An Approved Protocol to Evaluate 4-Aminopyridine (4-AP) for use as a Single-Dose Diagnostic Agent to Diagnose Peripheral Nerve Continuity in Humans
John C Elfar, MD, FACS, The Pennsylvania State University, Hershey, PA and M A Hassan Talukder, MBBS, PhD, The Pennsylvania State University College of Medicine, Hershey, PA
Introduction:Traumatic peripheral nerve injury (TPNI) presents particular diagnostic dilemmas to the treating surgeon. There is no adequate manner to distinguish nerve injuries where the nerve is intact but not functioning from injuries which completely sever the nerve. Current state of the art in diagnosis of this critical matter is left to electrodiagnostic studies which are not sensitive for weeks after the injury. We have found that 4-aminopyridine dosing can allow this distinction in multiple animal species with TPNI. There is an unmet need for a diagnostic tool which could address these issues for early diagnosis and subsequent treatment strategies.
Materials and Methods: 4-aminopyridine (4-AP) is a FDA-approved generic drug for symptomatic treatment of multiple sclerosis. We sought approval of an Investigational New Drug Application (IND) from the United States Food and Drug Administration to investigate 4-AP as a single dose diagnostic agent, based largely on our murine model data. We received approval to proceed with a formal trial in our center in 2019.
Trial Design: We propose a randomized crossover trial to test single dose 4AP (vs placebo) during a time when patients have nerve dysfunction after TPNI in two distinct problem subpopulations: Patients who present to the hospital with nerve injuries sustained in trauma and patients who sustain TPNI as a result of surgical intervention.The first key question we aim to answer: Is early distinction between severed nerves and non-severed non functional nerves possible?Any trial of a novel method of early diagnosis of nerve continuity should test the viability of the test relative to the current gold standard, which in this case is either surgical exploration or EDX studies at 6-10 weeks. Our second key question is to compare the classification of nerve injury in response to single dose 4AP to EDX studies at 6 and 12 weeks. The trial takes two groups of patients (post traumatic and post-surgical nerve dysfunction) in which nerve continuity is unknown and endeavors to effectively separate both groups into continuous and non-continuous nerve injuries. Every patient is exposed to both 4AP and placebo without any deviation from the current standard of care.
Conclusion:We present for discussion, what is believed to be the first investigator-initiated FDA IND approved trial of a single agent diagnostic for nerve continuity. Discussion of the ramifications and possible modifications of the plans for this trial is encouraged.
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