Amputation, SurgicalPreventPAPNCT06719245
Prevention of PostAmputation Pain With Targeted Muscle Reinnervation
A study testing Targeted Muscle Reinnervation (TMR) and Standard neurectomy in people with Amputation, Surgical and Phantom Limb Pain, run by Leiden University Medical Center at 7 sites in Netherlands.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Amputation, Surgical, Phantom Limb Pain, Neuroma Amputation
- What is being tested?
- Targeted Muscle Reinnervation (TMR) and Standard neurectomy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 203 participants
- Where
- 7 sitesNetherlands
- Study dates
- 31 Dec 2024to 1 Jan 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients aged between 18 and 75 years old.
- Scheduled for a transtibial, through-knee, or transfemoral amputation as a primary or secondary sequela of vascular disease.
Who cannot join
- Insensate limbs at the level of amputation.
- Complex Regional Pain Syndrome.
- Existing neuroma or prior neuroma surgery in the affected limb.
- Undergoing radiotherapy on the affected limb.
- Cognitive impairment, or delirium at the time of consent.
- Patients who are unfit for general anesthesia.
- No nerve surgeon trained in the TMR procedure is available
Trial locations and contacts
7 sites in 1 country. Contact the study team or a site near you to ask about taking part.
7 sites in 1 country
Netherlands7 sites, 7 recruiting
- Not yet recruiting
Amsterdam University Medical Center
Amsterdam, North Holland, 1105 AZ
- Recruiting
Leiden University Medical Center
Leiden, South Holland, 2333 ZA
Justus L Groen, Dr.
- Not yet recruiting
Alrijne Zorggroep
Leiderdorp, South Holland, 2353 GA
- Not yet recruiting
Erasmus Medical Center
Rotterdam, South Holland, 3015 GD
- Not yet recruiting
Haaglanden Medisch Centrum
The Hague, South Holland, 2512 VA
- Not yet recruiting
University Medical Center Utrecht
Utrecht, Utrecht, 3584 CX
- Not yet recruiting
Isala Zwolle
Zwolle, Overijssel, 8025 AB
About this study
Official title: Prevention of PostAmputation Pain With Targeted Muscle Reinnervation: A National, Multicenter, Randomized, Sham-controlled Superiority Trial, Comparing Standard Neurectomy With Targeted Muscle Reinnervation in Amputations of the Lower Extremities
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).
Read the detailed description
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.
- Conditions
- Amputation, Surgical, Phantom Limb Pain, Neuroma Amputation, Surgery
- Being tested
- Targeted Muscle Reinnervation (TMR), Standard neurectomy
- Keywords
- TMR, Amputation, Phantom pain, Neuroma
- Medical subject headings
- Phantom Limb, Neuroma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Targeted Muscle Reinnervation (TMR)Procedure or surgery
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.
Standard neurectomyProcedure or surgery
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.
| Study group | Role | What they receive |
|---|---|---|
| Standard Neurectomy (control) | Other | Standard Neurectomy during amputation (control) Receives: Procedure: Standard neurectomy |
| Targeted Muscle Reinnervation (intervention) | Other | Targeted Muscle Reinnervation (TMR) during amputation (intervention) Receives: Procedure: Targeted Muscle Reinnervation (TMR) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: at 12 months
Secondary outcomes (15)
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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: at 12 months
EuroQol-5D-5L
Quality of life using the EuroQol-5D-5L questionnaire. A higher score indicates worse quality of life.
Measured: 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)
Measured: 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)
Measured: 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
Measured: 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.
Measured: 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).
Measured: at 3, 6, 9 and 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Dec 2024
- Study start31 Dec 2024
- Primary completion1 Jan 2028 (estimated)
- Study completion1 Jan 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for Amputation, SurgicalStudies of the same condition, open and under way.
- More trials run by Leiden University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 203 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Leiden University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Alrijne Hospital, Medical Center Haaglanden, ZonMw: The Netherlands Organisation for Health Research and Development, UMC Utrecht, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Erasmus Medical Center, Isala
- Responsible party
- Principal investigator, jlgroen, Leiden University Medical Center
- Investigators
- Justus L Groen, MD PhD, Principal investigator, Leiden University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06719245
- Sponsor's protocol ID
- NL87196.058.24
- Acronym
- PreventPAP
- Status last verified
- Sep 2025
- First submitted
- 12 Jul 2024
- Last updated
- 19 Sep 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- 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
Publications
Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole MR. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001 Nov;94(2):149-158. doi: 10.1016/S0304-3959(01)00349-9.
