Dalfampridine + Stimulation/Exercise for Spinal Cord Injury

Overseen By Monica A Perez, PT, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Shirley Ryan AbilityLab

Must not be taking: Bupropion, Dolutegravir, Lacosamide, others

Disqualifiers: Renal impairment, Major depression, Seizures, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 weeks (10 sessions) for standard groups, 12 weeks (40 sessions) for extended sessions group

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to help people with spinal cord injuries improve leg movement. It combines Dalfampridine, a medication approved by the FDA to improve walking in patients with multiple sclerosis, with a special type of stimulation and exercise. Researchers divide participants into different groups to assess the effectiveness of this combination over various time periods. Ideal candidates have had a spinal cord injury for at least four weeks and can move their ankle or hip slightly. As an Early Phase 1 trial, this research aims to understand how the treatment works in people, offering participants a chance to contribute to groundbreaking advancements in spinal cord injury recovery.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically those acting on the central nervous system that lower the seizure threshold, as well as Bupropion, Dolutegravir, Lacosamide, Trilaciclib, or PR Interval prolonging drugs.

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

Research has shown that dalfampridine is generally safe for people with spinal cord injuries. When taken as directed, it is usually well-tolerated. However, like any medication, it can cause side effects. Common side effects include dizziness, seizures, and balance problems, though not everyone will experience these.

Research on the safety of STDP stimulation, a technique to improve nerve connections, is still ongoing. So far, studies have not raised major safety concerns, but since it is a newer method, more research is needed to understand any long-term effects.

Overall, both treatments appear reasonably safe, but discussing any concerns with a healthcare provider is always best. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for spinal cord injury focus on rehabilitation exercises and physical therapy to improve muscle function over time. But Dalfampridine works differently, targeting the nervous system to enhance signal transmission in damaged nerves. This drug is unique because it blocks potassium channels, which can improve nerve conduction and potentially lead to faster and more significant recovery of muscle function. Researchers are excited about the possibility that combining Dalfampridine with specific stimulation and exercise techniques could amplify these effects, offering a new hope for better functional recovery in patients with spinal cord injuries.

What evidence suggests that this trial's treatments could be effective for spinal cord injury?

Research has shown that Dalfampridine (4-AP), which participants in this trial may receive, can improve muscle control and sensation in individuals with long-term spinal cord injuries. Some studies found it can reduce symptoms like spasticity, where muscles remain tight and contracted. However, overall results are mixed, with some studies showing only slight benefits.

For spike-timing-dependent plasticity (STDP) stimulation, another component of this trial, early research suggests it can strengthen nerve connections and enhance movement. This method uses paired electrical signals to improve communication between the brain and spinal cord, potentially aiding recovery in people with spinal cord injuries. While these findings are promising, more research is needed to confirm its effectiveness. ^{1 6 7 8 9}

Who Is on the Research Team?

Monica Perez, PhD

Principal Investigator

Shirley Ryan Ability Lab

Are You a Good Fit for This Trial?

This trial is for men and women aged 18-85 with spinal cord injury (SCI) at or above L2, who are at least 4 weeks post-injury. They must be able to slightly move their hip flexor or dorsiflexion muscles. Excluded are those with a history of head injury, stroke, seizures, epilepsy, renal impairment, certain medication use (affecting the CNS), metal in the skull, uncontrolled medical issues, pre-existing debilitating diseases or mental health conditions.

Inclusion Criteria

My spinal cord injury happened over 4 weeks ago.

My spinal cord injury is at or above the L2 level.

I can slightly move my toes upwards and bend my hip.

Exclusion Criteria

I am currently taking Bupropion, Dolutegravir, Lacosamide, Trilaciclib, or drugs that prolong the PR Interval.

I am a woman of childbearing age unsure about being pregnant and refuse a pregnancy test, or I have a spinal cord condition.

I have had a head injury or stroke in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Dalfampridine (4-AP) combined with STDP stimulation and limb training for functional recovery of lower-limb muscles

3 weeks (10 sessions) for standard groups, 12 weeks (40 sessions) for extended sessions group

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Dalfampridine
• Exercise training
• Placebo drug
• STDP stimulation

Trial Overview The study tests Dalfampridine (FDA approved drug) combined with STDP stimulation and limb training to enhance lower limb motor function recovery in SCI patients. Participants will receive either this combination therapy or a placebo alongside exercise training to compare effectiveness.

