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symptomatic neuroma is excised, and the end of the peripheral nerve is implanted into a small denervated free muscle graft harvested from the patient

Surgeons will perform neuroma resection and RPNI creation using a free muscle graft from the brachioradialis muscle harvested through a small separate incision

Regenerative Peripheral Nerve Interface (RPNI) surgery

Surgeons will perform neuroma resection and traction neurectomy,

Traction Neurectomy

Isaac C Fleming

Ike Fleming

Alessandra Butanis

Aviram M Gildai, MD, MS

Jenni Hammill, M.P.H

Theodore A Kung, MD

Aviram M Giladi, MS, MD

This study is being done to demonstrate the effectiveness of Regenerative Peripheral Nerve Interfaces (RPNI) surgery in treating symptomatic neuromas of the hand and digits following amputation compared to standard of care using a Prospective, Observational Trial

This will be a prospective observational study that seeks to provide a comprehensive assessment of the outcomes after RPNI surgery compared to standard of care by utilizing multiple established and validated patient-reported outcomes measures, carefully tracking pre- and post-operative pain regimens, and performing functional and physiologic tests.

Regenerative Peripheral Nerve Interfaces to Treat Painful Digit and Hand Neuromas After Amputation

Regenerative Peripheral Nerve Interfaces to Treat Painful Digit and Hand Neuromas After Amputation: A Prospective Observational Trial"

PROMIS Pain Interference (PROMIS-PI) scale measures the extent to which pain hinders an individual's engagement with physical, mental, cognitive, emotional, recreational, and social activities over the past 7 days answering each questions with a response of not at all, a little bit, somewhat, quite a bit, and very much with not at all being the best and very much the worst.

theShort-form McGill Pain Questionnaire (SF-MPQ-2) measures 24 different qualities of pain and related symptoms using the intensity of pain and related symptoms felt during the past week on 0 to 10 scale, with 0 being no pain and 10 being the worst pain .

The Global Health Questionnaire contains 10 questions (7 general and 3 about the last 7 days). First 7 questions use a scale of excellent, very good, good, fair, and poor, poor being the worst with excellent being the best. The other three questions use different scales such as; never rarely, sometimes, often or always with never being the best and always being the worst; as well as none, mild, moderate, severe, very severe with none being the best and very severe being the worst; finally pain rating numbered 0-10 with 0 being no pain and 10 being the worst pain imaginable.

The PHQ-9 form is a brief, self-administered questionnaire that assesses depression symptoms over the last 2 weeks consisting of 10 questions. 9 will be answered on a scale of 0-3 with 0 being the best and 3 bing the worst. The last question will use a response of not difficult at all, somewhat difficult, very difficult, and extremely difficult with not difficult at all being the best and extremely difficult being the worst.

Generalized Anxiety Disorder measure (GAD-7) is a screening tool and severity measure for generalised anxiety disorder (GAD) over the past 2 weeks consisting of 7 questions answered on a scale of 0-3 with 0 being the best and 3 being the worst.

The Primary Care PTSD Screen for DSM-5 (PC-PTSD-5) is a 5-item screening tool with 'Yes/No" answers designed to identify individuals with probable PTSD. Yes" answers represent the worst and "no" represents the best.

PROMIS UpperExtremity (UE) is designed to evaluate upper extremity function using a scale of 1-5 with 5 being the best possible answer and 1 being the worst.

The Brief Michigan Hand Outcomes Questionnaire (bMHQ) evaluates six upper extremity domains of function, activities of daily living(ADLs), aesthetics, performance,pain,and satisfaction using a scale of 1-5 with 5 being the best possible answer and 1 being the worst.

A standard dynamometer will be used to evaluate grip strength

Evaluate key pinch (thumb to radial border of index) and three-point pinch (index, middle, and thumb tips) strength.

