Drugs + Hand Training for Spinal Cord Injury

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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to investigate the short-term effects of 3 approved FDA drugs (cyproheptadine (CPH), carbidopa-levodopa (CD-LD), and atomoxetine (ATX)) on motor responses when delivered in combination with hand training exercises in people with chronic spinal cord injury. The goal is to learn how to better strengthen connections between the brain and spinal cord after spinal cord injury, and if this connection is improved by one(or more) of the drugs. Multiple aspects of nerve transmission and muscle response will be measured via noninvasive brain and spinal cord stimulation, along with motor performance (dexterity and strength).

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.

What evidence supports the effectiveness of the drugs used in the clinical trial for spinal cord injury?

Research suggests that drugs affecting serotonin receptors, like cyproheptadine, can influence motor function and spasticity in spinal cord injury patients. Additionally, studies on animals show that serotonergic agents may improve motor function after spinal cord injury. ^{1 2 3 4 5}

Is the combination of drugs like Atomoxetine, Carbidopa-Levodopa, and Cyproheptadine generally safe for humans?

The drugs mentioned have been studied for safety in humans, primarily in the context of Parkinson's disease. Common side effects include insomnia, dizziness, nausea, and gastrointestinal issues, but serious side effects are rare. Always consult with a healthcare provider for personalized advice. ^{6 7 8 9 10}

How is the drug combination of Atomoxetine, Carbidopa-Levodopa, and Cyproheptadine unique for spinal cord injury?

This drug combination is unique because it combines medications typically used for other conditions, like ADHD and Parkinson's disease, to potentially enhance motor recovery in spinal cord injury patients, which is not a standard approach for this condition. ^{3 11 12 13 14}

Research Team

Lynda M Murray, PhD

Principal Investigator

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

Eligibility Criteria

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 am between 18 and 65 years old.

I can move my fingers or do a 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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Constitutively active 5-HT2/α1 receptors facilitate muscle spasms after human spinal cord injury. [2022]

2. United States 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. [2022]

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

Indorenate improves motor function in rats with chronic spinal cord injury. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Comparison of a serotonin antagonist, opioid antagonist, and TRH analog for the acute treatment of experimental spinal trauma. [2013]

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

Pharmacological management of acute spinal cord injury: a longitudinal multi-cohort observational study. [2023]

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

The tolerability and efficacy of entacapone over 3 years in patients with Parkinson's disease. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Entacapone in the management of Parkinson's disease. [2019]

8. France pubmed.ncbi.nlm.nih.gov

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

9. United States 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. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Opicapone for the treatment of Parkinson's disease: A review of a new licensed medicine. [2019]

11. United States 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. [2013]

12. United States pubmed.ncbi.nlm.nih.gov

Amphetamine-enhanced motor training after cervical contusion injury. [2021]

13. United States pubmed.ncbi.nlm.nih.gov

Activity-based therapies to promote forelimb use after a cervical spinal cord injury. [2021]

14. United States pubmed.ncbi.nlm.nih.gov

One day of motor training with amphetamine impairs motor recovery following spinal cord injury. [2013]