PubMed 11690728Mioton LM, Dumanian GA, Shah N, Qiu CS, Ertl WJ, Potter BK, Souza JM, Valerio IL, Ko JH, Jordan SW. Targeted Muscle Reinnervation Improves Residual Limb Pain, Phantom Limb Pain, and Limb Function: A Prospective Study of 33 Major Limb Amputees. Clin Orthop Relat Res. 2020 Sep;478(9):2161-2167. doi: 10.1097/CORR.0000000000001323.
PubMed 32452928Dal-Re R, Janiaud P, Ioannidis JPA. Real-world evidence: How pragmatic are randomized controlled trials labeled as pragmatic? BMC Med. 2018 Apr 3;16(1):49. doi: 10.1186/s12916-018-1038-2.
PubMed 29615035Torrance N, Lawson KD, Afolabi E, Bennett MI, Serpell MG, Dunn KM, Smith BH. Estimating the burden of disease in chronic pain with and without neuropathic characteristics: does the choice between the EQ-5D and SF-6D matter? Pain. 2014 Oct;155(10):1996-2004. doi: 10.1016/j.pain.2014.07.001. Epub 2014 Jul 11.
PubMed 25020004Parsons B, Schaefer C, Mann R, Sadosky A, Daniel S, Nalamachu S, Stacey BR, Nieshoff EC, Tuchman M, Anschel A. Economic and humanistic burden of post-trauma and post-surgical neuropathic pain among adults in the United States. J Pain Res. 2013 Jun 17;6:459-69. doi: 10.2147/JPR.S44939. Print 2013.
PubMed 23825931Groffen AJ, Klapwijk T, van Rootselaar AF, Groen JL, Tijssen MA. Genetic and phenotypic heterogeneity in sporadic and familial forms of paroxysmal dyskinesia. J Neurol. 2013 Jan;260(1):93-9. doi: 10.1007/s00415-012-6592-5. Epub 2012 Jun 30.
PubMed 22752065Valerio IL, Dumanian GA, Jordan SW, Mioton LM, Bowen JB, West JM, Porter K, Ko JH, Souza JM, Potter BK. Preemptive Treatment of Phantom and Residual Limb Pain with Targeted Muscle Reinnervation at the Time of Major Limb Amputation. J Am Coll Surg. 2019 Mar;228(3):217-226. doi: 10.1016/j.jamcollsurg.2018.12.015. Epub 2019 Jan 8.
PubMed 30634038Frantz TL, Everhart JS, West JM, Ly TV, Phieffer LS, Valerio IL. Targeted Muscle Reinnervation at the Time of Major Limb Amputation in Traumatic Amputees: Early Experience of an Effective Treatment Strategy to Improve Pain. JB JS Open Access. 2020 May 6;5(2):e0067. doi: 10.2106/JBJS.OA.19.00067. eCollection 2020 Apr-Jun.
PubMed 33123667Malessy MJA, de Boer R, Munoz Romero I, Eekhof JLA, van Zwet EW, Kliot M, Dahan A, Pondaag W. Predictive value of a diagnostic block in focal nerve injury with neuropathic pain when surgery is considered. PLoS One. 2018 Sep 12;13(9):e0203345. doi: 10.1371/journal.pone.0203345. eCollection 2018.
PubMed 30208078Deeyor ST, Kisana HM, Hui CH, Stecher C, Hustedt JW. Targeted Muscle Reinnervation Does Not Increase the Risk of Postsurgical Complication or Overall Cost. Plast Reconstr Surg Glob Open. 2022 Aug 24;10(8):e4488. doi: 10.1097/GOX.0000000000004488. eCollection 2022 Aug.
PubMed 36032374Schwingler PM, Moman RN, Hunt C, Ashmore Z, Ogletree SP, Uvodich ME, Murad MH, Hooten WM. Prevalence of postamputation pain and its subtypes: a meta-analysis with meta-regression. Pain Rep. 2021 May 4;6(1):e918. doi: 10.1097/PR9.0000000000000918. eCollection 2021.
PubMed 33981935Poyntz SA, Hacking NM, Dalal M, Fowler S. Peripheral Interventions for Painful Stump Neuromas of the Lower Limb: A Systematic Review. Clin J Pain. 2018 Mar;34(3):285-295. doi: 10.1097/AJP.0000000000000533.
PubMed 28678059Dumanian GA, Potter BK, Mioton LM, Ko JH, Cheesborough JE, Souza JM, Ertl WJ, Tintle SM, Nanos GP, Valerio IL, Kuiken TA, Apkarian AV, Porter K, Jordan SW. Targeted Muscle Reinnervation Treats Neuroma and Phantom Pain in Major Limb Amputees: A Randomized Clinical Trial. Ann Surg. 2019 Aug;270(2):238-246. doi: 10.1097/SLA.0000000000003088.
