Drugs + Hand Training for Spinal Cord Injury

Recruiting at 1 trial location

Overseen By Francisco E Castano, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Bronx VA Medical Center

Must not be taking: Amphetamines, Dalfampridine, Bupropion, others

Disqualifiers: Seizures, Stroke, Brain tumor, others

Compensation: Varies

Number of Visits: 8

Duration: 4 weeks

28 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore whether three FDA-approved drugs—cyproheptadine, carbidopa-levodopa, and atomoxetine—can enhance the connection between the brain and spinal cord when combined with hand training exercises. It targets individuals who have had a spinal cord injury for over a year and can move their fingers or perform a pinch with their thumb and index finger. Participants will receive one of the drugs or a placebo and engage in hand exercises to determine if their motor skills, such as dexterity and strength, improve. As a Phase 1 trial, the research focuses on understanding how the treatment functions in people.

Will I have to stop taking my current medications?

The trial requires that your current medications be stable for at least 30 days before starting. You cannot use medications that interact with the study drugs within 14 days prior to the trial.

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

Research shows that carbidopa-levodopa, cyproheptadine, and atomoxetine are generally safe when used as directed. Here's a simpler breakdown:

Carbidopa-levodopa is well-tolerated by people with Parkinson's disease. Some might experience mild nausea, but no major safety issues have emerged, even at doses higher than those in the trial.

Cyproheptadine is considered safe and primarily increases appetite. It can cause mild drowsiness, while serious effects, like liver problems, are rare unless misused.

Atomoxetine often treats ADHD (attention-deficit/hyperactivity disorder). Common side effects include dry mouth and trouble sleeping, but it is generally safe for short-term use. Some research even suggests it might help protect nerve cells after injury.

These drugs are all FDA-approved for other uses, which adds confidence about their safety. Always follow the prescribed dose to minimize risk. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for spinal cord injury because they offer new possibilities beyond existing therapies. Most current treatments focus on rehabilitation techniques and surgery, but these investigational drugs target neurological pathways in innovative ways. Atomoxetine (ATX) works by enhancing norepinephrine levels, potentially boosting nerve signaling. Cyproheptadine (CPH) is an antihistamine that might play a role in reducing inflammation and promoting nerve function. Carbidopa-Levodopa (CD-LD) is typically used for Parkinson's disease, but here it's being explored for its potential to improve motor function by increasing dopamine levels. This combination of drugs with hand training could open new avenues for recovery and improved quality of life for those with spinal cord injuries.

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

Research has shown that each of these three drugs may help treat spinal cord injuries. In this trial, participants will receive one of the following treatments: Carbidopa-levodopa, which can improve movement recovery when combined with physical training, aiding the reconnection of brain and spinal pathways; Cyproheptadine, which showed early results in reducing muscle tightness and improving movement in people with spinal injuries; or Atomoxetine, which was found to protect the spinal cord and enhance nerve function after an injury. These findings suggest that using these drugs along with hand exercises could strengthen connections between the brain and spinal cord, potentially improving dexterity and strength in patients with spinal cord injuries. ^{1 6 7 8 9}

Who Is on the Research Team?

Lynda M Murray, PhD

Principal Investigator

Bronx VA Medical Center / James J. Peters Veterans Affairs Medical Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with stable chronic spinal cord injury at or above C8, who have some hand muscle activity and are on a consistent medication and rehab plan. Participants must avoid alcohol, smoking, caffeine before visits, not use recreational drugs during the study, and commit to all sessions.

Inclusion Criteria

I can move my fingers or do a thumb-index finger pinch.

Detectable FDI/APB surface electromyography (EMG) muscle activity during thumb-index finger pinch

Must be able to abstain from alcohol, smoking, and caffeine consumption on the day prior/of each experiment

Exclusion Criteria

I do not have any health conditions that could make the study drug unsafe for me.

I rely on a ventilator to breathe or have an open tracheostomy.