How Is the Trial Designed?

Group I: Dalfampridine (4-AP)+STDP+training for extended sessions Experimental Treatment 3 Interventions

The long-term effects of the functional recovery of the lower-limb muscles will be determined after 40 sessions of 4-AP, STDP stimulation and training.

Group II: Dalfampridine (4-AP)+STDP+training Active Control 3 Interventions

The effects of the functional recovery of the lower-limb muscles will be determined after 10 sessions of 4-AP, STDP stimulation and training.

Group III: Placebo+STDP+training Placebo Group 3 Interventions

The effects of the functional recovery of the lower-limb muscles will be determined after 10 sessions of placebo drug, STDP stimulation and training.

Dalfampridine is already approved in United States, European Union for the following indications:

Approved in United States as Ampyra for:

• Improvement of walking in adults with multiple sclerosis

Approved in European Union as Fampyra for:

• Improvement of walking in adults with multiple sclerosis

Who Is Running the Clinical Trial?

Shirley Ryan AbilityLab

Lead Sponsor

Trials

212

Recruited

17,900+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Published Research Related to This Trial

In a study involving 20 patients with chronic, incomplete spinal cord injury, 4-aminopyridine (4-AP) did not show significant improvements in functional status or walking speed after four weeks of treatment.

While there was a statistically significant effect on vibration perception threshold in the left fingers, patients treated with 4-AP actually experienced a less favorable response compared to those on placebo, indicating no overall benefit from the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial of 4-aminopyridine in patients with chronic incomplete spinal cord injury. van der Bruggen, MA., Huisman, HB., Beckerman, H., et al.[2019]

Intrathecal administration of 4-aminopyridine (4-AP) in six chronic spinal cord injury patients showed no adverse systemic side effects, indicating a safe delivery method for this treatment.

Some patients experienced transient improvements in sensory function and motor control, suggesting that 4-AP may have the potential to modify spinal cord function when administered directly into the cerebrospinal fluid.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrathecal administration of 4-aminopyridine in chronic spinal injured patients. Halter, JA., Blight, AR., Donovan, WH., et al.[2019]

Fampridine-SR, a potassium channel blocker, was found to be well tolerated in 16 subjects with chronic, incomplete spinal cord injury, with mild to moderate adverse events reported, primarily dizziness.

The pharmacokinetics of Fampridine-SR showed a dose-dependent increase in plasma concentrations, allowing for convenient twice-daily administration, with a mean absorption time of 2.2 to 3.0 hours and a half-life of 5.7 to 6.9 hours.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine-SR) in subjects with chronic, incomplete spinal cord injury. Hayes, KC., Potter, PJ., Hsieh, JT., et al.[2019]

Dalfampridine is an FDA-approved oral medication that enhances nerve signal conduction in demyelinated axons, improving walking ability in patients with multiple sclerosis (MS).

Clinical trials have demonstrated the safety and efficacy of dalfampridine, focusing on its ability to significantly improve gait in MS patients, which is crucial given the disease's impact on mobility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dalfampridine: review of its efficacy in improving gait in patients with multiple sclerosis. Sahraian, MA., Maghzi, AH., Etemadifar, M., et al.[2021]

Fampridine, when given as a single oral dose, was rapidly absorbed in healthy volunteers, reaching peak plasma levels within 1 hour and showing a half-life of approximately 3.14 hours, indicating efficient absorption and elimination.

The study found that 96.36% of the administered dose was recovered in urine as unchanged drug, suggesting that fampridine undergoes minimal metabolic transformation, which may contribute to its efficacy and safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of 14C-radioactivity after oral intake of a single dose of 14C-labeled fampridine (4-aminopyridine) in healthy volunteers. Blight, AR., Henney, HR.[2014]

Dalfampridine-ER is an effective treatment for improving walking speed in patients with multiple sclerosis, as shown in two pivotal phase III clinical trials, where it was administered at a dose of 10 mg twice daily.

