PEG Fusion for Peripheral Nerve Injury
Recruiting in Palo Alto (17 mi)
+6 other locations
Overseen byJaimie Shores, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Major Extremity Trauma Research Consortium
Disqualifiers: Brachial plexus injury, Psychiatric disorder, Allergy to PEG, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?The overall objective of this study is to determine the safety of PEG fusion when used with primary repair or reconstruction in patients with an acute upper extremity peripheral nerve injury. PEG is safe and effective for extending the half-life of circulating pharmaceutical products, when used in conjunction with a topical hemostatic agent in surgical wounds, and when used as a colon cleanser for endoscopic surgical procedures. However, PEG fusion has not been rigorously tested as a safe reagent to promote nerve regeneration in humans. Therefore, the goal of this Phase 2a clinical trial is to establish safety data and to examine the effect of PEG fusion on clinical outcomes including recovery of sensory and motor function. Results will be externally validated using data collected in the DoD funded prospective NERVE study and will provide preliminary evidence to power a larger phase II efficacy trial.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the treatment NTX-001, Polyethylene Glycol (PEG) Mediated Fusion, for peripheral nerve injury?
Research shows that PEG fusion can rapidly restore nerve function and improve recovery in animal models with nerve injuries. In cases of nerve damage, PEG fusion has been shown to quickly reestablish nerve connections and improve sensory and motor recovery, suggesting it could be a promising treatment for peripheral nerve injuries.
12345Is PEG Fusion safe for humans?
PEG Fusion has been used in animal studies and early human case reports for nerve repair, showing promising results in restoring nerve function. However, some patients experienced side effects like swelling and scar development, which improved over time. Overall, the safety data is limited but suggests potential for safe use with careful monitoring.
12356How is the PEG Fusion treatment different from other treatments for peripheral nerve injury?
PEG Fusion is unique because it rapidly restores axonal continuity and improves sensory and motor recovery by fusing severed nerve ends, unlike traditional methods that rely on slow axonal regrowth. This approach prevents muscle atrophy and Wallerian degeneration, leading to faster and more effective recovery.
12345Eligibility Criteria
This trial is for adults aged 18-80 with acute upper extremity peripheral nerve injuries, specifically to the axillary, radial, median, ulnar, or musculocutaneous nerves. Candidates must present within 48 hours of injury and have both sensory and motor function impairment. Exclusions include brachial plexus injuries, purely sensory nerve damage beyond the wrist, previous neurological disorders or trauma, severe psychiatric conditions that could affect follow-up compliance or pose a self-harm risk.Inclusion Criteria
I am between 18 and 80 years old.
My condition involves a nerve that affects both feeling and movement.
My condition affects a nerve that controls both feeling and movement.
+2 more
Exclusion Criteria
Severe problems with maintaining follow up (e.g., patients who are prisoners or homeless at time of injury or who are intellectually challenged without adequate family support)
My injury affects a nerve in my arm that mainly controls feeling or a specific movement.
I have a health condition that prevents me from having surgery right now.
+10 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
1-2 weeks
Treatment
Patients receive either PEG mediated reconstruction or conventional nerve reconstruction within 24 hours of injury
1 day
1 visit (in-person)
Initial Follow-up
Participants are monitored for complications or problems within the first 30 days post-surgery
4 weeks
2 visits (in-person)
Extended Follow-up
Participants are monitored for recovery of sensory and motor function, pain, range of motion, and patient satisfaction
Up to 2 years
Participant Groups
The study tests PEG fusion's safety in promoting nerve regeneration after an acute injury. Participants will undergo primary repair or reconstruction using PEG fusion to evaluate its effect on restoring sensory and motor functions. This Phase 2a trial aims to provide safety data and preliminary evidence for a larger efficacy trial.
2Treatment groups
Experimental Treatment
Active Control
Group I: PEG mediated reconstructionExperimental Treatment1 Intervention
NTX-001 will be administered topically via isolation chamber medical device. Dose Unit: 2.5 mL NTX-001 is a single use surgical product intended for use as adjunct treatment in the repair of severed peripheral nerves in patients requiring standard suture neurorrhaphy.
Group II: Conventional nerve reconstructionActive Control1 Intervention
Conventional nerve reconstruction
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Walter Reed National Military Medical CenterBethesda, MD
OrthoCarolinaCharlotte, NC
Wellspan HealthYork, PA
Johns Hopkins University School of MedicineBaltimore, MD
More Trial Locations
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Who Is Running the Clinical Trial?
