Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT04204668 |
| Other study ID # |
IRB00235936 |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 1, 2021 |
| Est. completion date |
April 1, 2028 |
Study information
| Verified date |
May 2024 |
| Source |
Johns Hopkins University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Amputees often suffer from relentless pain and disability resulting from symptomatic neuromas
within the amputation stumps. When conservative measures fail to address these symptoms, two
contemporary surgical approaches to treat symptomatic neuromas have become the most popular.
Targeted muscle reinnervation (TMR) is a procedure which involves transferring the injured
proximal nerve stump into a terminal nerve branch entering muscle, such that the axons from
the proximal nerve stump will regenerate into the muscle and thereby prevent neuroma
recurrence. Regenerative peripheral nerve interfaces (RPNIs) are muscle grafts placed on the
proximal nerve stumps that serve as targets for the regenerating axons from the proximal
nerve stumps.
While TMR and RPNIs have demonstrated promise for the treatment of symptomatic neuromas,
prospective comparative data comparing outcomes with these two approaches is lacking.
The investigators have recently developed a novel approach to treat symptomatic neuromas that
provides vascularized, denervated muscle targets (VDMTs) for the axons regenerating from the
severed proximal nerve stump to reinnervate. This is accomplished by islandizing a segment of
muscle on its blood supply and ensuring complete denervation prior to implanting the
neighboring transected nerve stump into this muscle. VDMTs offer theoretical benefits in
comparison to RPNIs and TMR that the investigators also aim to test in the proposed study.
The investigators' objective is to enroll amputees with symptomatic neuromas into a
prospective study in which amputees will be randomized to undergo TMR, RPNI, or VDMT and
subsequently monitored for pain and disability for 1-year post-operatively. The
investigators' specific aims are as follows: 1) Test the hypothesis that VDMTs are more
effective than TMR and RPNIs with regards to treating pain and disability associated with
symptomatic neuromas; 2) Provide the first level one, prospective data directly comparing the
efficacy of TMR and RPNIs.
Description:
Extremity amputations are common operations both in the United States and other areas of the
world. It is estimated that there are nearly 2 million adults living in the United States
alone. Etiologies for extremity amputation are diverse but the most common indications
include complications of type 2 diabetes, non-diabetic peripheral vascular disease, trauma,
and oncologic conditions. Given the increasing prevalence of several of these pathologies,
conservative estimates suggest that the population of people living with an amputated limb
will likely double within the next several decades.
Patients who undergo limb amputation are at significant risk of developing chronic
neuropathic pain as a result of symptomatic neuroma formation, due in large part to the
abundance of sizeable nerves within the extremities that are necessarily transected as part
of the procedure. There are two distinct forms of pain experienced by patients who have
undergone major extremity amputations. Residual limb pain is the more straightforward form of
post-amputation pain attributable to neuroma formation within the amputation stump. Following
peripheral nerve transection, axons regenerating from the proximal stump tend to form
aggregates of disorganized neural growth called neuromas. Some neuromas will produce severe,
intractable pain causing significant impairment in prosthetic fit and function, activities of
daily living, and quality of life. Some estimates place the prevalence of residual limb pain
attributable to neuroma formation as high as 75%. The other form of pain is known as phantom
limb pain. While the underpinnings of phantom limb pain are the subject of ongoing debate, it
is thought by many to arise from chronic stimulation of the cerebral cortex with painful
inputs from peripheral neuromas, leading to unpredictable and poorly characterized
reorganization of the cortex. Informed estimates of phantom limb pain prevalence as high as
85% have been reported. Successful prevention and treatment of symptomatic neuromas in the
setting of limb amputation is therefore of paramount importance given the central role in the
pathogenesis of chronic post-amputation limb pain encompassing both residual limb pain and
phantom limb pain.
Treatment options for chronic post amputation pain caused by symptomatic neuromas are
diverse. Medical options for both phantom limb pain and residual limb pain have been met with
limited success. Despite the widespread use, the utility of neuromodulating medications, such
as gabapentin, has been called into question by recent large scale meta-analyses that failed
to demonstrate meaningful improvements. Neurotoxins, such as botulinum toxin, have also been
studied and found to offer limited, if any, pain resolution.
One of the most commonly used surgical approaches to treat and prevent symptomatic neuromas
involves burying the proximal nerve stump into nearby muscle. There is a widely-held
misconception that burying a proximal nerve stump into muscle will prevent a neuroma from
forming. However, elegant animal studies have proven that regeneration of a neuroma is
virtually guaranteed because innervated muscle will not accept additional innervation from
regenerating neurons.
In the past decade, two other surgical treatments for chronic post-amputation limb pain have
come into vogue. Targeted muscle reinnervation (TMR) was initially pioneered as a means of
providing intuitive control of advanced prostheses and only later observed to reduce neuroma
pain. TMR involves transferring the proximal nerve stump of the injured nerve into a nearby
distal motor branch. Early results are promising. A recently published randomized, controlled
trial demonstrated the superiority of the TMR approach over the 'bury in muscle' approach, so
much so that the trial concluded prematurely due to the superiority of the TMR compared to
the historical technique.
The other recently developed and widely popularized option for surgical treatment of chronic
post-amputation limb pain involves creation of a regenerative peripheral nerve interface
(RPNI). Similar to TMR, the RPNI was initially conceived as a method to provide an interface
with an advanced neuroprosthetic prior to being employed as a treatment strategy for
neuromas. RPNIs are muscle grafts that are coapted to the ends of severed proximal nerve
stumps. This technique has gained popularity because of its technical simplicity and
promising early clinical data. In contrast to the 'bury in muscle' approach, RPNIs are
denervated at the time of harvest and have been shown to accept reinnervation via direct
neurotization from the proximal nerve stump.
To address possible limitations of the strategies described above, the investigators propose
using muscle targets similar to RPNIs but maintaining vascularity - a vascularized,
denervated muscle target (VDMT). This is accomplished by raising a portion of muscle on a
vascular leash in proximity to the transected nerve. Perforating branches from larger blood
vessels that perfuse adjacent muscle can be found in abundance throughout the extremities.
Any nerves traveling with the vascular leashes will be divided to ensure complete denervation
of the muscle. Therefore, VDMTs will be receptive to reinnervation from the implanted
proximal nerve stump, maintain vascularity such that the VDMTs can be large enough to supply
an abundance of sensory receptors (spindle cells, Golgi apparati, etc) to accept regenerating
axons, and avoid the use of a nerve coaptation. In short, the VDMT offers possible
enhancements to the surgical techniques currently in use.
In terms of surgical outcomes, there is a robust body of data surrounding the TMR and RPNI
operations, with some more recent reports providing pre- and post-operative pain scores for
the individual operations. With the exception of one study that prospectively compared TMR to
the historical gold standard of neuroma excision and implantation into surrounding tissue,
there is a startling lack of prospective data on pain outcomes. Furthermore, the
investigators are not aware of prospective, head-to-head comparative data for RPNI vs TMR.
Robust, prospective, comparative data is now needed to validate the VDMT approach and assess
its efficacy in comparison to the other established techniques.
It is of prime importance to surgeons who perform extremity amputations (eg orthopedic
surgeons, vascular surgeons, trauma surgeons, plastic surgeons, and podiatrists) as well as
those who perform salvage procedures for post-amputation extremity pain to understand the
potential of these operations in treating this pain. Physicians are still lacking
evidence-based treatment guidelines. With the generation of this data, surgeons and patients
can make more informed decisions about which operative intervention provides the highest
likelihood of durable, significant pain relief.
