Prevention of PostAmputation Pain With Targeted Muscle Reinnervation (PreventPAP)

September 15, 2025 updated by: jlgroen, Leiden University Medical Center

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).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Estimated)

203

Phase

  • Not Applicable

Contacts and Locations

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

Study Contact

Study Locations

  • Netherlands
    • North Holland
      • Amsterdam, North Holland, Netherlands, 1105 AZ
        • Not yet recruiting
        • Amsterdam University Medical Center
    • Overijssel
      • Zwolle, Overijssel, Netherlands, 8025 AB
        • Not yet recruiting
        • Isala Zwolle
    • South Holland
      • Leiden, South Holland, Netherlands, 2333 ZA
        • Recruiting
        • Leiden University Medical Center
        • Contact:
          • Justus L Groen, Dr.
      • Leiderdorp, South Holland, Netherlands, 2353 GA
        • Not yet recruiting
        • Alrijne Zorggroep
      • Rotterdam, South Holland, Netherlands, 3015 GD
        • Not yet recruiting
        • Erasmus Medical Center
      • The Hague, South Holland, Netherlands, 2512 VA
        • Not yet recruiting
        • Haaglanden Medisch Centrum
    • Utrecht
      • Utrecht, Utrecht, Netherlands, 3584 CX
        • Not yet recruiting
        • University Medical Center Utrecht

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

Description

Inclusion criteria

  • 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.

Exclusion criteria

  • 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

Study Plan

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

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Standard Neurectomy (control)
Standard Neurectomy during amputation (control)
Procedure: Standard neurectomy
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.
Other: Targeted Muscle Reinnervation (intervention)
Targeted Muscle Reinnervation (TMR) during amputation (intervention)
Procedure: Targeted Muscle Reinnervation (TMR)
In short: each transected nerve is identified after amputation and is dissected proximally for length. A nerve stimulator is used to identify functional motor nerve branches. Near the point where the motor branch enters the muscle, the motor nerve branch is transected and an end-to-end coaptation is performed with a nearby amputated nerve.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
at 12 months
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.
at 12 months
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.
at 12 months
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
at 12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Postoperative residual limb pain
Time Frame: at 3, 6, and 9 months
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.
at 3, 6, and 9 months
Postoperative phantom limb pain
Time Frame: at 3, 6, and 9 months
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.
at 3, 6, and 9 months
Postoperative pain behavior
Time Frame: at 3, 6, and 9 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.
at 3, 6, and 9 months
Postoperative pain interference
Time Frame: at 3, 6, and 9 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
at 3, 6, and 9 months
Neuropathic pain
Time Frame: at 12 months
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
at 12 months
Hospital anxiety
Time Frame: at 12 months
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
at 12 months
Depression
Time Frame: at 12 months
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.
at 12 months
Global perceived effect
Time Frame: at 12 months
Using the Global Perceived effect (GPE-DV) questionnaire to evaluate the patients' view on recovery and satisfaction of the treatment.
at 12 months
Prosthetic rehabilitation
Time Frame: at 12 months
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.
at 12 months
EuroQol-5D-5L
Time Frame: at 2 weeks, and at 3, 6, 9 and 12 months
Quality of life using the EuroQol-5D-5L questionnaire. A higher score indicates worse quality of life.
at 2 weeks, and at 3, 6, 9 and 12 months
Medical consumption costs
Time Frame: at 3, 6, 9, and 12 months
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)
at 3, 6, 9, and 12 months
Productivity costs
Time Frame: at 3, 6, 9, and 12 months
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)
at 3, 6, 9, and 12 months
Budget impact analysis (BIA).
Time Frame: at 12 months
Budget impact analysis using the ZonMW BIA tool to estimate the financial impact of different implementation scenarios at the national level
at 12 months
Pain medication use
Time Frame: at 3, 6, 9, and 12 months
The Medication Quantification Scale measures the extent of pain medication use. A higher score indicates an increased use or dosage of pain medication.
at 3, 6, 9, and 12 months
Type of pain
Time Frame: at 3, 6, 9 and 12 months
Type of pain (local, diffuse, radiating) will be reported using the pain sketches from the Interdisciplinary Care for Amputees Network (ICAN).
at 3, 6, 9 and 12 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Surgical time
Time Frame: at 0 months
Surgical time measured in minutes
at 0 months
Length of hospital stay
Time Frame: at 0 months
Postoperative length of stay in the hospital
at 0 months
Adverse events
Time Frame: 30 days postoperative
i.e., infection, rebleed. Scored with the Clavien-Dindo score form 1 to 5. A higher score indicates a more severe complication.
30 days postoperative

Collaborators and Investigators

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

Sponsor

Leiden University Medical Center

Collaborators

UMC Utrecht
Erasmus Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Medical Center Haaglanden
ZonMw: The Netherlands Organisation for Health Research and Development
Isala
Alrijne Hospital

Investigators

  • Principal Investigator: Justus L Groen, MD PhD, Leiden University Medical Center

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

Helpful Links

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)

December 31, 2024

Primary Completion (Estimated)

January 1, 2028

Study Completion (Estimated)

January 1, 2028

Study Registration Dates

First Submitted

July 12, 2024

First Submitted That Met QC Criteria

December 2, 2024

First Posted (Actual)

December 5, 2024

Study Record Updates

Last Update Posted (Estimated)

September 19, 2025

Last Update Submitted That Met QC Criteria

September 15, 2025

Last Verified

September 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL87196.058.24

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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

IPD Sharing Time Frame

After completion of the study, the key file will be archived in the hospital's study documentation on a protected location on the network hard drive for 15 years in accordance with article 17 of the European good clinical practice directive.

IPD Sharing Access Criteria

Before acquiring the deidentified individual patient data used in the results of the published work related to this protocol (incl. tables, figures, supplementary files), researcher must sign a data sharing agreement. Data will made available to those who submit a reasonable request with a methodologically sound proposal.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

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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