4-Aminopyridine for Peripheral Nerve Injury

Overseen By Andrea Horne

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: University of Arizona

Must not be taking: Aminopyridines, OCT2 inhibitors

Disqualifiers: Neurological disorders, Renal impairment, Seizure, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the role of single dose 4-aminopyridine (4-AP) on the diagnosis of severing vs non-severing nerve injury after peripheral nerve traction and/or crush injury. The investigational treatment will be used to test the hypothesis that 4-aminopyridine can speed the determination of nerve continuity after peripheral nerve traction and/or crush injuries allowing the identification of incomplete injuries earlier than standard electrodiagnostic (EDX) and clinical assessment. Participants will be randomized to one of two groups to determine the order of treatment they receive (drug and placebo vs placebo and drug). Participants will undergo baseline testing for nerve assessment, receive either drug or placebo based on randomization and undergo hourly sensory and motor evaluation, EDX testing and serum 4AP levels for three hours after dosing. Participants will then repeat this with the crossover arm.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently using aminopyridine medications or organic cat-ion transporter 2 (OCT2) inhibitors like Cimetidine.

What data supports the effectiveness of the drug 4-Aminopyridine for peripheral nerve injury?

Research shows that 4-Aminopyridine, a drug used for multiple sclerosis, can improve nerve function and recovery after peripheral nerve injuries in mice. It helps with nerve healing, muscle strength, and reduces nerve damage, suggesting it might be effective for similar injuries in humans. ^{1 2 3 4 5}

Is 4-Aminopyridine safe for humans?

4-Aminopyridine (4-AP) is an FDA-approved drug used for improving walking in multiple sclerosis patients, indicating it has been deemed safe for human use in that context. However, the safety data for its use in peripheral nerve injury specifically is not detailed in the provided research articles. ^{1 2 3 4 5}

How does the drug 4-Aminopyridine differ from other treatments for peripheral nerve injury?

4-Aminopyridine is unique because it not only helps improve nerve function and muscle strength after a peripheral nerve injury, but it also acts as a diagnostic tool to differentiate between types of nerve injuries. Unlike other treatments, it can be administered orally, transdermally (through the skin), or by injection, and it promotes remyelination (repairing the protective covering of nerves) and enhances nerve conduction. ^{1 2 3 4 6}

Research Team

John Elfar, MD

Principal Investigator

University of Arizona

Eligibility Criteria

This trial is for adults aged 18-90 with unclear peripheral nerve injuries from trauma involving two or fewer limbs. Participants must be able to consent, report sensory and motor deficits, and undergo standard monitoring or surgery. They should be available for all test days and receive dosing within seven days of injury.

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

Ability to give written informed consent

Exclusion Criteria

Not able to complete dosing within seven days (168 hours) of nerve injury diagnosis

Distracting injury which prevents adequate examination

Intoxication during examination or evidence of cognitive deficit that emerges during examination

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Baseline Testing

Participants undergo baseline testing for nerve assessment, including high-resolution ultrasound, sensory and motor evaluation, and EDX study.

1 day

1 visit (in-person)

Crossover Treatment

Participants receive either the study drug or placebo, followed by hourly sensory and motor evaluation, EDX testing, and serum 4AP levels for three hours. This is repeated with the crossover arm.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for recovery and progress with follow-up visits at 2, 6, 12, 18, and 20 weeks post injury. EDX testing is completed at 6, 12, and 18 weeks. Telephone interviews are conducted at 9 and 15 weeks.

20 weeks

5 visits (in-person), 2 calls (virtual)

Treatment Details

Interventions

• 4-Aminopyridine (Potassium Channel Blocker)

Trial Overview The study tests if a single dose of 4-Aminopyridine (4-AP) can quickly determine nerve damage severity compared to standard assessments after crush or traction injuries. Patients are randomly assigned to first get either the drug or placebo, followed by hourly evaluations, then switch treatments in a crossover design.

Participant Groups

Group I: Placebo then 4AP (Group B) Experimental Treatment 2 Interventions

Subjects randomized to this group will receive the placebo first followed by the study drug (4AP)

Group II: 4AP then placebo (Group A) Experimental Treatment 2 Interventions

Subjects randomized to this group will receive the study drug (4AP) followed by the placebo.

