An interventional study of Targeted Muscle Reinnervation (TMR) and Standard neurectomy in Amputation, Surgical, Phantom Limb Pain and Neuroma Amputation, sponsored by Leiden University Medical Center. Recruiting at 7 sites in Netherlands. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2025-09-19.
Sponsored by Leiden University Medical Center · Not applicable, Interventional, and Prevention
The goal of this study is to compare postamputation pain (phantom limb pain and residual limb pain) one year postoperatively in patients who received a lower extremity amputation (LEA) with standard nerve handling (neurectomy) versus those who received Targeted Muscle Reinnervation (TMR).
Patients between 18 and 75 years old, scheduled for an LEA (transfemoral to transtibial) as a primary or secondary sequela of vascular disease, are randomized into standard neurectomy or TMR. TMR is a frequently studied surgical technique and prevents neuroma formation by rerouting a cut mixed nerve end to a functional motor nerve.
The investigators hypothesize that TMR during amputation surgery will significant improve PostAmputation Pain (PAP), quality of life, participation in family life and society, and reduction of health-related costs. Participants will be asked to complete multiple online questionnaires postoperatively regarding these outcomes at five evaluation moments (at 2 weeks, and at 3, 6, 9, and 12 months).
Rationale: In the Netherlands, approximately 3300 lower extremity amputations (sacroiliac to forefoot) are performed each year. In current amputation practice, the nerves are simply cut, without employing any nerve surgical techniques to prevent the development of chronic pain due to neuroma formation. Around 61% of these patients develop postamputation pain (PAP). PAP is a severe lifelong disabling condition profoundly affecting quality of life.
Microsurgical nerve handling can prevent the formation of a painful neuroma and its sequelae. In recent years, targeted muscle reinnervation (TMR) has been the most frequently studied technique with promising results. TMR prevents neuroma formation by rerouting a cut mixed nerve end to a functional motor nerve.
The expected benefit of the implementation of TMR during amputation surgery is a significant reduction in the incidence of PAP. Prevention of this chronic pain syndrome will lead to a significant improvement in quality of life, participation in family life and society, and reduction of health-related costs for thousands of amputation patients every year. To achieve this, a transformation of nerve handling during amputation is needed.
Objective: To compare postamputation pain (phantom limb pain and residual limb pain) one year postoperatively in patients who received a lower extremity amputation (LEA) with standard nerve handling (neurectomy) versus those who received TMR.
Study design: A national, multicenter, randomized, sham-controlled superiority trial, comparing standard neurectomy with TMR in amputations of the lower extremities.
Study population: Patients between 18 and 75 years old, scheduled for an LEA (transfemoral to transtibial) as a primary or secondary sequela of vascular disease.
Intervention: Patients with an LEA are randomized into standard neurectomy or TMR. TMR in short: each transected nerve is identified after amputation and is dissected proximally for length. A nerve stimulator is used to identify functional motor nerve branches. Near the point where the motor branch enters the muscle, the motor nerve branch is transected, and an end-to-end coaptation is performed with a nearby amputated nerve.
Main study parameters: The mean difference in pain scores for phantom limb pain and residual limb pain one year postoperatively. Pain is measured for 30 consecutive days (Pain Diary) on the 11-point (0-10) numerical rating scale (NRS) and according to the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Behavior and Interference Questionnaire Short Forms (7a and 8a, respectively).
Nature and extent of the burden and risks associated with participation, benefit, and group relatedness: The additional risks of performing TMR during amputation are negligible. TMR can be performed at any level of the lower extremities with a standardized technique. For TMR to be possible, in upper leg amputations, an additional incision (ca 10 centimetres) has to be made on the dorsal side of the leg, medial tot the sartorius muscle. In our experience this will not result in more postoperative pain or difficulty in sitting. To properly blind study participants this additional incision for upper leg amputations must also be superficially performed in the control group. Another factor that will differ from current standards is that the procedure will take 30 to 90 minutes longer. The extra time investment will depend on technical aspects related to the level of amputation and surgeon experience. Although an increase in surgical time of this length is associated with a slightly higher risk of infection, studies have not found more complications in patients undergoing acute TMR compared to those receiving standard care. The burden of the study is minimal, as participation only requires patients to fill out multiple online questionnaires at five evaluation moments (at 2 weeks, and at 3, 6, 9, and 12 months). Prophylactic TMR results in a reduction of the chance to develop PAP. The risks and the burden for patients are negligible.
