Symptomatic NeuromaRPNI-AMPUTEENCT07420192
Evaluation of RPNI for Symptomatic Neuromas in Lower Limb Amputees
An observational study of Symptomatic Neuroma and Phantom Limb Pain After Amputation, run by Saglik Bilimleri Universitesi at 1 site in Turkey (Türkiye).
Trial summary
This prospective, observational cohort study evaluates the long-term outcomes of Regenerative Peripheral Nerve Interface (RPNI) surgery in patients with major lower extremity amputations suffering from symptomatic neuromas. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Symptomatic Neuroma, Phantom Limb Pain After Amputation, Residual Limb Pain
- What is being tested?
- Regenerative Peripheral Nerve Interface (RPNI) Surgery
- Type of treatment
- Surgery or procedure
- How many people
- 20 participants
- Where
- 1 siteTurkey (Türkiye)
- Study dates
- 20 Jan 2026to Mar 2030
- How long will I take part?
- 24 Months
- Phase
- Observational
- 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 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Adult patients with major lower extremity amputations presenting to the tertiary Orthopedics and Traumatology clinic with complaints of chronic residual limb pain, phantom limb pain, and prosthesis intolerance, who are diagnosed with symptomatic neuroma and scheduled for surgical intervention.
Who may be able to join
- Age: Adults aged 18 to 70 years.
- Amputation Status: Unilateral major lower extremity amputation (Transtibial, Transfemoral, or Knee Disarticulation).
- Radiological Baseline: Absence of Heterotopic Ossification (HO) in the residual limb, confirmed by pre-operative X-rays (Walter Reed Classification Grade 0).
- Diagnosis: Confirmed diagnosis of "Symptomatic Neuroma" validated by the Clinical Triad:
- Neuropathic Pain: DN4 Questionnaire score ≥ 4.
- Pain Intensity: Numeric Rating Scale (NRS) score ≥ 4.
Show all 10Show fewer
- Physical Exam: Positive Tinel's sign or palpation tenderness at a specific trigger point.
- Radiology: Diagnostic Ultrasound visualization of the neuroma bulb.
- Surgical Indication: Scheduled for RPNI surgery as part of the routine standard of care treatment protocol due to prosthesis intolerance or severe pain.
- Consent: Willing and able to provide informed consent and attend follow-up visits.
Who cannot join
- CRPS: Diagnosis of Complex Regional Pain Syndrome (CRPS Type 1 or 2).
- Concurrent Bone Surgery: Patients requiring simultaneous stump revision surgery (e.g., bone shortening, osteotomy, spur excision) or having existing HO (Walter Reed Grade > 0).
- Systemic Conditions: Uncontrolled diabetes mellitus (HbA1c > 8.5%) or severe peripheral arterial disease compromising wound healing.
- Cognitive Status: Cognitive impairment or psychiatric conditions preventing reliable completion of patient-reported outcome measures (PEQ, DN4).
- History: Previous RPNI surgery at the same site (Recurrent RPNI cases).
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Turkey (Türkiye)1 site, 1 recruiting
- Recruiting
University of Health Sciences, Gulhane Training and Research Hospital, Department of Orthopedics and Traumatology
Ankara, Ankara, 06018
Ahmet Burak Bilekli, MD, Associate Professor, 05326007020, draburakbilekli@yahoo.com
Muhammed Burak Polat, MD, +90 545 340 73 23, burakp1512@gmail.com
About this study
Official title: The Effect of Regenerative Peripheral Nerve Interface (RPNI) Surgery on Neuropathic Pain and Functional Outcomes in Major Lower Extremity Amputations
This prospective, observational cohort study evaluates the long-term outcomes of Regenerative Peripheral Nerve Interface (RPNI) surgery in patients with major lower extremity amputations suffering from symptomatic neuromas. RPNI is a surgical technique where the transected nerve end is implanted into a free autologous muscle graft to serve as a physiological target for reinnervation. The study aims to objectively assess the reduction in mechanical hypersensitivity using Pressure Pain Threshold (PPT) measurements via a digital algometer. Additionally, it monitors subjective neuropathic pain levels, functional mobility, and prosthesis satisfaction over a 24-month follow-up period compared to pre-operative baselines.
Read the detailed description
Scientific Rationale and Background Traditional "passive" nerve management techniques (e.g., traction neurectomy, burying in muscle/bone) often fail to prevent neuroma recurrence due to the lack of a physiological target for regenerating axons. This study investigates the long-term efficacy of the "Regenerative Peripheral Nerve Interface (RPNI)" technique. RPNI is an "active" surgical approach where the transected nerve end is implanted into a free autologous muscle graft to promote physiological reinnervation, thereby preventing chaotic axonal sprouting and neuroma formation.
