Median nerve MRI magnetisation transfer ratio (MTR)	ratio; continuous data	Baseline
Secondary	Changes in median nerve MRI magnetisation transfer ratio (MTR)	ratio; continuous data	From baseline to post-intervention (after 6-weeks)
Secondary	Changes in median nerve conduction velocities from electrodiagnostic studies (m/s)	m/s; continuous data	From baseline to post-intervention (after 6-weeks)
Secondary	Changes in median sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs): amplitudes (mV)	mV; continuous data	From baseline to post-intervention (after 6-weeks)
Secondary	Thermal detection thresholds as assessed in Quantitative Sensory testing - warm and cold detection threshold; thermal sensory limen	Thermal detection thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger).; Data is measured in degrees celsius (point at which cold or warm is detected)	Baseline
Secondary	Change in thermal detection thresholds as assessed in Quantitative Sensory testing- warm and cold detection threshold; thermal sensory limen	Thermal detection thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger).; Data is measured in degrees celsius (point at which cold or warm is detected)	From baseline to post-intervention (after 6-weeks)
Secondary	Thermal pain thresholds as assessed in Quantitative Sensory testing- warm and cold painful threshold	Pain thermal thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger) and over the contralateral lower limb (tibial anterior).; Data is measured in degrees celsius (point at which cold or warm is initially detected as painful)	Baseline
Secondary	Change in thermal pain thresholds as assessed in Quantitative Sensory testing- warm and cold painful threshold	Pain thermal thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger) and over the contralateral lower limb (tibial anterior).; Data is measured in degrees celsius (point at which cold or warm is initially detected as painful)	From baseline to post-intervention (after 6-weeks)
Secondary	Mechanical detection thresholds as assessed in Quantitative sensory testing	Mechanical detection thresholds will be assessed using a standardised set of von Frey filaments (mN) over the index finger. Geometric mean will be calculated	Baseline
Secondary	Change in mechanical detection thresholds as assessed in Quantitative sensory testing	Mechanical detection thresholds will be assessed using a standardised set of von Frey filaments (mN) over the index finger. Geometric mean wil be calculated	From baseline to post-intervention (after 6-weeks)
Secondary	Mechanical pain thresholds as assessed in Quantitative sensory testing	Mechanical pain thresholds will be assessed using a series of weighted pin prick stimulators (mN). They will be assessed over the index finger and over the contralateral lower limb (tibial anterior).	Baseline
Secondary	Change in mechanical pain thresholds as assessed in Quantitative sensory testing	Mechanical pain thresholds will be assessed using a series of weighted pin prick stimulators (mN). They will be assessed over the index finger and over the contralateral lower limb (tibial anterior).	From baseline to post-intervention (after 6-weeks)
Secondary	Mechanical pain sensitivity as assessed in Quantitative sensory testing	Mechanical pain sensitivity will be assessed using a series of weighted pin prick stimulators (mN) over the index finger. Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating "no pain", and '100' indicating "most intense pain imaginable"). Geometric mean of all numerical ratings for pinprick stimuli will be calculated	Baseline
Secondary	Change in mechanical pain sensitivity as assessed in Quantitative sensory testing	Mechanical pain sensitivity will be assessed using a series of weighted pin prick stimulators (mN) over the index finger. Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating "no pain", and '100' indicating "most intense pain imaginable"). Geometric mean of all numerical ratings for pinprick stimuli will be calculated	From baseline to post-intervention (after 6-weeks)
Secondary	Dynamic mechanical allodynia as assessed in Quantitative sensory testing	Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating "no pain", and '100' indicating "most intense pain imaginable"). Geometric mean (compound measure) of all numerical ratings across light touch stimulators over the index finger	Baseline
Secondary	Change in dynamic mechanical allodynia as assessed in Quantitative sensory testing	Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating "no pain", and '100' indicating "most intense pain imaginable"). Geometric mean (compound measure) of all numerical ratings across light touch stimulators over the index finger	From baseline to post-intervention (after 6-weeks)
Secondary	Wind-up ratio as assessed in Quantitative sensory testing	Wind-up ration will be assessed using a pin prick (mN) over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Ratio, continous data	Baseline
Secondary	Change in wind-up ratio as assessed in Quantitative sensory testing	Change in wind-up ration will be assessed using a pin prick (mN) over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Ratio, continuous data	From baseline to post-intervention (after 6-weeks)
Secondary	Vibration detection thresholds as assessed in Quantitative sensory testing	Vibration detection thresholds will be assessed using a tuning fork (64 Hz, 8/8 scale) over a bony prominence over (e.g., palmar side of the distal end of the second metacarpal)	Baseline
Secondary	Change in vibration detection thresholds as assessed in Quantitative sensory testing	Change in vibration detection thresholds will be assessed using a tuning fork (64 Hz, 8/8 scale) over a bony prominence over (e.g., palmar side of the distal end of the second metacarpal)	From baseline to post-intervention (after 6-weeks)