Who Is Running the Clinical Trial?

University of Arizona

Lead Sponsor

Trials

545

Recruited

161,000+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Findings from Research

4-Aminopyridine (4-AP) significantly improves motor function and enhances recovery after traumatic peripheral nerve injuries in mice, regardless of whether it is administered orally or through injection.

Chronic daily treatment with 4-AP leads to better myelination, increased muscle mass, and improved muscle force, indicating its potential as an effective therapy for nerve injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human equivalent dose of oral 4-aminopyridine differentiates nerve crush injury from transection injury and improves post-injury function in mice. Hsu, CG., Talukder, MAH., Yue, L., et al.[2020]

Transdermal administration of 4-aminopyridine (TD-4-AP) significantly enhances functional recovery and nerve conduction after traumatic peripheral nerve injury in mice, showing promise as a treatment method.

Chronic treatment with TD-4-AP leads to fewer degenerating axons and thicker myelin sheaths compared to controls, indicating its potential to promote nerve repair and improve motor function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice. Clark, AR., Hsu, CG., Talukder, MAH., et al.[2021]

4-aminopyridine (4-AP) has shown potential as a diagnostic tool for differentiating traumatic peripheral nerve injuries (TPNIs) based on axonal continuity, as it restored muscle responses in rats with crush injuries but not in those with transection injuries.

In a study involving anesthetized rats, both systemic and local administration of 4-AP significantly improved muscle response to electrical stimulation after crush injuries, indicating its efficacy in cases where nerve continuity is maintained.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

4-Aminopyridine: A Single-Dose Diagnostic Agent to Differentiate Axonal Continuity in Nerve Injuries. Gurjar, AA., Manto, KM., Estrada, JA., et al.[2022]

In a study involving 20 subjects (10 in the 4-AP-treated group and 10 in the control group), 4-aminopyridine (4-AP) significantly reduced clinical scores of experimental autoimmune neuritis (EAN), indicating its potential effectiveness in treating this condition.

The 4-AP-treated group also showed improved motor conductance velocity without causing any pathological changes, suggesting that it may be a safe therapeutic option for demyelinating neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

4-Aminopyridine ameliorates experimental autoimmune neuritis in Lewis rats. Moriguchi, K., Miyamoto, K., Kusunoki, S.[2018]

4-aminopyridine (4-AP) significantly enhances recovery from traumatic peripheral nerve injury (TPI) in mouse models, improving behavioral outcomes and nerve conduction velocity, suggesting it may promote faster recovery than axonal regeneration alone.

4-AP not only aids in remyelination and increases axonal area post-injury but also helps differentiate between incomplete and complete nerve lesions, which could guide treatment decisions for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

4-Aminopyridine as a Single Agent Diagnostic and Treatment for Severe Nerve Crush Injury. Noble, M., Tseng, KC., Li, H., et al.[2021]

4-aminopyridine (4-AP) shows significant potential as a treatment for acute traumatic peripheral nerve injuries, enhancing recovery speed and extent beyond what can be attributed to axonal regeneration alone, based on studies in a mouse model.

In addition to promoting remyelination and improving nerve conduction velocity, 4-AP helps differentiate between incomplete and complete nerve lesions more quickly than current methods, which could lead to more tailored and effective treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury. Tseng, KC., Li, H., Clark, A., et al.[2021]

References

1. India pubmed.ncbi.nlm.nih.gov

Human equivalent dose of oral 4-aminopyridine differentiates nerve crush injury from transection injury and improves post-injury function in mice. [2020]

2. India pubmed.ncbi.nlm.nih.gov

Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice. [2021]

3. England pubmed.ncbi.nlm.nih.gov

4-Aminopyridine: A Single-Dose Diagnostic Agent to Differentiate Axonal Continuity in Nerve Injuries. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

4-Aminopyridine ameliorates experimental autoimmune neuritis in Lewis rats. [2018]

5. England pubmed.ncbi.nlm.nih.gov

4-Aminopyridine as a Single Agent Diagnostic and Treatment for Severe Nerve Crush Injury. [2021]

6. England pubmed.ncbi.nlm.nih.gov

4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury. [2021]