Evaluate active and passive range of motion of all joints in the affected extremity proximal to the amputation stump, total active and passive range of motion of all unaffected digits on the ipsilateral hand, and total active motion of fall digits and wrist on the contralateral hand as an internal control

Evaluate timed exercise during which nine relatively small pegs are picked up, one at a time, and put into nine corresponding holes. The pegs are then removed from the holes (one at a time) and placed back in the starting bin.

Evaluate whether the participant is able to perform the task, grip that was used, maximum weight used, and any compensatory findings. Subjects will be asked their pain level during each lift using a 10-point numerical scale

Evaluate tolerance for vibration and grip to perform a hammer task using

Evaluate vice grip Strength with all available digits using the Baltimore Therapeutic Equipment (BTE) PrimusRS work simulator.

Evaluate ability to grip, push and pull gear shift with all available digits using the Baltimore Therapeutic Equipment (BTE) PrimusRS work simulator

Evaluate the ability to preform this simulated task using the Baltimore Therapeutic Equipment (BTE) PrimusRS work simulator

United States Department of Defense

University of Michigan

Medstar Health Research Institute

Central Nervous System Depressants

All Drugs and Chemicals

Anesthetics

Patients will be randomized to either the current standard of care surgical treatment for neuromas (traction neurectomy) or the experimental intervention (targeted reinnervation). This arm involves the use of the current standard of care surgical treatment.

Patients will undergo the same pre-operative evaluation, anesthesia, and dissection to identify the painful residual limb neuroma(s). In the active comparator arm, gentle traction will be applied to the nerve while excising the neuroma (traction neurectomy) allowing the nerve to retract more proximally. It may be buried in healthy muscle to further pad the nerve ending. The intention is to place the inevitable recurrent end-neuroma away from superficial locations in which it is likely to become mechanically irritated.

Patients will be randomized to either the current standard of care surgical treatment for neuromas (traction neurectomy) or the experimental intervention (targeted reinnervation). This arm involves the use of the experimental surgical treatment.

Patients will undergo the same pre-operative evaluation, anesthesia, and dissection to identify the painful residual limb neuroma(s). Targeted muscle reinnervation involves transfer of residual nerves to otherwise redundant target muscles. Native motor innervation of the target muscle is cut, and the residual nerves-after excision of end-neuromas-are coapted to the motor end point of the motor nerve, close to its point of entry into the muscle.

Targeted Muscle Reinnervation

Subjects are being asked to participate in this study because they have an arm or leg amputation and have developed pain related to a neuroma (an ongoing localized pain related to a cut nerve ending).

We are studying two different types of surgery to treat the neuroma pain. Today there are many surgical options reported which often means that there is no one best treatment. The surgery that shows the best success so far, involves cutting out the scarred nerve ending (neuroma) and burying the freshly cut nerve ending in a nearby muscle. Recently, a new surgery has been developed called targeted reinnervation (TR). This surgery connects these cut nerve endings to nerves going into nearby nonfunctional muscles. This surgery was developed to allow amputees to have better prosthesis control. By chance, neuroma pain improved significantly with TR. We, therefore, are conducting this clinical trial to evaluate which of these two surgeries best treats neuroma pain. We will ask all participants to fill out a questionnaire both before and after surgery. This will help us understand how a neuroma affects the quality of life of amputees and will allow us to understand which surgery leads to the best improvement in neuroma pain.

In order to confirm the presence and location of the neuroma before surgery, a magnetic resonance image (MRI) will be performed. Taking these pictures requires subjects to lie still for a short period of time but does not involve any invasive procedures. After surgery, the MRI will be done again, this time to see if the nerve shows signs of scarring.