Major Extremity Trauma Research ConsortiumLead Sponsor
United States Department of DefenseCollaborator
References
Analysis of polyethylene glycol (PEG) fusion in cultured neuroblastoma cells via flow cytometry: Techniques & optimization. [2018]Polyethylene glycol (PEG) has long been used as a membrane fusogen, but recently it has been adopted as a technique for peripheral nerve repair. Vertebrate models using PEG fusion have shown improved outcomes when PEG is applied during repair of severed peripheral nerves. The cellular mechanism of PEG fusion in the peripheral nerve repair model has not previously been assessed via flow cytometry. PEG fusion was assessed in this experiment by dying B35 rat neuroblastoma cells with different color fluorescent labels. The different color cells were combined and PEG was applied in concentrations of 50%, 75% and 100%. The amount of cell fusion was assessed via flow cytometry as the percentage of double positive cells. Results showed increasing fusion and decreasing viability with increasing concentrations of PEG.
Polyethylene Glycol Fusion Restores Axonal Continuity and Improves Return of Function in a Rat Median Nerve Denervation Model. [2023]Polyethylene glycol (PEG) can fuse severed closely-apposed axolemmas and restore axonal continuity. We evaluated the effects of PEG-fusion on functional recovery in a rodent forelimb model of peripheral nerve injury.
Rapid and effective fusion repair of severed digital nerves using neurorrhaphy and bioengineered solutions including polyethylene glycol: A case report. [2023]Peripheral nerve injuries (PNIs) that consist of simple nerve severance often result in severe motor impairment and permanent loss of function. Such patients face significant costs and pose major burdens to healthcare systems. Currently, the most promising surgical technique to achieve the best clinical outcome after such PNIs is immediate primary coaptation of severed nerve ends by microsutures (neurorrhaphy). However, recovery is often poor and delayed for many months due to Wallerian degeneration (WD) and slow (1-2 mm/day) axonal outgrowths from severed proximal axons that may not properly reinnervate denervated afferent/efferent targets that have atrophied. In contrast, recent pre-clinical studies using polyethylene glycol (PEG) to facilitate primary nerve repair have greatly improved the rate and extent of sensory and motor recovery and prevented much WD and muscle atrophy. That is, PEG-fused axons rapidly establish proximal-distal axoplasmic/axolemmal continuity, which do not undergo WD and maintain the structure and function of neuromuscular junction (NMJ). PEG-fused axons rapidly reinnervate denervated NMJs, thereby preventing muscle atrophy associated with monthslong denervation due to slowly regenerating axonal outgrowths. We now describe PEG-mediated fusion repair of a digital nerve in each of two patients presenting with a digital laceration resulting in total loss of sensation. The first patient's tactile perception improved markedly at 3 days postoperatively (PO). Two-point discrimination improved from greater than 10 mm at initial presentation to 4 mm at 11-week PO, and the Semmes-Weinstein monofilament score improved from greater than 6.65 to 2.83 mm, a near-normal level. The second patient had severe PO edema and scar development requiring a hand compression glove and scar massage, which began improving at 11-week PO. The sensory function then improved for 4 months PO, with both two-point discrimination and Semmes-Weinstein scores approaching near-normal levels at the final follow-up. These case study data are consistent with data from animal models. All these data suggest that PEG-fusion technologies could produce a paradigm shift from the current clinical practice of waiting days to months to repair ablation PNIs with autografts, anucleated nerve allografts, or conduits in which the patient outcome is solely dependent upon axon regeneration over months or years.