Diagnostic Protocol (The Clinical Triad) To ensure accurate participant selection and strictly exclude non-neuroma pathologies such as Complex Regional Pain Syndrome (CRPS), the study employs a standardized "Clinical Triad" protocol for all potential candidates:
- Neuropathic Validation: Confirmation of neuropathic pain character via validated questionnaires.
- Anatomical Localization: Identification of a specific trigger point with a positive Tinel's sign triggering radiating paresthesia.
- Radiological Confirmation: Visualization of the neuroma bulb at the symptomatic site using high-resolution Diagnostic Ultrasound.
Surgical Methodology (Standard of Care) Participants undergo the standard RPNI procedure as per the clinic's routine protocol.
- Graft Harvesting: A free autologous muscle graft (approx. 30x15x5 mm) is harvested. To minimize donor site morbidity, graft selection is standardized based on the amputation level: Vastus Lateralis for transtibial amputees and Biceps Femoris for transfemoral amputees.
- Inlay Technique: The neuroma bulb is excised, and the fresh nerve end is implanted into the center of the muscle graft using the "Inlay Technique" to maximize neurotization interface and minimize axonal escape.
Investigational Modules
- Viscero-Somatic Convergence: The study uniquely investigates the potential "cross-talk" mechanism between pelvic autonomic nerves (parasympathetic S2-S4) and somatic nerves. Participants are monitored for "Viscero-Somatic Symptoms," defined as stump pain triggered specifically by micturition, defecation, or sexual activity.
- Phantom Motor Execution (PME): As a functional indicator of reinnervation, patients are assessed for the ability to voluntarily execute movements with their phantom limb.
Sample Size and Power Analysis Based on a priori power analysis using G*Power 3.1 software, the sample size was calculated referencing the pressure pain threshold (PPT) effect sizes reported in comparable literature (Kubiak et al., 2022). Assuming a large effect size (Cohen's d = 1.5), an alpha error of 0.05, and a power of 90% (1-beta), a minimum of 13 participants is required to detect statistical significance. To account for a potential 20% dropout rate over the 24-month follow-up, the target enrollment is set at 20 patients.
Statistical Analysis Plan Data analysis will be performed using IBM SPSS Statistics 26.0.
- Normality Testing: The Shapiro-Wilk test will be used to determine the distribution of continuous variables.
- Longitudinal Analysis: The Friedman Test will be employed to analyze changes in dependent variables (NRS, DN4, PPT, PEQ scores) across the five time points (Pre-op, 3, 6, 12, 24 months).
- Pairwise Comparisons: Significant differences identified by the Friedman test will be further analyzed using the Wilcoxon Signed-Rank Test with Bonferroni correction.
- Correlation: Spearman's correlation analysis will be used to assess the relationship between objective algometer measurements and subjective prosthesis usage time (DPUT).
- Significance Level: A p-value of <0.05 will be considered statistically significant.
- Conditions
- Symptomatic Neuroma, Phantom Limb Pain After Amputation, Residual Limb Pain, Neuropathic Pain, Lower Extremity Amputations
- Being tested
- Regenerative Peripheral Nerve Interface (RPNI) Surgery
- Keywords
- RPNI, Regenerative Peripheral Nerve Interface, Pressure Pain Threshold, PPT, Algometry, Prosthesis Satisfaction, Viscero-Somatic Convergence, Phantom Motor Execution
- Medical subject headings
- Neuralgia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Regenerative Peripheral Nerve Interface (RPNI) SurgeryProcedure or surgery
The surgical procedure is standardized as follows to preserve the residual limb (stump) anatomy:
- Approach: An 8-10 cm incision is made on the lateral thigh. For transtibial (below-knee) amputees, the incision is placed approximately 15 cm proximal to the knee joint. For transfemoral (above-knee) amputees, it is placed 5-10 cm proximal to the distal end of the residual limb.
- Nerve Dissection: The sciatic nerve is isolated, dissected, and transected at its most distal point. Subsequently, it is separated into the Common Peroneal and Tibial divisions.
- Fascicular Separation: Based on nerve thickness, intraneural dissection is performed to split the Common Peroneal nerve into 1 or 2 fascicles, and the Tibial nerve into 2 to 4 fascicles.
