- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04819503
Mechanisms and Treatment of Post-amputation Neuropathic Pain
November 24, 2023 updated by: Nadine Farnes, Oslo University Hospital
Dependency of the Peripheral Nervous System as a Driver for Post-amputation Pain and Therapeutic Effects of Deep Repetitive Transcranial Magnetic Stimulation in a Randomized Double-blind Sham-controlled Study
Phantom and residual limb pain are types of peripheral neuropathic pain that are difficult to treat and where the underlying mechanisms are still not fully understood.
Repetitive transcranial magnetic stimulation (rTMS) of the motor cortex is an increasingly studied technique for the treatment of neuropathic pain and has shown modest effects in pain intensity reduction for the treatment of neuropathic pain.
Newer rTMS coils provide the opportunity to stimulate larger brain areas, which could provide a better treatment option compared to conventional coils.
The aims of this study are to investigate whether the peripheral nervous system is a necessary driver of phantom limb pain and/or residual limb pain in patients with lower limb amputation using spinal anaesthesia, and to assess the analgesic efficacy of deep H-coil rTMS compared to sham stimulation in the same patients.
Study Overview
Status
Terminated
Conditions
Intervention / Treatment
Study Type
Interventional
Enrollment (Actual)
1
Phase
- Not Applicable
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Oslo, Norway, 0424
- Department of Pain Management and Research, Oslo University Hospital and Faculty of Medicine, University of Oslo,
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
16 years to 78 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Description
Inclusion Criteria:
- 18-80 years of age
- Unilateral or bilateral lower limb amputation resulting in residual limb pain and/or phantom pain, fulfilling the criteria for definite neuropathic pain
- Usual pain intensity at least 4/10 over the past 24 hrs using the numerical scale of the BPI at screening
- Daily pain
- Pain for at least 3 months
- Stable pharmacological treatment for pain or no pharmaceutical treatment at least 1 month prior to the study
- Patients who can be followed for the whole duration of the study
- Minimum 4/10 pain intensity at the time of spinal anaesthesia for sub-study 1
Exclusion Criteria:
- Any clinically significant or unstable medical or psychiatric disorder
- Subjects protected by law (guardianship or tutelage measure)
- History of or current substance abuse (alcohol, drugs)
- Pending litigation
- Contraindications to spinal anaesthetic block (e.g. use of prescribed or non-prescribed medication that can increase risk of bleeding such as anticoagulants, non-steroidal anti-inflammatory drugs and acetylsalicylic acid)
- Contraindication to rTMS (past severe head trauma, history of epilepsy or ongoing epilepsy, active cerebral tumour, past neurosurgical intervention, intracranial hypertension, implanted devices not compatible such as cardiac pacemaker and neurostimulator, cochlear implants, pregnancy or lactation. All women of childbearing age will be required to have negative pregnancy test at inclusion and to be using contraception)
- Other pain conditions more severe than phantom and residual limb pain.
- Inability to understand the protocol or to fill out the forms
- Other ongoing research protocol or recent past protocol within one month before the inclusion
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: Active and then sham repetitive transcranial magnetic stimulation
Deep rTMS is delivered with the Brainsway H7-coil (Brainsway, Jerusalem, Israel) applied via a helmet placed on the head targeting the primary motor cortex of the leg. Sham stimulation is delivered with a sham coil placed in the helmet encasing the active rTMS coil. Sham rTMS sessions will use exactly the same parameters of stimulation as active rTMS. |
We will conduct two sub-studies on the same patient group.
Sub-study 1 is an observational study where patients with phantom and/or residual limb pain after lower limb amputation will be given spinal anaesthesia with 1% Chloroprocaine in an open label manner to investigate whether the peripheral nervous system is a necessary driver of their pain.
After sub-study 1, the same patients will enter sub-study 2 where they are randomly assigned to receive either first active rTMS (10 days over 2 weeks), and then after a 9 week washout period, sham rTMS (10 days over 2 weeks), or they first receive sham rTMS, and then after 9 weeks of washout, active rTMS.