I have had repeated episodes of autonomic dysreflexia in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-Training

Participants partake in two motor training practice sessions for task familiarity

1-2 weeks

2 visits (in-person)

Treatment

Participants receive a single dose of one of the study drugs (CPH, CD-LD, ATX, or placebo) in a randomized crossover design, combined with hand training exercises

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including tracking side effects and cardiovascular responses

1 week

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Atomoxetine
• Carbidopa-Levodopa
• Cyproheptadine

Trial Overview The study tests if FDA-approved drugs (cyproheptadine, carbidopa-levodopa, atomoxetine) combined with hand exercises can improve brain-spinal cord connections in people with chronic spinal cord injuries. It measures nerve transmission and muscle response through noninvasive stimulation.

How Is the Trial Designed?

Group I: CPH + hand training Experimental Treatment 1 Intervention

A single dose of Cyproheptadine (CPH) (8 mg) will be administered. Supplied as 2 over-encapsulated pills of 4 mg each.

Group II: CD-LD + hand training Experimental Treatment 1 Intervention

A single dose of IR Carbidopa-levodopa (CD-LD) (50/200 mg) will be administered. Supplied as 2 over-encapsulated pills (25 mg carbidopa / 100 mg levodopa each).

Group III: ATX + hand training Experimental Treatment 1 Intervention

A single dose of Atomoxetine (ATX) (40 mg) will be administered. Supplied as 1 over-encapsulated pill of 40 mg plus 1 placebo capsule.

Group IV: Placebo + hand training Placebo Group 1 Intervention

A single dose of Placebo will be administered. Supplied as 2 gelatin capsules, identical in number, size, shape and color, filled with microcrystalline cellulose.

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

Approved in United States as Strattera for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Approved in European Union as Strattera for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Approved in Canada as Strattera for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Who Is Running the Clinical Trial?

Bronx VA Medical Center

Lead Sponsor

Trials

22

Recruited

1,300+

Published Research Related to This Trial

In a study of 2040 individuals with spinal cord injury, a total of 775 unique medications were administered within the first 60 days post-injury, highlighting a significant prevalence of polypharmacy, with some patients taking up to 43 medications per day.

The findings suggest that the high number of medications, including those given for prophylactic reasons, could potentially influence neurological recovery, emphasizing the need for careful management of pharmacological treatments in acute spinal cord injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological management of acute spinal cord injury: a longitudinal multi-cohort observational study. Jutzeler, CR., Bourguignon, L., Tong, B., et al.[2023]

Combining amphetamine (AMPH) with skilled motor training after spinal cord injury (SCI) improved qualitative reaching performance compared to control animals, but did not enhance skilled reaching abilities.

The study suggests that the benefits of AMPH-enhanced motor training may stem from effects on brain function rather than direct improvements in spinal cord health, as there was no evidence of neuroprotection or kinematic improvements in reaching quality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amphetamine-enhanced motor training after cervical contusion injury. Krisa, L., Frederick, KL., Canver, JC., et al.[2021]

In a study using a rat model of spinal trauma, three different drugs (mianserin, nalmefene, and YM-14673) were found to significantly improve motor recovery and preserve certain spinal fibers after injury, indicating their potential efficacy in treating spinal cord injuries.

Despite their positive effects on motor function and axon survival, none of the drugs were effective in preserving central gray matter or myelin in the injured spinal tissue, suggesting that while they may aid recovery, they do not prevent all types of spinal cord damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of a serotonin antagonist, opioid antagonist, and TRH analog for the acute treatment of experimental spinal trauma. Puniak, MA., Freeman, GM., Agresta, CA., et al.[2013]

Enriched housing combined with skilled training significantly improved skilled forelimb function (like reaching) and coordinated limb function (measured by gridwalk performance) in adult rats after a cervical spinal cord injury, indicating effective rehabilitation strategies.