- Graft Harvesting: Autologous muscle grafts are harvested to wrap these created fascicles. The donor site is standardized by amputation level: Vastus Lateralis muscle for transtibial amputees and Biceps Femoris muscle for transfemoral amputees.
| Study group | Role | What they receive |
|---|---|---|
| RPNI Group | Adult patients (18-70 years) with unilateral major lower extremity amputations (transtibial or transfemoral) who are diagnosed with "Symptomatic Neuroma" confirmed by the clinical triad (DN4 score ≥4, positive Tinel sign, and diagnostic ultrasound). These patients are scheduled to undergo Regenerative Peripheral Nerve Interface (RPNI) surgery as part of the routine standard of care treatment protocol. Receives: Procedure: Regenerative Peripheral Nerve Interface (RPNI) Surgery |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Pressure Pain Threshold (PPT)
Objective measurement of mechanical hypersensitivity at the neuroma site using a digital pressure algometer. The device applies increasing pressure in kg/cm² until the patient reports pain. Measurements are taken from the most tender point of the neuroma and a control point. Higher values indicate higher pain tolerance (improvement).
Measured: Baseline (Pre-op), 3, 6, 12, and 24 months post-operation.
Secondary outcomes (8)
Change in Pain Intensity (NRS)
Self-reported pain intensity measured by the Numeric Rating Scale (NRS). Scale ranges from 0 (No pain) to 10 (Worst possible pain).
Measured: Baseline, 3, 6, 12, and 24 months.
Change in Neuropathic Pain Characteristics (DN4 Score)
Assessment using the Douleur Neuropathique 4 (DN4) questionnaire. Total score ranges from 0 to 10. A score of 4 or higher indicates neuropathic pain.
Measured: Baseline, 3, 6, 12, and 24 months.
Prosthesis Satisfaction and Quality of Life (PEQ)
Evaluation using the Turkish validated version of the Prosthesis Evaluation Questionnaire (PEQ). Scores are normalized to a 0-100 scale (Higher scores indicate better outcome).
Measured: Baseline, 3, 6, 12, and 24 months.
Change in Functional Mobility (TUG Test)
Timed Up and Go (TUG) test measuring the time (in seconds) required to stand, walk 3 meters, turn, walk back, and sit down. Lower time indicates better mobility.
Measured: Baseline, 3, 6, 12, and 24 months.
Daily Prosthesis Usage Time (DPUT)
Self-reported average duration of prosthesis usage per day, measured in hours/day.
Measured: Baseline, 3, 6, 12, and 24 months.
Quality of Phantom Motor Execution (PME)
Assessment of the patient's ability to voluntarily execute specific movements with the phantom limb. Documenting the change from pre-operative baseline to post-operative reinnervation status. Rated on a 3-point ordinal scale:
0 (None): No contraction or movement sensation felt.
- (Weak/General): Contraction felt, but unable to distinguish specific movement (General stump contraction).
- (Strong/Clear): Distinct contraction specific to the intended movement (e.g., thumb vs. wrist) is felt clearly. Higher scores indicate superior motor control.
Measured: Baseline (Pre-op), 3, 6, 12, and 24 months post-operation.
Severity of Viscero-Somatic Convergence Symptoms
Assessment of "Viscero-Somatic Convergence" (cross-talk between pelvic autonomic nerves and somatic nerves). Participants are queried about stump or phantom pain triggered by 1) Micturition, 2) Defecation, and 3) Sexual activity. Each item is rated on a 3-point ordinal scale (0=No, 1=Mild, 2=Severe). Total score ranges from 0 to 6. The goal is to observe if RPNI surgery reduces or eliminates these pre-existing cross-talk symptoms compared to baseline.
Measured: Baseline (Pre-op), 3, 6, 12, and 24 months post-operation.
Incidence of New Heterotopic Ossification (HO)
Radiological evaluation of new bone formation in soft tissues at the amputation stump using standard A/P and Lateral X-rays. Baseline Requirement: All participants must have a Grade 0 status at baseline to be eligible. Post-Op Grading: At 24 months, any new ossification is graded according to the Walter Reed Classification System:
- Grade 0: No ectopic bone formation within the soft-tissue envelope.
- Grade I (Mild): 0%-25% of the soft-tissue envelope occupied by ectopic bone.
- Grade II (Moderate): >25%-50% of the soft-tissue envelope occupied by ectopic bone.
- Grade III (Severe): >50% of the soft-tissue envelope occupied by ectopic bone. Outcomes will be reported as the frequency of each grade developed post-operatively.