163 studies on the registry are indexed under Phantom Limb; 35 are open to participants now.
This study's planned enrollment of 203 is above the median of 30 across 125 interventional studies indexed under Phantom Limb.
Browse Phantom Limb studies →Leiden University Medical Center is the lead sponsor of 334 studies on the registry; 110 are open to participants now.
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Exclusion criteria
Standard Neurectomy during amputation (control)
Procedure: Standard neurectomy
Targeted Muscle Reinnervation (TMR) during amputation (intervention)
Procedure: Targeted Muscle Reinnervation (TMR)
In short: each transected nerve is identified after amputation and is dissected proximally for length. A nerve stimulator is used to identify functional motor nerve branches. Near the point where the motor branch enters the muscle, the motor nerve branch is transected and an end-to-end coaptation is performed with a nearby amputated nerve.
During the amputation a standard neurectomy will be performed based on the surgeons preference. Standard neurectomy will include cutting of the nerve, with or without traction, with or without coagulation, and with or without infiltration with a local anesthetic (i.e., ropivacaine) or phenol. Ligation of the nerve will not be allowed.
Postoperative residual limb pain
Postoperative residual limb pain will be scored on the 11-point (0-10) Numeric Rating Scale (NRS) for 30 consecutive days in a pain diary. A higher score indicates more pain.
Time frame: at 12 months
Postoperative phantom limb pain
Postoperative phantom limb pain will be scored on the 11-point (0-10) Numeric Rating Scale (NRS) for 30 consecutive days in a pain diary. A higher score indicates more pain.
Time frame: at 12 months
Postoperative pain behavior
Postoperative pain behavior will be scored using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Behavior Short Form 7a. The results will be scored on a scale from 7 to 35 points, with a higher score indicating that pain has a greater influence on behavior.
Time frame: at 12 months
Postoperative pain interference
Postoperative pain interference will be scored using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference Short Form 8a. The results will be scored on a scale from 8 to 40 points, where a higher score indicates greater interference of pain with daily life
Time frame: at 12 months
Postoperative residual limb pain
Postoperative residual limb pain will be scored on the 11-point (0-10) Numeric Rating Scale (NRS) at one timepoint. A higher score indicates more pain.
Time frame: at 3, 6, and 9 months
Postoperative phantom limb pain
Postoperative phantom limb pain will be scored on the 11-point (0-10) Numeric Rating Scale (NRS) at one timepoint. A higher score indicates more pain.
Time frame: at 3, 6, and 9 months
Postoperative pain behavior
Postoperative pain behavior will be scored using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Behavior Short Form 7a. The results will be scored on a scale from 7 to 35 points, with a higher score indicating that pain has a greater influence on behavior.
Time frame: at 3, 6, and 9 months
Postoperative pain interference
Postoperative pain interference will be scored using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference Short Form 8a. The results will be scored on a scale from 8 to 40 points, where a higher score indicates greater interference of pain with daily life
Time frame: at 3, 6, and 9 months
Neuropathic pain
Using the Neuropathic pain component in chronic pain syndromes (PainDetect) questionnaire. The results will be scored on a scale from 0 to 38. A higher score indicates a greater likelihood of experiencing neuropathic pain
Time frame: at 12 months
Hospital anxiety
Using the Hospital Anxiety and Depression Scale (HADS). The results will be scored on a scale from 0 to 21. A higher score indicates a greater likelihood of experiencing anxiety
Time frame: at 12 months
Depression
Using the Hospital Anxiety and Depression Scale (HADS). The results will be scored on a scale from 0 to 21. A higher score indicates a greater likelihood of experiencing depression.
