Clinical trial NCT04026568: A Single Dose Pharmaco-Diagnostic for Peripheral Nerve Continuity After Trauma
Official title: A Single Dose Pharmaco-Diagnostic for Peripheral Nerve Continuity After Trauma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Nerve Injury
Keywords: Peripheral nerve trauma
laceration
blast injury
mangled limb
Lead sponsor: Milton S. Hershey Medical Center
Sponsor class: OTHER
First posted: 2019-07-19
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: The purpose of this study is to evaluate the role of 4-aminopyridine (4-AP) on the course of recovery after peripheral nerve traction and/or crush injury. The investigational treatment will be used to test the hypothesis that 4-aminopyridine speeds the often slow and unpredictable recovery after peripheral nerve traction and/or crush injuries.

Detailed description: This proposal contains two distinct aims to be investigated in two similar but distinct groups of patients.

Aim 1: To examine the mechanistic effect of 4AP on the return of sensorimotor function and EDX sensitivity in the setting of nerve dysfunction from orthopaedic trauma. This aim tests the hypothesis that oral one-time administration of 4AP provides transient return of function and EDX sensitivity to the traumatically denervated limb in alert patients with known limb injuries not involving the central nervous system.

Aim 2: To examine the mechanistic effect of 4AP on the return of sensorimotor function and EDX sensitivity in the setting of iatrogenic nerve injury after surgical intervention. This aim tests the identical hypothesis as in Aim 1 in a distinct group of patients, whose nerve dysfunction is the result of a clinical intervention, and whose function before that intervention was intact.

Scientific Background and Gaps

Neurological injury in the form of traction or crush to nerves that control muscles and sensory function is common. Because an understanding of these injuries is only now beginning to emerge, research on potential treatments is an important next step. Through experiments performed on animals with the Acorda Therapeutics, Inc. version of the drug (AMPYRA®), 4-aminopyridine (4-AP) has been strikingly effective in ameliorating the effect of a standardized peripheral nerve crush injury. The peripheral nerve injury used in the experiments was a standard model of peripheral nerve injury used to measure recovery in animals and is a model of peripheral nerve traction and crush injury that has been studied for over thirty years. The investigators have found that:

1. 4-AP administration in a single dose given on day three after the injury led to a drastic reduction in the dysfunction afforded by a crush injury just days after the crush itself.
2. 4-AP treatment's effect was short-lived after a single dose and was, in effect, diagnostic of the potential to recover in a nerve that was crushed but not shattered.
3. Severed nerves show no capacity to recover even with 4-AP treatment.
4. The treatment in a daily regimen led to profound, lasting, permanent improvement in the speed of recovery in these animals.

4-AP is used in some of the most fragile of neurologically-ailing patients and is currently a mainline treatment in the setting of multiple sclerosis (1). Multiple sclerosis patients suffer a demyelinating disorder that causes the stripping of the myelin sheath from around neurons in the peripheral and central nervous system. The myelin covering allows for normal conduction of impulses and, without such covering, impulses are small, impaired, impeded, and ineffective. The recognition that crush injuries to nerves do not simply sever the axonal fibers but also demyelinate some population of nerve cells has led to the idea to study the treatment of peripheral nerve traumatic injuries in humans using 4-AP.

Previous Data

4-AP has been studied in humans since the early 1980s, and principles of safe usage are extremely well established. For the purposes of this proposal, the immediate release formulation of 4-AP, sometimes called fampridine will be referred to as IR 4-AP. The proposed version of the drug used in this study is an extended release formulation of 4-AP, called dalfampridine, which was marketed under the trade name AMPYRA, by Acorda Therapeutics. Recently, this extended release formulation has become available as a generic, which will be referred to as generic AMPYRA or dalfampridine. Essentially identical principles apply whether 4-AP is provided in an orally available immediate release formulation (IR 4-AP) or an orally available sustained release formulation (dalfampridine). The safety of 4-AP appears to be determined solely by serum levels.

It has long been recognized that the most significant safety concern regarding 4-AP is an increased frequency in seizures, which occurs in a small percentage of patients if serum levels exceed 100 ng/ml. Therefore, dosages are chosen to maintain serum levels that do not exceed 50-60ng/ml. In this proposal, 5mg of study drug will be administered once every six hours, for a total dosage per day of 20 mg. This total dose, as indicated by multiple previous studies on immediate release 4-AP, has an excellent safety profile even in the fragile population of patients with multiple sclerosis. A sustained release formulation of 4-AP (AMPYRA®) at this same dose is FDA approved for use in the multiple sclerosis population even with a known risk of seizure activity in these patients.