Measured: Baseline (Pre-op) and 24 months post-operation.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Feb 2026
- Study start20 Jan 2026
- Primary completionNov 2029 (estimated)
- Study completionMar 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for Symptomatic NeuromaStudies of the same condition, open and under way.
- More trials run by Saglik Bilimleri UniversitesiThe 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 20 participants (estimated)
- Target duration
- 24 Months
Sponsor and investigators
- Lead sponsor
- Saglik Bilimleri Universitesi
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ahmet Burak Bilekli, Saglik Bilimleri Universitesi
- Investigators
- Ahmet Burak Bilekli, MD, Associate Professor, Principal investigator, University of Health Sciences, Gülhane Training and Research Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07420192
- Sponsor's protocol ID
- RPNI-SBU-AMPUTEE-2026
- Other IDs
- 2026-24
- Acronym
- RPNI-AMPUTEE
- Status last verified
- Feb 2026
- First submitted
- 12 Feb 2026
- Last updated
- 19 Feb 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: A formal plan for sharing individual participant data (IPD) has not yet been established. The investigators intend to evaluate the feasibility of sharing anonymized data upon reasonable request to the Principal Investigator following the publication of study results. However, a final decision will depend on strict compliance with local data protection regulations (KVKK) and institutional ethical approval mechanisms regarding data transfer. Currently, no specific public repository has been designated.
Publications
Yuan M, Gallo M, Gallo L, Huynh MH, McRae M, McRae MC, Thoma A, Coroneos CJ, Voineskos SH. Targeted Muscle Reinnervation and Regenerative Peripheral Nerve Interfaces Versus Standard Management in the Treatment of Limb Amputation: A Systematic Review and Meta-Analysis. Plast Surg (Oakv). 2024 May;32(2):253-264. doi: 10.1177/22925503221107462. Epub 2022 Jun 16.
PubMed 38681253Watson CPN, Midha R, Ng DW. Causalgia: A Review of Nerve Resection, Amputation, Immunotherapy, and Amputated Limb CRPS II Pathology. Can J Neurol Sci. 2024 May;51(3):351-356. doi: 10.1017/cjn.2023.260. Epub 2023 Jul 25.
PubMed 37489506Vaskov A, Wallace D, Desai K, Laidlaw A, Kung T, Gates D, Kemp S, Chestek C, Cederna P. A Robust Neuromuscular Interface to Restore Lost Function in People with Amputations. Res Sq [Preprint]. 2025 May 14:rs.3.rs-5989030. doi: 10.21203/rs.3.rs-5989030/v1.
PubMed 40470247Senger JL, Thorkelsson A, Wang BY, Chan KM, Kemp SWP, Webber CA. Comparison of 2 Regenerative Peripheral Nerve Interface Techniques for the Treatment of Rat Neuroma Pain. Plast Reconstr Surg. 2024 Aug 1;154(2):346-349. doi: 10.1097/PRS.0000000000010911. Epub 2023 Jul 4.
PubMed 37400949Raasveld FV, Lehle CH, Hwang CD, Cross RE, Husseini JS, Simeone FJ, Newman ET, Tuano K, Lozano-Calderon SA, Valerio IL, Eberlin KR. The influence of nerve surgical techniques at time of amputation on the prevalence of heterotopic ossification in transtibial amputees. Injury. 2025 Feb;56(2):112047. doi: 10.1016/j.injury.2024.112047. Epub 2024 Nov 20.
PubMed 39608134Pettersen E, Sassu P, Pedrini FA, Granberg H, Reinholdt C, Breyer JM, Roche A, Hart A, Ladak A, Power HA, Leung M, Lo M, Valerio I, Eberlin KR, Ko J, Dumanian GA, Kung TA, Cederna P, Ortiz-Catalan M. Regenerative Peripheral Nerve Interface: Surgical Protocol for a Randomized Controlled Trial in Postamputation Pain. J Vis Exp. 2024 Mar 15;(205). doi: 10.3791/66378.
PubMed 38557950Lin Z, Yu P, Chen Z, Li G. Regenerative peripheral nerve interface reduces the incidence of neuroma in the lower limbs after amputation: a retrospective study based on ultrasound. J Orthop Surg Res. 2023 Aug 24;18(1):619. doi: 10.1186/s13018-023-04116-6.
PubMed 37620955Lans J, Groot OQ, Hazewinkel MHJ, Kaiser PB, Lozano-Calderon SA, Heng M, Valerio IL, Eberlin KR. Factors Related to Neuropathic Pain following Lower Extremity Amputation. Plast Reconstr Surg. 2022 Aug 1;150(2):446-455. doi: 10.1097/PRS.0000000000009334. Epub 2022 Jul 27.
