A Single Dose Pharmaco-Diagnostic for Peripheral Nerve Continuity After Trauma

NCT04026568 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: STUDY00012040
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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.

Conditions

Nerve Injury

Keywords

Peripheral nerve trauma; laceration; blast injury; mangled limb

Outcome Measures

Primary Outcomes (1)

• Subjective Return of Sensation

  Return of lost sensation after nerve injury attributable to circulating 4-AP. Subjective return of sensation in the injured limb or portion of the limb. Patients for this trial are not able to sense in portions of their limbs. The measure will be sensation, measured on the binary scale of yes or no (able to feel the extremity versus unable to feel) This is assessed through clinical examination of the injured limb.

  During dosing of drug intervention (5 hours) and 2, 6, 9, 12, 15, 20 weeks post injury

Study Arms (2)

Single dose 4AP

EXPERIMENTAL

15mm opaque capsule containing 10mg of 4-AP

Drug: 4-Aminopyridine

Placebo

PLACEBO COMPARATOR

Opaque capsule identical looking to the 4AP placebo pill

Drug: Placebo oral tablet

Interventions

4-Aminopyridine DRUG

Single drug test for nerve continuity

Also known as: oral dalfampridine

Single dose 4AP

Placebo oral tablet DRUG

Placebo arm

Also known as: Generic placebo

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Milton S. Hershey Medical Center: lead

Study Sites (1)

MS Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

Related Publications (28)

• Robinson LR. Role of neurophysiologic evaluation in diagnosis. J Am Acad Orthop Surg. 2000 May-Jun;8(3):190-9. doi: 10.5435/00124635-200005000-00006.

  PMID: 10874226 BACKGROUND

• Robinson LR. Traumatic injury to peripheral nerves. Muscle Nerve. 2000 Jun;23(6):863-73. doi: 10.1002/(sici)1097-4598(200006)23:63.0.co;2-0.

  PMID: 10842261 BACKGROUND

• Wilbourn AJ. The electrodiagnostic examination with peripheral nerve injuries. Clin Plast Surg. 2003 Apr;30(2):139-54. doi: 10.1016/s0094-1298(02)00099-8.

  PMID: 12737349 BACKGROUND

• Seddon HJ, Medawar PB, Smith H. Rate of regeneration of peripheral nerves in man. J Physiol. 1943 Sep 30;102(2):191-215. doi: 10.1113/jphysiol.1943.sp004027. No abstract available.

  PMID: 16991601 BACKGROUND

• SEDDON HJ. Nerve grafting. Ann R Coll Surg Engl. 1963 May;32(5):269-80. No abstract available.

  PMID: 13987582 BACKGROUND

• SUNDERLAND S, BRADLEY KC. Denervation atrophy of the distal stump of a severed nerve. J Comp Neurol. 1950 Dec;93(3):401-9. doi: 10.1002/cne.900930304. No abstract available.

  PMID: 14803568 BACKGROUND

• SUNDERLAND S. A classification of peripheral nerve injuries producing loss of function. Brain. 1951 Dec;74(4):491-516. doi: 10.1093/brain/74.4.491. No abstract available.

  PMID: 14895767 BACKGROUND

• Korompilias AV, Lykissas MG, Kostas-Agnantis IP, Vekris MD, Soucacos PN, Beris AE. Approach to radial nerve palsy caused by humerus shaft fracture: is primary exploration necessary? Injury. 2013 Mar;44(3):323-6. doi: 10.1016/j.injury.2013.01.004. Epub 2013 Jan 23.

  PMID: 23352153 BACKGROUND

• Niver GE, Ilyas AM. Management of radial nerve palsy following fractures of the humerus. Orthop Clin North Am. 2013 Jul;44(3):419-24, x. doi: 10.1016/j.ocl.2013.03.012. Epub 2013 Apr 24.

  PMID: 23827843 BACKGROUND

• Li Y, Ning G, Wu Q, Wu Q, Li Y, Feng S. Review of literature of radial nerve injuries associated with humeral fractures-an integrated management strategy. PLoS One. 2013 Nov 8;8(11):e78576. doi: 10.1371/journal.pone.0078576. eCollection 2013.

  PMID: 24250799 BACKGROUND

• Rocchi M, Tarallo L, Mugnai R, Adani R. Humerus shaft fracture complicated by radial nerve palsy: Is surgical exploration necessary? Musculoskelet Surg. 2016 Dec;100(Suppl 1):53-60. doi: 10.1007/s12306-016-0414-3. Epub 2016 Nov 30.

  PMID: 27900704 BACKGROUND

• Han SH, Hong IT, Lee HJ, Lee SJ, Kim U, Kim DW. Primary exploration for radial nerve palsy associated with unstable closed humeral shaft fracture. Ulus Travma Acil Cerrahi Derg. 2017 Sep;23(5):405-409. doi: 10.5505/tjtes.2017.26517.

  PMID: 29052827 BACKGROUND

• Chang G, Ilyas AM. Radial Nerve Palsy After Humeral Shaft Fractures: The Case for Early Exploration and a New Classification to Guide Treatment and Prognosis. Hand Clin. 2018 Feb;34(1):105-112. doi: 10.1016/j.hcl.2017.09.011.

  PMID: 29169591 BACKGROUND

• Perry JD. Electrodiagnosis in musculo-skeletal disease. Best Pract Res Clin Rheumatol. 2005 Jun;19(3):453-66. doi: 10.1016/j.berh.2005.01.007.