The drug works by blocking potassium channels to restore axonal conduction and was generally well tolerated, with no increased risk of seizures compared to placebo, although it is contraindicated in patients with a history of seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of dalfampridine, a novel pharmacologic approach for treating walking impairment in multiple sclerosis. Blight, AR., Henney, HR., Cohen, R.[2014]

In a study of 27 patients with long-term spinal cord injury, those treated with 4-aminopyridine (4-AP) showed significant improvements in motor function (92% vs. 46% for placebo) and overall sensorimotor changes, indicating its efficacy as a treatment.

The drug was found to be generally safe, with 56% of patients experiencing mild to moderate adverse reactions, including one case of posterior tibial artery vasospasm, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of 4-aminopyridine in patients with long-term spinal cord injury: a randomized, double-blind, placebo-controlled trial. Grijalva, I., Guízar-Sahagún, G., Castañeda-Hernández, G., et al.[2019]

In a randomized, double-blind, placebo-controlled trial involving 15 chronic spinal cord injury patients, 4-aminopyridine (4-AP) did not show statistically significant improvements in lower limb muscle strength or gait patterns compared to placebo.

Despite some positive feedback from participants, the study highlights the necessity of rigorous placebo-controlled trials and objective measures to accurately assess the efficacy of treatments like 4-AP for enhancing gait in spinal cord injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of 4-aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial. DeForge, D., Nymark, J., Lemaire, E., et al.[2013]

Extended-release dalfampridine has been shown to significantly increase ambulation speed in patients with multiple sclerosis, particularly in those identified as 'timed walk responders' during two phase III trials.

While effective, extended-release dalfampridine can cause side effects such as urinary tract infections, insomnia, and rare seizure events, highlighting the need for careful monitoring in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended-release dalfampridine in the management of multiple-sclerosis-related walking impairment. Hersh, C., Rae-Grant, A.[2021]

In a study involving 21 patients with long-standing spinal cord injury, long-term administration of 4-aminopyridine (4-AP) at a dose of 30 mg/day led to significant improvements in both motor and sensory function after 3 months.

Patients taking 4-AP also experienced enhanced pulmonary function and reduced spasticity, with no significant drug toxicity observed, indicating that 4-AP is a safe treatment option for individuals with spinal cord injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of 4-aminopyridine in humans with spinal cord injury: a long-term, controlled trial. Segal, JL., Pathak, MS., Hernandez, JP., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6241229/

Effectiveness of 4-Aminopyridine for the Management ... Conclusion: There is weak evidence supporting the effectiveness of 4-AP in reducing spasticity post SCI. Future research should utilize contemporary measures of ...

2. frontiersin.org frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.1034730/full

Functional improvement in individuals with chronic spinal ... Most of the studies reviewed reported some degree of patient improvement in one or more of the following parameters: motor, sensitivity and ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9744758/

Functional improvement in individuals with chronic spinal cord ... Erection frequency and firmness, ability to maintain erections and levels of sexual desire showed greater improvement in the fampridine groups ...

4. archives-pmr.org archives-pmr.org/article/S0003-9993(17)31001-8/fulltext

The Effectiveness of 4-Aminopyridine for The Management ... There is conflicting evidence regarding the effectiveness of oral and intravenous 4-AP in managing spasticity after SCI. However, it should be noted that ...

5. nature.com nature.com/articles/sc2013137

Two phase 3, multicenter, randomized, placebo-controlled ... Several studies of fampridine that evaluated the effects on neurological outcomes, including spasticity, in chronic spinal cord injury (SCI) ...

6. safety365.sevron.co.uk safety365.sevron.co.uk/substances/accessSDS/SDS-115222-57dff1ead16635.80687593

Safety Data Sheet No evidence of developmental toxicity including teratogenic potential was seen in rats or rabbits administered fampridine orally by gavage. Target Organs.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0003999303006518

Pharmacokinetics and safety of multiple oral doses ... Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine-SR) in subjects with chronic, incomplete spinal cord injury.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37781705/

Post-marketing safety surveillance of dalfampridine for ... Results: A total of 44,092 dalfampridine-related AE reports were obtained, and 335 AE signals were identified, including 11,889 AE reports. AEs ...

9. frontiersin.org frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1226086/full

Post-marketing safety surveillance of dalfampridine for ... In the PT item analysis, the most significant AE signal was spinal cord injury cauda equina, which may be related to disease progression, as ...