PubMed 35687412Best CS, Cederna PS, Kung TA. Regenerative Peripheral Nerve Interface (RPNI) Surgery for Mitigation of Neuroma and Postamputation Pain. JBJS Essent Surg Tech. 2024 Feb 12;14(1):e23.00009. doi: 10.2106/JBJS.ST.23.00009. eCollection 2024 Jan-Mar.
PubMed 38348364Lauzon JC, Boyd KU, Dudek NL. What to expect following targeted muscle reinnervation/regenerative peripheral nerve interface: Pain outcomes in an amputee population. J Plast Reconstr Aesthet Surg. 2024 Dec;99:373-376. doi: 10.1016/j.bjps.2024.10.017. Epub 2024 Oct 13.
PubMed 39426252Kubiak CA, Kemp SWP, Cederna PS. Regenerative Peripheral Nerve Interface for Management of Postamputation Neuroma. JAMA Surg. 2018 Jul 1;153(7):681-682. doi: 10.1001/jamasurg.2018.0864. No abstract available.
PubMed 29847613Hu Y, Ursu DC, Sohasky RA, Sando IC, Ambani SLW, French ZP, Mays EA, Nedic A, Moon JD, Kung TA, Cederna PS, Kemp SWP, Urbanchek MG. Regenerative peripheral nerve interface free muscle graft mass and function. Muscle Nerve. 2021 Mar;63(3):421-429. doi: 10.1002/mus.27138. Epub 2020 Dec 20.
PubMed 33290586de Lange JWD, Hundepool CA, Power DM, Rajaratnam V, Duraku LS, Zuidam JM. Prevention is better than cure: Surgical methods for neuropathic pain prevention following amputation - A systematic review. J Plast Reconstr Aesthet Surg. 2022 Mar;75(3):948-959. doi: 10.1016/j.bjps.2021.11.076. Epub 2021 Dec 5.
PubMed 34955394
Study at a glance
From the registry record, last updated by the sponsor on 19 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Regenerative Peripheral Nerve Interface (RPNI) Surgery on Neuropathic Pain and Functional Outcomes in Major Lower Extremity Amputations
- ClinicalTrials.gov ID
- NCT07420192
- Acronym / sponsor ID
- RPNI-AMPUTEE / RPNI-SBU-AMPUTEE-2026
- Conditions
- Symptomatic Neuroma, Phantom Limb Pain After Amputation, Residual Limb Pain, Neuropathic Pain, Lower Extremity Amputations
- Keywords
- RPNI, Regenerative Peripheral Nerve Interface, Pressure Pain Threshold, PPT, Algometry, Prosthesis Satisfaction, Viscero-Somatic Convergence, Phantom Motor Execution
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- Saglik Bilimleri UniversitesiUniversity, hospital or other
- Study start
- 20 Jan 2026 (actual)
- Primary completion
- Nov 2029 (estimated)
- Study completion
- Mar 2030 (estimated)
- First posted
- 19 Feb 2026 (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.
This prospective, observational cohort study evaluates the long-term outcomes of Regenerative Peripheral Nerve Interface (RPNI) surgery in patients with major lower extremity amputations suffering from symptomatic neuromas. RPNI is a surgical technique where the transected nerve end is implanted into a free autologous muscle graft to serve as a physiological target for reinnervation. The study aims to objectively assess the reduction in mechanical hypersensitivity using Pressure Pain Threshold (PPT) measurements via a digital algometer. Additionally, it monitors subjective neuropathic pain levels, functional mobility, and prosthesis satisfaction over a 24-month follow-up period compared to pre-operative baselines.
Detailed description
Scientific Rationale and Background Traditional "passive" nerve management techniques (e.g., traction neurectomy, burying in muscle/bone) often fail to prevent neuroma recurrence due to the lack of a physiological target for regenerating axons. This study investigates the long-term efficacy of the "Regenerative Peripheral Nerve Interface (RPNI)" technique. RPNI is an "active" surgical approach where the transected nerve end is implanted into a free autologous muscle graft to promote physiological reinnervation, thereby preventing chaotic axonal sprouting and neuroma formation.
Diagnostic Protocol (The Clinical Triad) To ensure accurate participant selection and strictly exclude non-neuroma pathologies such as Complex Regional Pain Syndrome (CRPS), the study employs a standardized "Clinical Triad" protocol for all potential candidates:
- Neuropathic Validation: Confirmation of neuropathic pain character via validated questionnaires.