PubMed 30371518Berger LE, Shin S, Haffner ZK, Huffman SS, Spoer DL, Sayyed AA, Franzoni G, Bekeny JC, Attinger CE, Kleiber GM. The application of targeted muscle reinnervation in lower extremity amputations: A systematic review. Microsurgery. 2023 Oct;43(7):736-747. doi: 10.1002/micr.31030. Epub 2023 Mar 2.
PubMed 36864779Walsh AR, Lu J, Rodriguez E, Diamond S, Sultan SM. The Current State of Targeted Muscle Reinnervation: A Systematic Review. J Reconstr Microsurg. 2023 Mar;39(3):238-244. doi: 10.1055/s-0042-1755262. Epub 2022 Aug 21.
PubMed 35988579
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prevention of PostAmputation Pain With Targeted Muscle Reinnervation: A National, Multicenter, Randomized, Sham-controlled Superiority Trial, Comparing Standard Neurectomy With Targeted Muscle Reinnervation in Amputations of the Lower Extremities
- ClinicalTrials.gov ID
- NCT06719245
- Acronym / sponsor ID
- PreventPAP / NL87196.058.24
- Conditions
- Amputation, Surgical, Phantom Limb Pain, Neuroma Amputation, Surgery
- Keywords
- TMR, Amputation, Phantom pain, Neuroma
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 203 participants (estimated)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Collaborators
- Alrijne Hospital, Medical Center Haaglanden, ZonMw: The Netherlands Organisation for Health Research and Development, UMC Utrecht, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Erasmus Medical Center, Isala
- Study start
- 31 Dec 2024 (actual)
- Primary completion
- 1 Jan 2028 (estimated)
- Study completion
- 1 Jan 2028 (estimated)
- First posted
- 5 Dec 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Standard Neurectomy (control) | Other | Procedure: Standard neurectomyStandard Neurectomy during amputation (control) |
| Targeted Muscle Reinnervation (intervention) | Other | Procedure: Targeted Muscle Reinnervation (TMR)Targeted Muscle Reinnervation (TMR) during amputation (intervention) |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Patients aged between 18 and 75 years old.
- Scheduled for a transtibial, through-knee, or transfemoral amputation as a primary or secondary sequela of vascular disease.
Key exclusion criteria (7 listed)
- Insensate limbs at the level of amputation.
- Complex Regional Pain Syndrome.
- Existing neuroma or prior neuroma surgery in the affected limb.
- Undergoing radiotherapy on the affected limb.
- Cognitive impairment, or delirium at the time of consent.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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. | Procedure or surgery | Targeted Muscle Reinnervation (intervention) |
| Standard neurectomyDuring 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. | Procedure or surgery | Standard Neurectomy (control) |
Primary outcome
Postoperative residual limb pain
Time frame: at 12 months
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.
Postoperative phantom limb pain
Time frame: at 12 months
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.
Postoperative pain behavior
Time frame: at 12 months
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.
Postoperative pain interference
Time frame: at 12 months
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
15 secondary outcomes
Postoperative residual limb pain
Time frame: at 3, 6, and 9 months
Postoperative phantom limb pain
Time frame: at 3, 6, and 9 months
Postoperative pain behavior
Time frame: at 3, 6, and 9 months
Postoperative pain interference
Time frame: at 3, 6, and 9 months
Neuropathic pain
Time frame: at 12 months
Hospital anxiety
Time frame: at 12 months
Depression
Time frame: at 12 months
Global perceived effect
Time frame: at 12 months
Prosthetic rehabilitation
Time frame: at 12 months
EuroQol-5D-5L
Time frame: at 2 weeks, and at 3, 6, 9 and 12 months
Medical consumption costs
Time frame: at 3, 6, 9, and 12 months
Productivity costs
Time frame: at 3, 6, 9, and 12 months
Budget impact analysis (BIA).
Time frame: at 12 months
Pain medication use
Time frame: at 3, 6, 9, and 12 months
Type of pain
Time frame: at 3, 6, 9 and 12 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2025.
- Background: PubMed 11690728Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole MR. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001 Nov;94(2):149-158. doi: 10.1016/S0304-3959(01)00349-9.
- Background: PubMed 32452928Mioton LM, Dumanian GA, Shah N, Qiu CS, Ertl WJ, Potter BK, Souza JM, Valerio IL, Ko JH, Jordan SW. Targeted Muscle Reinnervation Improves Residual Limb Pain, Phantom Limb Pain, and Limb Function: A Prospective Study of 33 Major Limb Amputees. Clin Orthop Relat Res. 2020 Sep;478(9):2161-2167. doi: 10.1097/CORR.0000000000001323.