Thus, patients undergo stimulation with deep rTMS in a double blinded randomised controlled trial with a 2 x 2 cross-over design, receiving both active and placebo stimulation
|
Other: Sham and then active repetitive transcranial magnetic stimulation
Deep rTMS is delivered with the Brainsway H7-coil (Brainsway, Jerusalem, Israel) applied via a helmet placed on the head targeting the primary motor cortex of the leg.Sham stimulation is delivered with a sham coil placed in the helmet encasing the active rTMS coil.
Sham rTMS sessions will use exactly the same parameters of stimulation as active rTMS.
|
We will conduct two sub-studies on the same patient group.
Sub-study 1 is an observational study where patients with phantom and/or residual limb pain after lower limb amputation will be given spinal anaesthesia with 1% Chloroprocaine in an open label manner to investigate whether the peripheral nervous system is a necessary driver of their pain.
After sub-study 1, the same patients will enter sub-study 2 where they are randomly assigned to receive either first active rTMS (10 days over 2 weeks), and then after a 9 week washout period, sham rTMS (10 days over 2 weeks), or they first receive sham rTMS, and then after 9 weeks of washout, active rTMS.
Thus, patients undergo stimulation with deep rTMS in a double blinded randomised controlled trial with a 2 x 2 cross-over design, receiving both active and placebo stimulation
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percentage spontaneous pain intensity reduction (sub-study 1)
Time Frame: Maximum reduction during a time interval from 5-60 minutes after spinal anaesthesia
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Measured on an 11-point numerical rating scale (0 %= no pain reduction; 100 % = complete pain reduction).
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Maximum reduction during a time interval from 5-60 minutes after spinal anaesthesia
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Change in usual pain intensity over the past 24 hours from baseline to 1 week after each treatment (sub-study 2
Time Frame: Average of usual pain scores one week before each treatment (baseline week) and 1 week after each treatment
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Usual pain intensity over the past 24 hours is measured on a 11-point numerical rating scale (0 = no pain, 10 = worst pain intensity imaginable of the current pain condition) every day in a diary at the same hour (end of the day).
Analgesic efficacy of active and sham treatment is considered the decrease in usual pain intensity scores between the average of each baseline week (one week before treatment) and average of 1 week after last stimulation of each treatment.
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Average of usual pain scores one week before each treatment (baseline week) and 1 week after each treatment
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Intensity of brush induced allodynia (sub-study 1)
Time Frame: Measured before, 5 minutes and 30 minutes after spinal anaesthesia
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Maximal pain intensity after 3 brush strokes (SOMEDIC brush) to the area of maximal pain with 2 seconds intervals and 3 cm brush strokes lasting 1 second on a 0-10 numerical rating scale (0 = no pain, 10 = worst pain imaginable)
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Measured before, 5 minutes and 30 minutes after spinal anaesthesia
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Intensity of pressure induced allodynia (sub-study 1)
Time Frame: Measured before, 5 minutes and 30 minutes after spinal anaesthesia
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Maximal pain intensity after 3 presses using an algometer (10 kPa) to the area of maximal pain with 2 seconds intervals lasting 10 seconds on a 0-10 numerical rating scale (0 = no pain, 10 = worst pain imaginable)
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Measured before, 5 minutes and 30 minutes after spinal anaesthesia
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Pin-prick sensitivity (sub-study 1)
Time Frame: Measured before, 5 minutes and 30 minutes after spinal anaesthesia
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Compared to contralateral area, sensitivity is measured with a weighted needle (512 mN) on a 0-10 numerical rating scale where 5 is normal sensation, 0 is no sensation and 10 is maximal painful/intense sensation
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Measured before, 5 minutes and 30 minutes after spinal anaesthesia
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Spontaneous pain intensity right now (sub-study 1)
Time Frame: Measured before, and 5, 10, 15, 20, 25, 30, 60, 90 and 120 minutes after spinal anaesthesia
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Measured on a 0-10 numerical rating scale where 0 indicates no pain and 10 indicates worst pain imaginable
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Measured before, and 5, 10, 15, 20, 25, 30, 60, 90 and 120 minutes after spinal anaesthesia
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Usual pain intensity over the past 24 hours (sub-study 2)
Time Frame: Analgesic efficacy of active and sham treatment is measured as the decrease in pain intensity scores between baseline values (one week before treatment) and 3 weeks after the last stimulation.