- Anatomical Localization: Identification of a specific trigger point with a positive Tinel's sign triggering radiating paresthesia.
- Radiological Confirmation: Visualization of the neuroma bulb at the symptomatic site using high-resolution Diagnostic Ultrasound.
Surgical Methodology (Standard of Care) Participants undergo the standard RPNI procedure as per the clinic's routine protocol.
- Graft Harvesting: A free autologous muscle graft (approx. 30x15x5 mm) is harvested. To minimize donor site morbidity, graft selection is standardized based on the amputation level: Vastus Lateralis for transtibial amputees and Biceps Femoris for transfemoral amputees.
- Inlay Technique: The neuroma bulb is excised, and the fresh nerve end is implanted into the center of the muscle graft using the "Inlay Technique" to maximize neurotization interface and minimize axonal escape.
Investigational Modules
- Viscero-Somatic Convergence: The study uniquely investigates the potential "cross-talk" mechanism between pelvic autonomic nerves (parasympathetic S2-S4) and somatic nerves. Participants are monitored for "Viscero-Somatic Symptoms," defined as stump pain triggered specifically by micturition, defecation, or sexual activity.
- Phantom Motor Execution (PME): As a functional indicator of reinnervation, patients are assessed for the ability to voluntarily execute movements with their phantom limb.
Sample Size and Power Analysis Based on a priori power analysis using G*Power 3.1 software, the sample size was calculated referencing the pressure pain threshold (PPT) effect sizes reported in comparable literature (Kubiak et al., 2022). Assuming a large effect size (Cohen's d = 1.5), an alpha error of 0.05, and a power of 90% (1-beta), a minimum of 13 participants is required to detect statistical significance. To account for a potential 20% dropout rate over the 24-month follow-up, the target enrollment is set at 20 patients.
Statistical Analysis Plan Data analysis will be performed using IBM SPSS Statistics 26.0.
- Normality Testing: The Shapiro-Wilk test will be used to determine the distribution of continuous variables.
- Longitudinal Analysis: The Friedman Test will be employed to analyze changes in dependent variables (NRS, DN4, PPT, PEQ scores) across the five time points (Pre-op, 3, 6, 12, 24 months).
- Pairwise Comparisons: Significant differences identified by the Friedman test will be further analyzed using the Wilcoxon Signed-Rank Test with Bonferroni correction.
- Correlation: Spearman's correlation analysis will be used to assess the relationship between objective algometer measurements and subjective prosthesis usage time (DPUT).
- Significance Level: A p-value of <0.05 will be considered statistically significant.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 24 Months
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| RPNI Group | – | Procedure: Regenerative Peripheral Nerve Interface (RPNI) SurgeryAdult patients (18-70 years) with unilateral major lower extremity amputations (transtibial or transfemoral) who are diagnosed with "Symptomatic Neuroma" confirmed by the clinical triad (DN4 score ≥4, positive Tinel sign, and diagnostic ultrasound). These patients are scheduled to undergo Regenerative Peripheral Nerve Interface (RPNI) surgery as part of the routine standard of care treatment protocol. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Adult patients with major lower extremity amputations presenting to the tertiary Orthopedics and Traumatology clinic with complaints of chronic residual limb pain, phantom limb pain, and prosthesis intolerance, who are diagnosed with symptomatic neuroma and scheduled for surgical intervention.
Key inclusion criteria (10 listed)
- Age: Adults aged 18 to 70 years.
- Amputation Status: Unilateral major lower extremity amputation (Transtibial, Transfemoral, or Knee Disarticulation).
- Radiological Baseline: Absence of Heterotopic Ossification (HO) in the residual limb, confirmed by pre-operative X-rays (Walter Reed Classification Grade 0).
- Diagnosis: Confirmed diagnosis of "Symptomatic Neuroma" validated by the Clinical Triad:
- Surgical Indication: Scheduled for RPNI surgery as part of the routine standard of care treatment protocol due to prosthesis intolerance or severe pain.
Key exclusion criteria (5 listed)
- CRPS: Diagnosis of Complex Regional Pain Syndrome (CRPS Type 1 or 2).
- Concurrent Bone Surgery: Patients requiring simultaneous stump revision surgery (e.g., bone shortening, osteotomy, spur excision) or having existing HO (Walter Reed Grade > 0).
- Systemic Conditions: Uncontrolled diabetes mellitus (HbA1c > 8.5%) or severe peripheral arterial disease compromising wound healing.