However, the study found no significant improvements in automatic forelimb functions such as locomotion and vertical exploration, suggesting that different rehabilitation approaches may be needed for various types of motor functions following spinal cord injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity-based therapies to promote forelimb use after a cervical spinal cord injury. Dai, H., MacArthur, L., McAtee, M., et al.[2021]

Entacapone is a COMT inhibitor that enhances the effectiveness of levodopa in treating Parkinson's disease, particularly for patients experiencing motor fluctuations.

It has a favorable safety profile compared to tolcapone, as it does not require liver function monitoring, although it may cause side effects like worsening dyskinesias, hypotension, constipation, and urine discoloration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entacapone in the management of Parkinson's disease. Henchcliffe, C., Waters, C.[2019]

In a study involving female Sprague-Dawley rats with spinal cord injuries, administering amphetamine alongside training on a beam walking task significantly impaired locomotor recovery, contrary to previous findings in brain injury models.

The combination of amphetamine and training not only worsened recovery outcomes but also increased lesion severity in the spinal cord, highlighting that this drug/training regimen is detrimental for spinal cord injuries, unlike its effects on cortical injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

One day of motor training with amphetamine impairs motor recovery following spinal cord injury. Wong, JK., Steward, O.[2013]

In individuals with incomplete spinal cord injuries, the serotonin reuptake inhibitor citalopram increased reflex responses, indicating that functional monoamine receptors are active below the injury site, which may contribute to spasticity.

In contrast, in those with complete spinal cord injuries, blocking constitutive serotonin and norepinephrine receptor activity with cyproheptadine reduced muscle spasms, suggesting that targeting these receptors could be an effective strategy for managing spasticity in severe cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Constitutively active 5-HT2/α1 receptors facilitate muscle spasms after human spinal cord injury. D'Amico, JM., Murray, KC., Li, Y., et al.[2022]

Indorenate, a 5-HT1A agonist, significantly improved motor performance in rats with chronic spinal cord injury compared to a saline solution, as measured by the BBB rating scale.

The study found that 80% of the indorenate-treated rats showed no detriment in motor activity, and those with lower baseline motor function experienced notable recovery, suggesting that serotonergic agents could enhance motor function in similar injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indorenate improves motor function in rats with chronic spinal cord injury. Bravo, G., Ibarra, A., Guizar-Sahagún, G., et al.[2013]

ATL-146e, an adenosine A2A receptor agonist, demonstrated equivalent efficacy to methylprednisolone in preserving motor function and neuronal viability in a rabbit model of acute spinal cord injury, suggesting it could be a viable alternative to steroids.

Both ATL-146e and methylprednisolone significantly improved neuronal viability compared to a control group, but ATL-146e showed better early motor function recovery, indicating its potential benefits without the adverse effects associated with steroid treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of adenosine A2A agonism and methylprednisolone in attenuating neuronal damage and improving functional outcome after experimental traumatic spinal cord injury in rabbits. Okonkwo, DO., Reece, TB., Laurent, JJ., et al.[2013]

Entacapone, when used with levodopa and a dopadecarboxylase inhibitor, can moderately improve motor function in Parkinson's patients by increasing 'on' periods by about one hour, although it may not enhance overall patient satisfaction.

The main side effects of entacapone include dyskinesias and gastrointestinal issues like diarrhea, and while it shows promise, the risk of rare severe side effects, such as hepatitis, cannot be dismissed due to the limited number of patients studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entacapone: new preparation. Comparative data are lacking. [2013]

In a study involving 12 healthy male volunteers, the novel COMT inhibitor entacapone significantly increased the plasma concentration of levodopa by 65% at the highest dose, suggesting it enhances the effectiveness of levodopa treatment.

Entacapone also reduced the levels of the metabolite 3-O-methyldopa by 58%, indicating a potential mechanism for improving levodopa's therapeutic effects without causing any adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of catechol-O-methyl transferase inhibition by entacapone on the pharmacokinetics and metabolism of levodopa in healthy volunteers. Keränen, T., Gordin, A., Harjola, VP., et al.[2019]

Opicapone, a new once-daily catechol-O-methyl transferase inhibitor, has been shown to significantly reduce OFF time in Parkinson's disease patients by about 60 minutes daily compared to placebo, without increasing troublesome dyskinesias.