- Background: PubMed 29615035Dal-Re R, Janiaud P, Ioannidis JPA. Real-world evidence: How pragmatic are randomized controlled trials labeled as pragmatic? BMC Med. 2018 Apr 3;16(1):49. doi: 10.1186/s12916-018-1038-2.
- Background: PubMed 25020004Torrance N, Lawson KD, Afolabi E, Bennett MI, Serpell MG, Dunn KM, Smith BH. Estimating the burden of disease in chronic pain with and without neuropathic characteristics: does the choice between the EQ-5D and SF-6D matter? Pain. 2014 Oct;155(10):1996-2004. doi: 10.1016/j.pain.2014.07.001. Epub 2014 Jul 11.
- Background: PubMed 23825931Parsons B, Schaefer C, Mann R, Sadosky A, Daniel S, Nalamachu S, Stacey BR, Nieshoff EC, Tuchman M, Anschel A. Economic and humanistic burden of post-trauma and post-surgical neuropathic pain among adults in the United States. J Pain Res. 2013 Jun 17;6:459-69. doi: 10.2147/JPR.S44939. Print 2013.
- Background: PubMed 22752065Groffen AJ, Klapwijk T, van Rootselaar AF, Groen JL, Tijssen MA. Genetic and phenotypic heterogeneity in sporadic and familial forms of paroxysmal dyskinesia. J Neurol. 2013 Jan;260(1):93-9. doi: 10.1007/s00415-012-6592-5. Epub 2012 Jun 30.
- Background: PubMed 30634038Valerio IL, Dumanian GA, Jordan SW, Mioton LM, Bowen JB, West JM, Porter K, Ko JH, Souza JM, Potter BK. Preemptive Treatment of Phantom and Residual Limb Pain with Targeted Muscle Reinnervation at the Time of Major Limb Amputation. J Am Coll Surg. 2019 Mar;228(3):217-226. doi: 10.1016/j.jamcollsurg.2018.12.015. Epub 2019 Jan 8.
- Background: PubMed 33123667Frantz TL, Everhart JS, West JM, Ly TV, Phieffer LS, Valerio IL. Targeted Muscle Reinnervation at the Time of Major Limb Amputation in Traumatic Amputees: Early Experience of an Effective Treatment Strategy to Improve Pain. JB JS Open Access. 2020 May 6;5(2):e0067. doi: 10.2106/JBJS.OA.19.00067. eCollection 2020 Apr-Jun.
- Background: PubMed 30208078Malessy MJA, de Boer R, Munoz Romero I, Eekhof JLA, van Zwet EW, Kliot M, Dahan A, Pondaag W. Predictive value of a diagnostic block in focal nerve injury with neuropathic pain when surgery is considered. PLoS One. 2018 Sep 12;13(9):e0203345. doi: 10.1371/journal.pone.0203345. eCollection 2018.
- Background: PubMed 36032374Deeyor ST, Kisana HM, Hui CH, Stecher C, Hustedt JW. Targeted Muscle Reinnervation Does Not Increase the Risk of Postsurgical Complication or Overall Cost. Plast Reconstr Surg Glob Open. 2022 Aug 24;10(8):e4488. doi: 10.1097/GOX.0000000000004488. eCollection 2022 Aug.
- Background: PubMed 33981935Schwingler PM, Moman RN, Hunt C, Ashmore Z, Ogletree SP, Uvodich ME, Murad MH, Hooten WM. Prevalence of postamputation pain and its subtypes: a meta-analysis with meta-regression. Pain Rep. 2021 May 4;6(1):e918. doi: 10.1097/PR9.0000000000000918. eCollection 2021.
- Background: PubMed 28678059Poyntz SA, Hacking NM, Dalal M, Fowler S. Peripheral Interventions for Painful Stump Neuromas of the Lower Limb: A Systematic Review. Clin J Pain. 2018 Mar;34(3):285-295. doi: 10.1097/AJP.0000000000000533.
- Study coordinating centerLink provided by the sponsor.
- Individual participant dataSharing planned: 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
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Justus L Groen, MD PhD principal investigator
Leiden University Medical Center
7 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Targeted Muscle Reinnervation (TMR) and Standard neurectomy in people with Amputation, Surgical and Phantom Limb Pain, run by Leiden University Medical Center at 7 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 19 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Justus L Groen, Md PhD (+31715262109, j.l.groen@lumc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Postoperative residual limb pain (time frame: at 12 months). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06719245, which also lists 26 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2025.