Secondary	Pressure pain thresholds as assessed in Quantitative sensory testing	Pressure pain thresholds will be assessed using an algometer (kg) on the thenar eminence and over the contralateral lower limb (tibialis anterior)	Baseline
Secondary	Change in pressure pain thresholds as assessed in Quantitative sensory testing	Change in pressure pain thresholds will be assessed using an algometer (kg) on the thenar eminence and over the contralateral lower limb (tibialis anterior)	From baseline to post-intervention (after 6-weeks)
Secondary	Pinch strength test - maximum isometric strength	Pinch grip dynamometry. Continuous data, kg	Baseline
Secondary	Change in pinch strength test - maximum isometric strength	Pinch grip dynamometry. Continuous data, kg	From baseline to post-intervention (after 6-weeks)
Secondary	Nerve mechanosensitivity- upper limb neurodynamic test (median nerve)	Evaluation of nerve mechanosensitivity in response to mechanical load (increased tension) applied to the nerve. Range of elbow extension at point of symptoms (degrees)	Baseline
Secondary	Change in nerve mechanosensitivity- upper limb neurodynamic test (median nerve)	Change in nerve mechanosensitivity in response to mechanical load (increased tension) applied to the nerve. Range of elbow extension at point of symptoms (degrees)	From baseline to post-intervention (after 6-weeks)
Secondary	Nerve mechanosensitivity - positive upper limb neurodynamic tests	Upper limb neurodynamic tests will be assessed to determine the presence of increased mechanosensitivity. The neurodynamic test will be graded as 'positive', when there is at least partial reproduction of symptoms plus when symptoms can be modified with structural differentiation. Otherwise, the neurodynamic test will be graded as 'negative'	Baseline
Secondary	Change in nerve mechanosensitivity - positive upper limb neurodynamic tests	Upper limb neurodynamic tests will be assessed to determine the presence of increased mechanosensitivity. The neurodynamic test will be graded as 'positive', when there is at least partial reproduction of symptoms and when symptoms can be modified with structural differentiation. Otherwise, the neurodynamic test will be graded as 'negative'	From baseline to post-intervention (after 6-weeks)
Secondary	Symptom severity and limitations in hand function as assessed by the Boston carpal tunnel syndrome questionnaire	Patient reported symptoms and limitations on the Boston carpal tunnel syndrome questionnaire	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Symptom intensity levels on a Visual Analogue Scale (VAS)	Patient reported average intensity of pain, paraesthesia and numbness on 10cm visual analogue scales, ranging from no symptoms to worst symptoms ever	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Location of symptoms in a body and a hand diagram	Patient reported location of symptoms in a body diagram and a hand diagram.	Baseline, post-intervention (after 6 weeks)
Secondary	Presence of central sensitisation as assessed with the Central Sensitisation Inventory	Patient reported central sensitisation on the Central Sensitisation Inventory	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Functional deficits- Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire	Participant reported outcomes on ability to perform activities as per quick DASH questionnaire	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Functional deficits- Patient specific functional scale (PSFS)	Participant reported outcomes on the patient specific functional scale	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Presence of neuropathic pain - DN4	Patient screened for neuropathic pain using DN4	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Presence of neuropathic pain - pain DETECT	Patient screened for neuropathic pain using pain DETECT	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Neuropathic pain symptoms - Neuropathic Pain Symptom Inventory	Patient reported outcomes on neuropathic pain symptoms as assessed on Neuropathic Pain Symptom Inventory.	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Presence of psychological co-morbidities - The Depression, Anxiety, and Positive Outlook Scale (DAPOS)	Participant reported outcomes on depression and anxiety as per DAPOS	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Presence of psychological co-morbidities - short-form Pain Anxiety Symptoms Scale (PASS-20)	Participant reported outcomes on depression and anxiety as per short-form Pain Anxiety Symptoms Scale (PASS-20)	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Presence of psychological co-morbidities - pain catastrophizing scale (PCS)	Participant reported outcomes on depression and anxiety as per pain catastrophising scale (PCS)	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Assessment of quality of life - EQ-5D-5L	Participant reported outcomes on quality of life as per EQ-5D-5L questionnaire	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Assessment of sleep interference - Insomnia Severity Index	Participant reported outcomes on sleep interference with the Insomnia Severity Index.	Baseline, post-intervention (after 6 weeks), 6-months follow up
Secondary	Adverse and serious adverse events	Patient self-reported adverse events	From start of intervention until end of intervention (6 weeks)
Secondary	Exercise adherence to the neurodynamic home-based intervention - number of sessions	Patient self-reported number of sessions per day throughout the intervention in an exercise diary	From start of intervention until end of intervention (6 weeks)