Evaluation of RPNI for Symptomatic Neuromas in Lower Limb Amputees (RPNI-AMPUTEE)

February 12, 2026 updated by: Ahmet Burak Bilekli, Saglik Bilimleri Universitesi

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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:

  1. Neuropathic Validation: Confirmation of neuropathic pain character via validated questionnaires.
  2. Anatomical Localization: Identification of a specific trigger point with a positive Tinel's sign triggering radiating paresthesia.
  3. 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 Type

Observational

Enrollment (Estimated)

20

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Turkey (Türkiye)
    • Ankara
      • Ankara, Ankara, Turkey (Türkiye), 06018
        • Recruiting
        • University of Health Sciences, Gulhane Training and Research Hospital, Department of Orthopedics and Traumatology
        • Contact:
        • Contact:
        • Principal Investigator:
          • Ahmet Burak Bilekli, MD, Associate Professor
        • Sub-Investigator:
          • Muhammed Burak Polat, MD
        • Sub-Investigator:
          • Hasan Dönmez, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

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.

Description

Inclusion Criteria:

  • 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:

    1. Neuropathic Pain: DN4 Questionnaire score ≥ 4.
    2. Pain Intensity: Numeric Rating Scale (NRS) score ≥ 4.
    3. Physical Exam: Positive Tinel's sign or palpation tenderness at a specific trigger point.
    4. 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.

Exclusion Criteria:

  • 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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
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.
Procedure: Regenerative Peripheral Nerve Interface (RPNI) 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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).
Baseline (Pre-op), 3, 6, 12, and 24 months post-operation.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Pain Intensity (NRS)
Time Frame: Baseline, 3, 6, 12, and 24 months.
Self-reported pain intensity measured by the Numeric Rating Scale (NRS). Scale ranges from 0 (No pain) to 10 (Worst possible pain).
Baseline, 3, 6, 12, and 24 months.
Change in Neuropathic Pain Characteristics (DN4 Score)
Time Frame: Baseline, 3, 6, 12, and 24 months.
Assessment using the Douleur Neuropathique 4 (DN4) questionnaire. Total score ranges from 0 to 10. A score of 4 or higher indicates neuropathic pain.
Baseline, 3, 6, 12, and 24 months.
Prosthesis Satisfaction and Quality of Life (PEQ)
Time Frame: Baseline, 3, 6, 12, and 24 months.
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).
Baseline, 3, 6, 12, and 24 months.
Change in Functional Mobility (TUG Test)
Time Frame: Baseline, 3, 6, 12, and 24 months.
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.
Baseline, 3, 6, 12, and 24 months.
Daily Prosthesis Usage Time (DPUT)
Time Frame: Baseline, 3, 6, 12, and 24 months.
Self-reported average duration of prosthesis usage per day, measured in hours/day.
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.

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.

  1. (Weak/General): Contraction felt, but unable to distinguish specific movement (General stump contraction).
  2. (Strong/Clear): Distinct contraction specific to the intended movement (e.g., thumb vs. wrist) is felt clearly. Higher scores indicate superior motor control.
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.
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.
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.

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.
Baseline (Pre-op) and 24 months post-operation.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Charlson Comorbidity Index (CCI)
Time Frame: Baseline (Pre-op) only.
Weighted index to predict risk of death from comorbidities. Used to standardize baseline health status.
Baseline (Pre-op) only.
Elixhauser Comorbidity Index (ECI)
Time Frame: Baseline (Pre-op) only.
Index categorizing comorbidities based on ICD diagnosis codes to adjust for confounding factors.
Baseline (Pre-op) only.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Saglik Bilimleri Universitesi

Investigators

  • Principal Investigator: Ahmet Burak Bilekli, MD, Associate Professor, University of Health Sciences, Gülhane Training and Research Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 20, 2026

Primary Completion (Estimated)

November 1, 2029

Study Completion (Estimated)

March 1, 2030

Study Registration Dates

First Submitted

February 12, 2026

First Submitted That Met QC Criteria

February 12, 2026

First Posted (Actual)

February 19, 2026

Study Record Updates

Last Update Posted (Actual)

February 19, 2026

Last Update Submitted That Met QC Criteria

February 12, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RPNI-SBU-AMPUTEE-2026
  • 2026-24 (Other Identifier: University of Health Sciences Gulhane Scientific Research Ethics Committee)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

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.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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