Polyethylene glycol rapidly restores axonal integrity and improves the rate of motor behavior recovery after sciatic nerve crush injury. [2018]The inability to rapidly (within minutes to hours) improve behavioral function after severance of peripheral nervous system axons is an ongoing clinical problem. We have previously reported that polyethylene glycol (PEG) can rapidly restore axonal integrity (PEG-fusion) between proximal and distal segments of cut- and crush-severed rat axons in vitro and in vivo. We now report that PEG-fusion not only reestablishes the integrity of crush-severed rat sciatic axons as measured by the restored conduction of compound action potentials (CAPs) and the intraaxonal diffusion of fluorescent dye across the lesion site, but also produces more rapid recovery of appropriate hindlimb motor behaviors. Improvement in recovery occurred during the first few postoperative weeks for the foot fault (FF) asymmetry test and between week 2 and week 3 for the Sciatic Functional Index (SFI) based on analysis of footprints. That is, the FF test was the more sensitive indicator of early behavioral recovery, showing significant postoperative improvement of motor behavior in PEG-treated animals at 24-48 h. In contrast, the SFI more sensitively measured longer-term postoperative behavioral recovery and deficits at 4-8 wk, perhaps reflecting the development of fine (distal) motor control. These and other data show that PEG-fusion not only rapidly restores physiological and morphological axonal continuity, but also more quickly improves behavioral recovery.
Effects of extracellular calcium and surgical techniques on restoration of axonal continuity by polyethylene glycol fusion following complete cut or crush severance of rat sciatic nerves. [2019]Complete crush or cut severance of sciatic nerve axons in rats and other mammals produces immediate loss of axonal continuity. Loss of locomotor functions subserved by those axons is restored only after months, if ever, by outgrowths regenerating at ∼1 mm/day from the proximal stumps of severed axonal segments. The distal stump of a severed axon typically begins to degenerate in 1-3 days. We recently developed a polyethylene glycol (PEG) fusion technology, consisting of sequential exposure of severed axonal ends to hypotonic Ca(2+) -free saline, methylene blue, PEG in distilled water, and finally Ca(2+) -containing isotonic saline. This study examines factors that affect the PEG fusion restoration of axonal continuity within minutes, as measured by conduction of action potentials and diffusion of an intracellular fluorescent dye across the lesion site of rat sciatic nerves completely cut or crush severed in the midthigh. Also examined are factors that affect the longer-term PEG fusion restoration of lost behavioral functions within days to weeks, as measured by the sciatic functional index. We report that exposure of cut-severed axonal ends to Ca(2+) -containing saline prior to PEG fusion and stretch/tension of proximal or distal axonal segments of cut-severed axons decrease PEG fusion success. Conversely, trimming cut-severed ends in Ca(2+) -free saline just prior to PEG fusion increases PEG fusion success. PEG fusion prevents or retards the Wallerian degeneration of cut-severed axons, as assessed by measures of axon diameter and G ratio. PEG fusion may produce a paradigm shift in the treatment of peripheral nerve injuries. © 2016 Wiley Periodicals, Inc.
Conundrums and confusions regarding how polyethylene glycol-fusion produces excellent behavioral recovery after peripheral nerve injuries. [2020]Current Neuroscience dogma holds that transections or ablations of a segment of peripheral nerves produce: (1) Immediate loss of axonal continuity, sensory signaling, and motor control; (2) Wallerian rapid (1-3 days) degeneration of severed distal axons, muscle atrophy, and poor behavioral recovery after many months (if ever, after ablations) by slowly-regenerating (1 mm/d), proximal-stump outgrowths that must specifically reinnervate denervated targets; (3) Poor acceptance of microsutured nerve allografts, even if tissue-matched and immune-suppressed. Repair of transections/ablations by neurorrhaphy and well-specified-sequences of PEG-fusion solutions (one containing polyethylene glycol, PEG) successfully address these problems. However, conundrums and confusions regarding unorthodox and dramatic results of PEG-fusion repair in animal model systems often lead to misunderstandings. For example, (1) Axonal continuity and signaling is re-established within minutes by non-specifically PEG-fusing (connecting) severed motor and sensory axons across each lesion site, but remarkable behavioral recovery to near-unoperated levels takes several weeks; (2) Many distal stumps of inappropriately-reconnected, PEG-fused axons do not ever (Wallerian) degenerate and continuously innervate muscle fibers that undergo much less atrophy than otherwise-denervated muscle fibers; (3) Host rats do not reject PEG-fused donor nerve allografts in a non-immuno-privileged environment with no tissue matching or immunosuppression; (4) PEG fuses apposed open axonal ends or seals each shut (thereby preventing PEG-fusion), depending on the experimental protocol; (5) PEG-fusion protocols produce similar results in animal model systems and early human case studies. Hence, iconoclastic PEG-fusion data appropriately understood might provoke a re-thinking of some Neuroscience dogma and a paradigm shift in clinical treatment of peripheral nerve injuries.