- Cognitive Status: Cognitive impairment or psychiatric conditions preventing reliable completion of patient-reported outcome measures (PEQ, DN4).
- History: Previous RPNI surgery at the same site (Recurrent RPNI cases).
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 |
|---|---|---|
| Regenerative Peripheral Nerve Interface (RPNI) SurgeryThe surgical procedure is standardized as follows to preserve the residual limb (stump) anatomy: * Approach: An 8-10 cm incision is made on the lateral thigh. For transtibial (below-knee) amputees, the incision is placed approximately 15 cm proximal to the knee joint. For transfemoral (above-knee) amputees, it is placed 5-10 cm proximal to the distal end of the residual limb. * Nerve Dissection: The sciatic nerve is isolated, dissected, and transected at its most distal point. Subsequently, it is separated into the Common Peroneal and Tibial divisions. * Fascicular Separation: Based on nerve thickness, intraneural dissection is performed to split the Common Peroneal nerve into 1 or 2 fascicles, and the Tibial nerve into 2 to 4 fascicles. * Graft Harvesting: Autologous muscle grafts are harvested to wrap these created fascicles. The donor site is standardized by amputation level: Vastus Lateralis muscle for transtibial amputees and Biceps Femoris muscle for transfemoral amputees. | Procedure or surgery | RPNI Group |
Primary outcome
Change in Pressure Pain Threshold (PPT)
Time frame: Baseline (Pre-op), 3, 6, 12, and 24 months post-operation.
Objective measurement of mechanical hypersensitivity at the neuroma site using a digital pressure algometer. The device applies increasing pressure in kg/cm² until the patient reports pain. Measurements are taken from the most tender point of the neuroma and a control point. Higher values indicate higher pain tolerance (improvement).
8 secondary outcomes
Change in Pain Intensity (NRS)
Time frame: Baseline, 3, 6, 12, and 24 months.
Change in Neuropathic Pain Characteristics (DN4 Score)
Time frame: Baseline, 3, 6, 12, and 24 months.
Prosthesis Satisfaction and Quality of Life (PEQ)
Time frame: Baseline, 3, 6, 12, and 24 months.
Change in Functional Mobility (TUG Test)
Time frame: Baseline, 3, 6, 12, and 24 months.
Daily Prosthesis Usage Time (DPUT)
Time frame: Baseline, 3, 6, 12, and 24 months.
Quality of Phantom Motor Execution (PME)
Time frame: Baseline (Pre-op), 3, 6, 12, and 24 months post-operation.
Severity of Viscero-Somatic Convergence Symptoms
Time frame: Baseline (Pre-op), 3, 6, 12, and 24 months post-operation.
Incidence of New Heterotopic Ossification (HO)
Time frame: Baseline (Pre-op) and 24 months post-operation.
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 Feb 2026.
- Background: PubMed 38681253Yuan M, Gallo M, Gallo L, Huynh MH, McRae M, McRae MC, Thoma A, Coroneos CJ, Voineskos SH. Targeted Muscle Reinnervation and Regenerative Peripheral Nerve Interfaces Versus Standard Management in the Treatment of Limb Amputation: A Systematic Review and Meta-Analysis. Plast Surg (Oakv). 2024 May;32(2):253-264. doi: 10.1177/22925503221107462. Epub 2022 Jun 16.
- Background: PubMed 37489506Watson CPN, Midha R, Ng DW. Causalgia: A Review of Nerve Resection, Amputation, Immunotherapy, and Amputated Limb CRPS II Pathology. Can J Neurol Sci. 2024 May;51(3):351-356. doi: 10.1017/cjn.2023.260. Epub 2023 Jul 25.
- Background: PubMed 40470247Vaskov A, Wallace D, Desai K, Laidlaw A, Kung T, Gates D, Kemp S, Chestek C, Cederna P. A Robust Neuromuscular Interface to Restore Lost Function in People with Amputations. Res Sq [Preprint]. 2025 May 14:rs.3.rs-5989030. doi: 10.21203/rs.3.rs-5989030/v1.
- Background: PubMed 37400949Senger JL, Thorkelsson A, Wang BY, Chan KM, Kemp SWP, Webber CA. Comparison of 2 Regenerative Peripheral Nerve Interface Techniques for the Treatment of Rat Neuroma Pain. Plast Reconstr Surg. 2024 Aug 1;154(2):346-349. doi: 10.1097/PRS.0000000000010911. Epub 2023 Jul 4.