It is important to note that multiple studies on 4-AP also include patients with chronic stroke, chronic spinal cord injury, transverse myelitis, primary lateral sclerosis, Lambert-Eaton myasthenic syndrome, ocular nystagmus, nonarteritic anterior ischemic optic neuropathy, spinal muscular atrophy, chronic Guillain-Barre syndrome, episodic ataxia Type 2, obstructive sleep apnea and spinocerebellar ataxias. Over 45 clinical trials have been conducted in the US alone (as listed on the Clinicaltrials.gov website). There are also 49 primary publications on clinical trials outcomes on 4-AP, which include patients with multiple sclerosis, chronic spinal cord injury, spinocerebellar ataxias and chronic stroke.

The many trials on 4-AP have been conducted using both immediate release 4-AP and sustained release 4-AP. The difference between the immediate release and sustained release formulations are that the sustained release formulation helps to decrease the peaks and troughs in serum levels that can occur with larger doses of immediate release formulations.

The Study Rationale is to evaluate the role of 4-aminopyridine (4AP) on the diagnosis of complete (severed) vs incomplete (non-severed) peripheral nerve injury (PNI). The investigational treatment will be used to test the hypothesis that 4AP allows the identification of incomplete injuries earlier than standard electrodiagnostic (EDX) and clinical assessment.

Eligibility criteria: Inclusion Criteria:

* Patients with trauma involving two or less limbs where the continuity of a given peripheral nerve or nerves is unclear on presenting physical examination.
* Closed soft tissue envelope obscuring direct observation of the continuity of the affected nerve.
* Cognitive ability to report sensory and motor deficit during examination.
* Able to complete dosing within four days (96 hours) of nerve injury diagnosis.
* Able to provide informed consent
* Eligible for standard of care plan of monitoring vs surgical exploration of the nerve.
* Adults subject aged 18-90
* Known limb trauma which resulted in nerve injury (aim 1) or post-operative/post intervention nerve injury (aim 2).
* Ability to give written informed consent.
* Capable of safely undergoing electrodiagnostic testing (EDX).
* Availability for all testing days and main trial day.

Exclusion Criteria:

* Not able to complete dosing within four days (96 hours) of nerve injury diagnosis
* Distracting injury which prevents adequate examination.
* Plan for surgical exploration of the nerve during the ensuing 48 hours.
* Plan for surgical exploration of the nerve as part of another surgical procedure within 48 hours of evaluation.
* Intoxication during examination or evidence of cognitive deficit that emerges during examination.
* History of multiple sclerosis, stroke or any other diagnosed neurological disorder
* History of hypersensitivity to AMPYRA® or 4-aminopyridine
* Renal impairment based on calculated GFR (GFR\<80 mL/min) This laboratory value is measured in all inpatient trauma patients as part of the standard of care.
* History of difficult compliance with timely follow up or plan to seek care at another institution closer to home.
* Patients outside the age range or unable to consent.
* Patients with a known history of a seizure disorder (4AP overdose can, in selected cases, result in limited seizure activity).
* Patients with a concomitant traumatic brain injury.
* Patients unable to communicate return or loss of sensation.
* Patients unable to exhibit motor control on the affected limb at baseline.
* Patients unwilling to complete the study requirements.
* Patients with injuries too extensive to isolate a single nerve(s) for testing.
* Pregnancy, breastfeeding or incarcerated individuals.
* Patients currently taking organic cat-ion transporter 2 (OCT2) inhibitors, eg. Cimetidine.

Primary outcomes:
measure: Subjective Return of Sensation
timeFrame: During dosing of drug intervention (5 hours) and 2, 6, 9, 12, 15, 20 weeks post injury
Secondary outcomes:
Other outcomes:
Locations:
city: Hershey
country: United States
facility: MS Hershey Medical Center
state: Pennsylvania
Study officials:
affiliation: Milton S. Hershey Medical Center
name: John C Elfar, MD
role: PRINCIPAL_INVESTIGATOR
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