Clinical trial NCT06719245: Prevention of PostAmputation Pain with Targeted Muscle Reinnervation
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Amputation, Surgical
Phantom Limb Pain
Neuroma Amputation
Surgery
Keywords: TMR
Amputation
Phantom pain
Neuroma
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Alrijne Hospital
name: Medical Center Haaglanden
name: ZonMw: The Netherlands Organisation for Health Research and Development
name: UMC Utrecht
name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Erasmus Medical Center
name: Isala
First posted: 2024-12-05
Enrollment: 203
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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).

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.

Eligibility criteria: Inclusion Criteria:

* Patients scheduled for a lower extremity amputation (transfemoral to transtibial) as a primary or secondary sequela of vascular disease.

Exclusion Criteria:

* Less than 18 years of age
* Over 75 years of age
* Other reasons for amputation besides a primary or secondary sequela of vascular disease (i.e., traumatic or neoplasms)
* Insensate limbs at the level of amputation
* CRPS (Complex Regional Pain Syndrome)
* Existing neuroma or prior neuroma surgery in the affected limb
* Physiologically unstable patients at the time of amputation
* Cognitive impairment, delirium
* Undergoing radiotherapy on the affected limb
* Unfit for general anesthesia
* No nerve surgeon available to perform TMR

Primary outcomes:
measure: Postoperative residual limb pain
timeFrame: at 12 months
measure: Postoperative phantom limb pain
timeFrame: at 12 months
measure: Postoperative pain behavior
timeFrame: at 12 months
measure: Postoperative pain interference
timeFrame: at 12 months
Secondary outcomes:
measure: Postoperative residual limb pain
timeFrame: at 3, 6, and 9 months
measure: Postoperative phantom limb pain
timeFrame: at 3, 6, and 9 months
measure: Postoperative pain behavior
timeFrame: at 3, 6, and 9 months
measure: Postoperative pain interference
timeFrame: at 3, 6, and 9 months
measure: Neuropathic pain
timeFrame: at 12 months
measure: Hospital anxiety
timeFrame: at 12 months
measure: Depression
timeFrame: at 12 months
measure: Global perceived effect
timeFrame: at 12 months
measure: Prosthetic rehabilitation
timeFrame: at 12 months
measure: EuroQol-5D-5L
timeFrame: at 2 weeks, and at 3, 6, 9 and 12 months
measure: Medical consumption costs
timeFrame: at 3, 6, 9, and 12 months
measure: Productivity costs
timeFrame: at 3, 6, 9, and 12 months
measure: Budget impact analysis (BIA).
timeFrame: at 12 months
measure: Pain medication use
timeFrame: at 3, 6, 9, and 12 months
measure: Type of pain
timeFrame: at 3, 6, 9 and 12 months
Other outcomes:
measure: Surgical time
timeFrame: at 0 months
measure: Length of hospital stay
timeFrame: at 0 months
measure: Adverse events
timeFrame: 30 days postoperative
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Center
state: North Holland
city: Zwolle
country: Netherlands
facility: Isala Zwolle
state: Overijssel
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
state: South Holland
city: Leiderdorp
country: Netherlands
facility: Alrijne Zorggroep
state: South Holland
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
state: South Holland
city: The Hague
country: Netherlands
facility: Haaglanden Medisch Centrum
state: South Holland
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: Leiden University Medical Center
name: Justus L Groen, MD PhD
role: PRINCIPAL_INVESTIGATOR
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