- Background: PubMed 39608134Raasveld FV, Lehle CH, Hwang CD, Cross RE, Husseini JS, Simeone FJ, Newman ET, Tuano K, Lozano-Calderon SA, Valerio IL, Eberlin KR. The influence of nerve surgical techniques at time of amputation on the prevalence of heterotopic ossification in transtibial amputees. Injury. 2025 Feb;56(2):112047. doi: 10.1016/j.injury.2024.112047. Epub 2024 Nov 20.
- Background: PubMed 38557950Pettersen E, Sassu P, Pedrini FA, Granberg H, Reinholdt C, Breyer JM, Roche A, Hart A, Ladak A, Power HA, Leung M, Lo M, Valerio I, Eberlin KR, Ko J, Dumanian GA, Kung TA, Cederna P, Ortiz-Catalan M. Regenerative Peripheral Nerve Interface: Surgical Protocol for a Randomized Controlled Trial in Postamputation Pain. J Vis Exp. 2024 Mar 15;(205). doi: 10.3791/66378.
- Background: PubMed 37620955Lin Z, Yu P, Chen Z, Li G. Regenerative peripheral nerve interface reduces the incidence of neuroma in the lower limbs after amputation: a retrospective study based on ultrasound. J Orthop Surg Res. 2023 Aug 24;18(1):619. doi: 10.1186/s13018-023-04116-6.
- Background: PubMed 35687412Lans J, Groot OQ, Hazewinkel MHJ, Kaiser PB, Lozano-Calderon SA, Heng M, Valerio IL, Eberlin KR. Factors Related to Neuropathic Pain following Lower Extremity Amputation. Plast Reconstr Surg. 2022 Aug 1;150(2):446-455. doi: 10.1097/PRS.0000000000009334. Epub 2022 Jul 27.
- Background: PubMed 38348364Best CS, Cederna PS, Kung TA. Regenerative Peripheral Nerve Interface (RPNI) Surgery for Mitigation of Neuroma and Postamputation Pain. JBJS Essent Surg Tech. 2024 Feb 12;14(1):e23.00009. doi: 10.2106/JBJS.ST.23.00009. eCollection 2024 Jan-Mar.
- Background: PubMed 39426252Lauzon JC, Boyd KU, Dudek NL. What to expect following targeted muscle reinnervation/regenerative peripheral nerve interface: Pain outcomes in an amputee population. J Plast Reconstr Aesthet Surg. 2024 Dec;99:373-376. doi: 10.1016/j.bjps.2024.10.017. Epub 2024 Oct 13.
- Background: PubMed 29847613Kubiak CA, Kemp SWP, Cederna PS. Regenerative Peripheral Nerve Interface for Management of Postamputation Neuroma. JAMA Surg. 2018 Jul 1;153(7):681-682. doi: 10.1001/jamasurg.2018.0864. No abstract available.
- Background: PubMed 33290586Hu Y, Ursu DC, Sohasky RA, Sando IC, Ambani SLW, French ZP, Mays EA, Nedic A, Moon JD, Kung TA, Cederna PS, Kemp SWP, Urbanchek MG. Regenerative peripheral nerve interface free muscle graft mass and function. Muscle Nerve. 2021 Mar;63(3):421-429. doi: 10.1002/mus.27138. Epub 2020 Dec 20.
- Individual participant dataSharing planned: Undecided. A formal plan for sharing individual participant data (IPD) has not yet been established. The investigators intend to evaluate the feasibility of sharing anonymized data upon reasonable request to the Principal Investigator following the publication of study results. However, a final decision will depend on strict compliance with local data protection regulations (KVKK) and institutional ethical approval mechanisms regarding data transfer. Currently, no specific public repository has been designated.
Related trials for Symptomatic Neuroma
Active, not recruiting
Tolerability and Feasibility Pilot Clinical Study of a Large-Diameter Nerve Cap for Protecting and Preserving Terminated Nerve Ends
Symptomatic Neuroma, Amputation
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.
Ahmet Burak Bilekli, MD, Associate Professor principal investigator
University of Health Sciences, Gülhane Training and Research Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Symptomatic Neuroma and Phantom Limb Pain After Amputation, run by Saglik Bilimleri Universitesi at 1 site in Turkey (Türkiye).
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 10 inclusion and 5 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 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Turkey (Türkiye). 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 Ahmet Burak Bilekli, MD, Associate Professor (+905326007020, draburakbilekli@yahoo.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Pressure Pain Threshold (PPT) (time frame: Baseline (Pre-op), 3, 6, 12, and 24 months post-operation.). 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 NCT07420192, which also lists 13 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 Feb 2026.