Time frame: at 12 months
Global perceived effect
Using the Global Perceived effect (GPE-DV) questionnaire to evaluate the patients' view on recovery and satisfaction of the treatment.
Time frame: at 12 months
Prosthetic rehabilitation
Measured with the Prosthetic Limb Users Survey of Mobility (PLUS-M, seven items short form). The results will be scored on a scale from 7 to 35. A higher score indicates a better prosthetic rehabilitation.
Time frame: at 12 months
EuroQol-5D-5L
Quality of life using the EuroQol-5D-5L questionnaire. A higher score indicates worse quality of life.
Time frame: at 2 weeks, and at 3, 6, 9 and 12 months
Medical consumption costs
Cost effectiveness analysis with a trial-based cost-utility analysis from a societal perspective (i.e., cost per QALY). Using the Medical Consumption Questionnaire (iMCQ)
Time frame: at 3, 6, 9, and 12 months
Productivity costs
Cost effectiveness analysis with a trial-based cost-utility analysis from a societal perspective (i.e., cost per QALY). Using the Productivity Costs Questionnaire (iPCQ)
Time frame: at 3, 6, 9, and 12 months
Budget impact analysis (BIA).
Budget impact analysis using the ZonMW BIA tool to estimate the financial impact of different implementation scenarios at the national level
Time frame: at 12 months
Pain medication use
The Medication Quantification Scale measures the extent of pain medication use. A higher score indicates an increased use or dosage of pain medication.
Time frame: at 3, 6, 9, and 12 months
Type of pain
Type of pain (local, diffuse, radiating) will be reported using the pain sketches from the Interdisciplinary Care for Amputees Network (ICAN).
Time frame: at 3, 6, 9 and 12 months
Surgical time
Surgical time measured in minutes
Time frame: at 0 months
Length of hospital stay
Postoperative length of stay in the hospital
Time frame: at 0 months
Adverse events
i.e., infection, rebleed. Scored with the Clavien-Dindo score form 1 to 5. A higher score indicates a more severe complication.
Time frame: 30 days postoperative
Plan to share: Yes — By embracing the FAIR principles (Findability, Accessibility, Interoperability and Reusability of digital assets), we underscore our commitment to robust, transparent, and ethically sound scientific practices that advance research integrity and propel scientific progress. Using the Leiden University Medical Center (LUMC) Data Management Tool, with support of the LUMC section of Advanced Data Management we ensure that our data is findable, enabling easy discovery through well-structured metadata and standardized identifiers. Through our commitment to accessibility, we guarantee that both researchers and the broader community can access our data with minimal barriers, fostering collaboration and knowledge dissemination. Interoperability remains a focal point, as we structure our data in standardized formats and utilize established vocabularies, facilitating seamless integration with other datasets and tools. Our dedication to reusability ensures that the data generated through our trial
Supporting information: Study protocol
Time frame: After completion of the study, the key file will be archived in the hospital's study documentation on a protected location on the network hard drive for 15 years in accordance with article 17 of the European good clinical practice directive.
Access criteria: Before acquiring the deidentified individual patient data used in the results of the published work related to this protocol (incl. tables, figures, supplementary files), researcher must sign a data sharing agreement. Data will made available to those who submit a reasonable request with a methodologically sound proposal.
Started Dec 2024 (actual). Primary completion is estimated for Jan 2028, 36 months after the start.
Of 61 non-industry interventional studies with no phase under Phantom Limb, half reached primary completion within 32 months of starting (the median), counting those still running; a quarter within 12 and three quarters within 47. This study's planned 36 months is above that.
Counting every sponsor, half of 64 studies reached it within 34 months; a quarter within 13 and three quarters within 50.
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