Loss of an arm or leg is a significant injury that affects a person's job prospects, personal relationships, and overall quality of life. Approximately 25% of all amputees will develop chronic local pain in the remaining part of their amputated limb. This pain is caused by neuromas- disorganized nerve endings and scar tissue that form when an injured nerve tries to heal. Every cut nerve will develop a neuroma unless the two ends of the nerve can be rejoined. With limb amputation, the nerves are cut and one end is lost with the limb, preventing the nerve from repairing itself. Instead, the cut nerve ending forms a painful neuroma. Chronic pain from neuromas is a major reason that amputees cannot wear or use their prostheses comfortably and increases their disability. The current standard surgical treatment for a neuroma is to cut if off and bury the nerve ending in a muscle, to provide cushioning when the neuroma grows back. Even though this is the best current treatment, it is not always successful.

Even when a limb is amputated, the nerves that used to control that limb still carry messages from the brain. Those messages are intended to tell the muscles how or when to move the missing limb, but after amputation, these limb-control nerves are no longer connected to muscles. In 2002, researchers at Northwestern Memorial Hospital in conjunction with the Rehabilitation Institute of Chicago developed a new type of surgery called targeted muscle reinnervation (TMR). In TMR, limb-control nerves are transferred so that they can control new target muscles. The neuromas from the limb-control nerves are removed, then the small nerve that controls the target muscle is cut. The two nerves are joined together so that the limb-control nerve can then grow into, or reinnervate the target muscle. After TMR, when the person tries to move the missing limb, the target muscle contracts instead and these signals can be detected and used to control a prosthesis. TMR has now been done successfully almost 100 times worldwide. Interestingly, almost all of the patients who had painful neuromas before TMR had no neuroma pain after surgery. This result was investigated in laboratory studies - both rat and rabbit amputee neuromas were "cured" with TMR. We think that giving the cut nerve endings somewhere to go and something to do prevents a neuroma from forming.

We plan to compare TMR versus the current standard surgical treatment for painful neuromas. We will measure the effectiveness of both surgeries using an internet-based amputee pain questionnaire. We will also use magnetic resolution imaging (MRI) to look at the nerves before and after surgery. We have received a grant to complete a 4 year study in four hospitals across the US, in around 200 patients, making this the largest neuroma study ever performed. We expect that TMR will be significantly more effective for neuroma pain than the standard treatment. This will change how patients with neuroma pain are treated and help thousands of patients with amputations.

Targeted Reinnervation as a Means to Treat Neuromas Associated With Major Limb Amputation

Difference in patient-reported pain scores before and after surgical treatment using the online survey tool.

Compare patient-reported pre-operative survey results to those after surgical intervention at intervals over time (1 month, 3 months,6 months, 9 months,1 year, and then every six months thereafter until the conclusion of the study).

Using the same PROMIS platform, general health, physical functioning (including functional prosthesis wear), and satisfaction following surgery will also be assessed as important secondary outcomes, resulting in a more comprehensive and objective understanding of the effects of the two surgical approaches on neuroma pain.

Another particularly useful tool for this study is the Orthotics and Prosthetics User Survey (OPUS) Functional Status. The OPUS is a validated instrument that assesses how well patients are using their prostheses. Thus, we will examine a very important secondary measure of neuroma pain-the ability to use a prosthesis. Prosthesis use is often the primary problem for individuals with painful neuromas; they hurt most during walking with a prosthesis or when wearing a prosthetic arm. Thus we expect OPUS to be a useful additional measure for quantifying the outcomes of the two types of neuroma surgeries

In our study, pre- and post-operative neuroma size (at one year) will be quantified using MRI scans. Pre-operative MRI measurements will be compared to the removed neuroma specimen to verify the accuracy of the modality. Post-operative MRI measurements will be used to assess whether a neuroma recurred at the site of the surgery and to determine the size of any new lesion.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Regenerative Peripheral Nerve Interfaces to Treat Painful Digit and Hand Neuromas After Amputation	NCT05008185	Neuroma	Regenerative Pe... Traction Neurec...	18 Years -	Medstar Health Research Institute
Targeted Reinnervation as a Means to Treat Neuromas Associated With Major Limb Amputation	NCT02205385	Neuroma Neuroma Amputat... Pain	Targeted Muscle... Traction Neurec...	18 Years -	Northwestern University

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