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Measured every day in a diary at the same hour (end of the day) on an 11-point numerical rating scale (0 = no pain, 10 = worst pain intensity imaginable of the current pain condition)
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Analgesic efficacy of active and sham treatment is measured as the decrease in pain intensity scores between baseline values (one week before treatment) and 3 weeks after the last stimulation.
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Pain intensity (sub-study 2)
Time Frame: Before, 1 week and 3 weeks after the end of each stimulation period
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Pain intensity right now, maximum and minimum pain intensity over the last 24 hours, rated on a numerical rating scale from 0 (no pain) to 10 (pain as bad as you can imagine)
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Before, 1 week and 3 weeks after the end of each stimulation period
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Pain unpleasantness (sub-study 2)
Time Frame: Before, 1 week and 3 weeks after the end of each stimulation period
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Pain unpleasantness right now, maximum, minimum, and usual pain unpleasantness during the last 24 hours, rated in a numerical rating scale from 0 (no pain/unpleasantness) to 10 (unpleasantness as bad as you can imagine)
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Before, 1 week and 3 weeks after the end of each stimulation period
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Pain diary of pain duration, paroxysms and pain interference on sleep (sub-study 2)
Time Frame: Every day 1 week before each stimulation period and up to three weeks after
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Pain duration (percentage wakefulness in pain on an 11-point numerical rating scale; 0% = pain and 100 % = pain all the time), number, duration and usual intensity of pain paroxysms (11-point numerical rating scale; 0 = no pain and 10 = pain as bad as you can imagine), and pain interference on sleep (11-point numerical rating scale; 0 = no interference on sleep, 10 = pain interference on sleep as bad as you can imagine)
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Every day 1 week before each stimulation period and up to three weeks after
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Proportion of responders (sub-study 2)
Time Frame: Before,1 week and 3 weeks after the end of each stimulation period
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Proportion of responders with at least 30% and 50% usual pain intensity reduction compared to prestimulation values allowing to calculate Numbers Needed to Treat for 30 % and 50 % pain relief.
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Before,1 week and 3 weeks after the end of each stimulation period
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Percentage pain intensity reduction (sub-study 2)
Time Frame: Before,1 week and 3 weeks after the end of each stimulation period
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Percentage pain intensity reduction on an 11-point numerical rating scale (0 %= no pain reduction; 100% complete pain reduction)
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Before,1 week and 3 weeks after the end of each stimulation period
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Pain interference (sub-study 2)
Time Frame: Before,1 week and 3 weeks after the end of each stimulation period
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7 items for pain interference on physical and psychological function from the Brief Pain Inventory rated from 0 (does not interfere), to 10 (complete interference)
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Before,1 week and 3 weeks after the end of each stimulation period
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Neuropathic Pain Symptom Inventory (sub-study 2)
Time Frame: Before,1 week and 3 weeks after the end of each stimulation period
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Measures mean intensity of 10 neuropathic symptoms during the last 24 hours on 11-point (0-10) numerical scales.
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Before,1 week and 3 weeks after the end of each stimulation period
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Short form McGill Pain questionnaire (sub-study 2)
Time Frame: Before,1 week and 3 weeks after the end of each stimulation period
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The sensory and affective score of the short form McGill Pain questionnaire which consists of 15 items measured on a 4 point scale.