The drug has a favorable safety profile and received marketing authorization in Europe as an adjunctive therapy to levodopa, making it a promising option for managing end-of-dose motor fluctuations in Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Opicapone for the treatment of Parkinson's disease: A review of a new licensed medicine. Fabbri, M., Ferreira, JJ., Lees, A., et al.[2019]

In a study involving 12 individuals with chronic incomplete spinal cord injury, the administration of 5-HT medications showed significant effects on motor function, particularly in strength and spasticity, but did not notably improve walking ability.

The 5-HT antagonist cyproheptadine decreased strength and increased spasticity, while the SSRI escitalopram increased strength and spasticity, highlighting the complex role of serotonin in motor function after spinal cord injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Divergent modulation of clinical measures of volitional and reflexive motor behaviors following serotonergic medications in human incomplete spinal cord injury. Thompson, CK., Hornby, TG.[2022]

In a 3-year study involving 132 patients with Parkinson's disease, entacapone combined with levodopa significantly improved motor function, increasing the duration of levodopa's benefit from 2.1 to 2.8 hours.

Entacapone demonstrated a good long-term safety profile, with only 14% of patients discontinuing due to adverse events, and 69% of patients reported improvement in their condition while on the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The tolerability and efficacy of entacapone over 3 years in patients with Parkinson's disease. Larsen, JP., Worm-Petersen, J., Sidén, A., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4834117/

Neuroprotective effects of atomoxetine against traumatic ... As a result of these functional tests, both atomoxetine and MP treatments following SCI protected the spinal cord and improved neurological functions. All the ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/27114797/

Neuroprotective Effects of Atomoxetine Against Traumatic ... This is the first experimental evidence showing meaningful neuroprotective effects of atomoxetine over SCI through anti-apoptotic, anti-inflammatory, ...

3. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05708274/pharmacological-agents-for-chronic-spinal-cord-injury-sci

Pharmacological Agents for Chronic Spinal Cord Injury (SCI) The purpose of this study is to investigate the short-term effects of 3 approved FDA drugs (cyproheptadine (CPH), carbidopa-levodopa (CD-LD) ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT00702364

Efficacy Study of Strattera for Treating Attention Disorders ... Moderate to severe TBI as indicated by Glasgow Coma Score (GCS) score of 12 or less; or Post Traumatic Amnesia (PTA) of seven days or more; at ...

5. researchgate.net researchgate.net/publication/372982856_Case_report_Atomoxetine_improves_chronic_pain_with_comorbid_post-traumatic_stress_disorder_and_attention_deficit_hyperactivity_disorder

(PDF) Case report: Atomoxetine improves chronic pain with ... Moreover, we found that ATX can improve chronic pain with PTSD and cerebral blood flow. Aggressive screening of ADHD is important because once ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/021411s050lbl.pdf

Strattera - accessdata.fda.gov The most commonly observed adverse reactions in patients treated with STRATTERA (incidence of 5% or greater and at least twice the incidence in placebo patients ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9982187/

Effects of Atomoxetine for the Treatment of Neurogenic ... Atomoxetine is an effective and safe option for short-term nOH management, which could be more evident in patients with central autonomic dysfunction such as ...

8. researchgate.net researchgate.net/publication/7318619_Atomoxetine_for_Individuals_With_Traumatic_Brain_Injury

Atomoxetine for Individuals With Traumatic Brain Injury Neuroprotective effects of atomoxetine against traumatic spinal cord injury in rats. Article. Full-text available. Mar 2016. Qing-Xian Hou · Li ...

9. frontiersin.org frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2024.1453100/full

Increased risk of injury and adult attention deficit ... Similarly, atomoxetine significantly reduced the injury risk. These findings underscore the importance of injury prevention strategies in adults ...