  PMID: 15939369 BACKGROUND

• Korte N, Schenk HC, Grothe C, Tipold A, Haastert-Talini K. Evaluation of periodic electrodiagnostic measurements to monitor motor recovery after different peripheral nerve lesions in the rat. Muscle Nerve. 2011 Jul;44(1):63-73. doi: 10.1002/mus.22023.

  PMID: 21674522 BACKGROUND

• Capacio BR, Byers CE, Matthews RL, Chang FC. A method for determining 4-aminopyridine in plasma: pharmacokinetics in anaesthetized guinea pigs after intravenous administration. Biomed Chromatogr. 1996 May-Jun;10(3):111-6. doi: 10.1002/(SICI)1099-0801(199605)10:33.0.CO;2-E.

  PMID: 8792860 BACKGROUND

• Elfar JC, Yaseen Z, Stern PJ, Kiefhaber TR. Individual finger sensibility in carpal tunnel syndrome. J Hand Surg Am. 2010 Nov;35(11):1807-12. doi: 10.1016/j.jhsa.2010.08.013.

  PMID: 21050964 BACKGROUND

• Sahin F, Atalay NS, Akkaya N, Ercidogan O, Basakci B, Kuran B. The correlation of neurophysiological findings with clinical and functional status in patients following traumatic nerve injury. J Hand Surg Eur Vol. 2014 Feb;39(2):199-206. doi: 10.1177/1753193413479507. Epub 2013 Mar 1.

  PMID: 23456925 BACKGROUND

• Sims SE, Engel L, Hammert WC, Elfar JC. Hand Sensibility, Strength, and Laxity of High-Level Musicians Compared to Nonmusicians. J Hand Surg Am. 2015 Oct;40(10):1996-2002.e5. doi: 10.1016/j.jhsa.2015.06.009. Epub 2015 Aug 5.

  PMID: 26253604 BACKGROUND

• Chimenti PC, McIntyre AW, Childs SM, Hammert WC, Elfar JC. Prospective cohort study of symptom resolution outside of the ulnar nerve distribution following cubital tunnel release. Hand (N Y). 2015 Jun;10(2):177-83. doi: 10.1007/s11552-014-9688-9.

  PMID: 26034427 BACKGROUND

• Chimenti PC, McIntyre AW, Childs SM, Hammert WC, Elfar JC. Combined Cubital and Carpal Tunnel Release Results in Symptom Resolution Outside of the Median or Ulnar Nerve Distributions. Open Orthop J. 2016 May 24;10:111-9. doi: 10.2174/1874325001610010111. eCollection 2016.

  PMID: 27347239 BACKGROUND

• Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986 Feb 8;1(8476):307-10.

  PMID: 2868172 BACKGROUND

• Roberts C. Modelling patterns of agreement for nominal scales. Stat Med. 2008 Mar 15;27(6):810-30. doi: 10.1002/sim.2945.

  PMID: 17634968 BACKGROUND

• Kim J, Farahmand M, Dunn C, Davies Z, Frisbee E, Milla C, Wine JJ. Evaporimeter and Bubble-Imaging Measures of Sweat Gland Secretion Rates. PLoS One. 2016 Oct 21;11(10):e0165254. doi: 10.1371/journal.pone.0165254. eCollection 2016.

  PMID: 27768743 BACKGROUND

• Kiistala R, Kiistala U, Parkkinen MU, Mustakallio KK. Local sweat stimulation with the skin prick technique. Acta Derm Venereol. 1984;64(5):384-8.

  PMID: 6208715 BACKGROUND

• Park SJ, Tamura T. Distribution of evaporation rate on human body surface. Ann Physiol Anthropol. 1992 Nov;11(6):593-609. doi: 10.2114/ahs1983.11.593.

  PMID: 1476561 BACKGROUND

• Buchmann SJ, Penzlin AI, Kubasch ML, Illigens BM, Siepmann T. Assessment of sudomotor function. Clin Auton Res. 2019 Feb;29(1):41-53. doi: 10.1007/s10286-018-0530-2. Epub 2018 May 8.

  PMID: 29737432 BACKGROUND

• Cardenas DD, Ditunno J, Graziani V, Jackson AB, Lammertse D, Potter P, Sipski M, Cohen R, Blight AR. Phase 2 trial of sustained-release fampridine in chronic spinal cord injury. Spinal Cord. 2007 Feb;45(2):158-68. doi: 10.1038/sj.sc.3101947. Epub 2006 Jun 13.

  PMID: 16773037 BACKGROUND

Related Links

• Hand sensibility, strength, and laxity of high-level musicians compared to nonmusicians

MeSH Terms

Conditions

Lacerations; Blast Injuries

Interventions

4-Aminopyridine

Condition Hierarchy (Ancestors)

Wounds and Injuries; Barotrauma

Intervention Hierarchy (Ancestors)

Aminopyridines; Amines; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

The study was terminated early due to lack of funding and the investigator and IND holder leaving the institution.

Results Point of Contact

• Title: Kenneth Taylor, MD, Professor of Orthopaedics and Rehabilitation
• Organization: Penn State Hershey Medical Center

ktaylor3@pennstatehealth.psu.edu

717-531-2948

Study Officials

• John C Elfar, MD

  Milton S. Hershey Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2019
• First Posted: July 19, 2019
• Study Start: August 17, 2021
• Primary Completion: July 18, 2022
• Study Completion: July 18, 2022
• Last Updated: October 18, 2022
• Results First Posted: September 14, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)