4-Aminopyridine for Peripheral Nerve Injury

Overseen By Andrea Horne

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Arizona

Must not be taking: Aminopyridines, OCT2 inhibitors

Disqualifiers: Neurological disorders, Renal impairment, Seizure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 7

68 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a drug called 4-aminopyridine (4-AP) can help doctors quickly determine the type of nerve injury after an arm or leg injury. Researchers aim to see if 4-AP can speed up the diagnosis of whether the nerve is completely severed or just damaged. Participants will receive both the drug and a placebo (a substance with no active ingredients) in different orders to compare results. The study seeks individuals with injuries involving no more than two limbs where nerve damage is unclear during a physical exam. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that 4-aminopyridine (4-AP) may aid in nerve injury recovery. Studies have found that it can accelerate the return of movement and sensation after nerve damage, potentially allowing individuals to regain these functions more quickly.

Regarding safety, the FDA has already approved 4-AP for another condition, suggesting it might be relatively safe. However, like all treatments, it can cause side effects. Some individuals have experienced minor issues like dizziness or nausea, though serious problems are rare.

This study is in an early phase, so researchers are still determining the optimal doses and potential side effects. Participants in this trial will help establish how 4-AP could be used safely in the future. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for peripheral nerve injury?

Most treatments for peripheral nerve injury focus on managing symptoms and promoting nerve repair through physical therapy, pain relievers, or surgical interventions. But 4-Aminopyridine (4AP) works differently, targeting the ion channels on nerve cells to improve nerve signal transmission. Researchers are excited about 4AP because it offers a unique approach to enhancing nerve function directly, potentially speeding up recovery and improving outcomes for patients with nerve damage. Unlike traditional methods that may take longer to show benefits, 4AP could provide quicker and more effective results in restoring nerve function.

What evidence suggests that 4-aminopyridine might be an effective treatment for peripheral nerve injury?

Research has shown that 4-aminopyridine (4-AP) can significantly aid recovery after injuries to nerves outside the brain and spinal cord. Studies have found that 4-AP accelerates the return of movement and sensation, which typically take a long time to recover after nerve damage. It also promotes nerve healing and improves muscle health. In this trial, participants will be randomized into two groups: one group will receive 4-AP followed by a placebo, and the other group will receive a placebo first followed by 4-AP. In cases of sudden nerve injury, 4-AP rapidly enhances recovery, particularly in restoring movement. This treatment works by improving nerve signal transmission, which is crucial for regaining lost abilities. ^{1 4 6 7 8}

Who Is on the Research Team?

John Elfar, MD

Principal Investigator

University of Arizona

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• 4-Aminopyridine

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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) 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) 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03701581

NCT03701581 | 4-aminopyridine Treatment for Nerve Injury This study aims to test the hypothesis that 4-aminopyridine speeds the often slow and unpredictable recovery after peripheral nerve traction and/or crush ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0363502322001198

Effects of 4-Aminopyridine on Combined Nerve and Muscle ... 4-Aminopyridine significantly accelerated the postinjury motor and sensory function recovery, improved muscle histomorphometry, increased muscle satellite cell ...

3. embopress.org embopress.org/doi/10.15252/emmm.201506035

4‐Aminopyridine promotes functional recovery and ... 4‐AP rapidly enhances functional recovery in acute peripheral nerve injury. As restoration of motor function is the primary goal in treatment ...

4. trialsjournal.biomedcentral.com trialsjournal.biomedcentral.com/articles/10.1186/s13063-024-08102-z

4-Aminopyridine treatment for nerve injury resulting ... - Trials After TPNI, nerve recovery can occur weeks to years after injury. Clinically, patients begin regaining erectile function and continence as well ...

5. neurology.org neurology.org/doi/10.1212/NXI.0000000000000976

Neuroprotective Properties of 4-Aminopyridine 4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury. EMBO Mol Med 2016;8:1409–1420. Go to ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7716044/

Human equivalent dose of oral 4-aminopyridine differentiates ... Daily oral 4-AP treatment significantly prevented muscle loss in crush injury but not in denervation injury. On day 14, mean TA and EDL muscle mass (mg) in ...

7. academic.oup.com academic.oup.com/milmed/article/184/Supplement_1/379/5418675

4-Aminopyridine as a Single Agent Diagnostic and Treatment ... Improved outcome after peripheral nerve ... 4-aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6862422/

Transdermal delivery of 4-aminopyridine accelerates motor ... Here we report for the first time that 4-AP can be used as a transdermal therapeutic agent that promotes durable motor functional recovery of ...