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Before,1 week and 3 weeks after the end of each stimulation period
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Hospital Anxiety and Depression Scale (sub-study 2)
Time Frame: Before,1 week and 3 weeks after the end of each stimulation period
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The Hospital Anxiety and Depression Scale includes 14 items scored as anxiety and depression scores, 7 items assessing depression and 7 anxiety
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Before,1 week and 3 weeks after the end of each stimulation period
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Pain Catastrophizing Scale (sub-study 2)
Time Frame: Before,1 week and 3 weeks after the end of each stimulation period
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Consists of 13 items describing the occurrence of thoughts and feelings that individuals may experience when in pain rated from 0 (not at all) to 4 (all the time).
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Before,1 week and 3 weeks after the end of each stimulation period
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Patient Global Impression of Change (sub-study 2)
Time Frame: Before,1 week and 3 weeks after the end of each stimulation period
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Consists of 7 items to evaluate the subjective improvement or deterioration (from very much improved to very much deteriorated)
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Before,1 week and 3 weeks after the end of each stimulation period
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Insomnia Severity Index (sub-study 2)
Time Frame: Before,1 week and 3 weeks after the end of each stimulation period
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Consists of self-rated questions which maps sleep difficulties specific to insomnia on a 5 point Likert scale
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Before,1 week and 3 weeks after the end of each stimulation period
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Patient-Specific Functional Scale (sub-study 2)
Time Frame: Before,1 week and 3 weeks after the end of each stimulation period
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The Patient-Specific Functional Scale is a numeric rating scale that measures individually chosen functions that are inhibited by the pain.
Patients rate from 0 (unable to perform activity) to 10 (able to perform activity)
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Before,1 week and 3 weeks after the end of each stimulation period
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Executive functioning using the CANTAB battery
Time Frame: Before,1 week and 3 weeks after the end of each stimulation period
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Composite score and individual scores of the paired associates learning test, stop signal task, spatial working memory test and the multitasking test
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Before,1 week and 3 weeks after the end of each stimulation period
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Side-effects (sub-study 2)
Time Frame: Immediately after the first rTMS session for both stimulation periods, before and after all other rTMS sessions, and 1 week and 3 weeks after each stimulation period
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Side effects using a specific side effects questionnaire specifically designed for assessment of safety in rTMS studies
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Immediately after the first rTMS session for both stimulation periods, before and after all other rTMS sessions, and 1 week and 3 weeks after each stimulation period
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Blinding (sub-study 2)
Time Frame: 3 weeks after the end of each stimulation period
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blinding questionnaire
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3 weeks after the end of each stimulation period
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Study Director: Audun Stubhaug, DMedSci, Oslo University Hospital
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
January 1, 2021
Primary Completion (Actual)
December 3, 2021
Study Completion (Actual)
December 3, 2021
Study Registration Dates
First Submitted
March 16, 2021
First Submitted That Met QC Criteria
March 25, 2021
First Posted (Actual)
March 29, 2021
Study Record Updates
Last Update Posted (Actual)
November 29, 2023
Last Update Submitted That Met QC Criteria
November 24, 2023
Last Verified
November 1, 2023
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Nervous System Diseases
- Postoperative Complications
- Pain
- Neurologic Manifestations
- Neurobehavioral Manifestations
- Neuromuscular Diseases
- Peripheral Nervous System Diseases
- Perceptual Disorders
- Pain, Postoperative
- Neuralgia
- Phantom Limb
- Physiological Effects of Drugs
- Central Nervous System Depressants
- Anesthetics
Other Study ID Numbers
- 77110
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
YES
IPD Plan Description
Deidentified individual participant data collected during the trial will be available to other researchers who provide a methodologically sound proposal, and who adhere to institutional guidelines.
IPD Sharing Time Frame
All the individual participant data collected during the trial will be available after deidentification, beginning 3 months and lasting 5 years after publication.
IPD Sharing Access Criteria
Requestors will need to sign a data access agreement.
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- ICF
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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