Amantadine for Traumatic Brain Injury

Recruiting at 14 trial locations

Overseen By Adhiraj Dharmadhikari

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: SHINKEI Therapeutics, Inc

Must not be taking: Amantadine, CNS stimulants, others

Disqualifiers: Spinal cord injury, Seizures, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 3 weeks

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called Amantadine Hydrochloride to determine its safety and effectiveness for people with traumatic brain injuries (TBI). Researchers will compare the drug's effects to a placebo (a harmless substance resembling the drug) over three weeks. The goal is to assess whether the drug improves recovery and reduces time in intensive care. Individuals with a TBI confirmed by a scan, injured between 72 hours and one week ago, may be suitable for this trial. Participants must currently be in an acute care setting and unable to consistently follow commands. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop all current medications, but you cannot have taken an investigational drug, CNS stimulant, dopamine antagonist/agonist within 4 weeks, or a systemic anticholinergic medication within 1 week before screening.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that amantadine hydrochloride is generally safe for people. Studies have found that it can help patients with traumatic brain injury recover faster without increasing the risk of death, suggesting it likely doesn't pose serious safety issues. However, one study found it might slightly affect thinking skills in some cases.

Overall, amantadine appears well-tolerated, but like any treatment, it may have some side effects. Those interested in participating in trials should discuss the possible risks and benefits with their healthcare providers. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Amantadine Hydrochloride is unique because it offers a different approach to treating traumatic brain injuries compared to the standard options like rehabilitation therapies and medications that often focus on managing symptoms rather than enhancing recovery. Unlike typical treatments, Amantadine is thought to work by influencing dopamine pathways in the brain, potentially boosting cognitive and physical recovery. Researchers are excited about this treatment because it might speed up recovery and improve outcomes more effectively than current therapies, offering new hope for patients with traumatic brain injuries.

What evidence suggests that Amantadine Hydrochloride might be an effective treatment for traumatic brain injury?

Research has shown that amantadine hydrochloride may speed up recovery from traumatic brain injury (TBI). In this trial, participants will receive either amantadine or a placebo. Studies have found that patients taking amantadine recover faster than those taking a placebo, which contains no active medicine. One study demonstrated that patients on amantadine experienced better recovery and improved daily functioning. It also helps reduce irritability and aggression, common after a severe TBI. Importantly, amantadine does not increase the risk of death. Overall, early research suggests that amantadine can be a helpful option for people with TBI. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with severe traumatic brain injury (TBI) who were admitted to acute care within the past week and have a Glasgow Coma Score of 3-8. They must be unable to follow commands or communicate functionally, have at least one reactive pupil, stable vital signs, and TBI confirmed by imaging. A legal representative must consent.

Inclusion Criteria

I have someone legally authorized to make decisions for me.

I have been in the hospital for at least 2 days before joining the study.

I experienced a trauma between 3 days and 1 week ago.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive MR-301 or placebo intravenously BID for up to 3 weeks

3 weeks

Daily visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Amantadine Hydrochloride

Trial Overview The study tests the safety of Amantadine Hydrochloride IV solution (MR-301) versus a placebo in patients with severe TBI. Over three weeks, participants will receive either MR-301 or a placebo twice daily while researchers monitor their overall outcome, neurological response, ICU/hospital stay duration, and mortality rates.

How Is the Trial Designed?

Group I: MR-301 Active Control 1 Intervention

On first day, patient will receive MR-301 at 100 mg intravenous infusion BID. On second day, the dose is elevated to 150 mg intravenous infusion BID. On third day, the dose is further elevated to 200 mg intravenous infusion BID and maintained up to Day 21

Group II: Placebo Placebo Group 1 Intervention

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

Approved in United States as Gocovri for:

• Dyskinesia associated with Parkinson's disease
• Influenza A viral infection

Approved in European Union as Symmetrel for:

• Parkinson's disease
• Extrapyramidal side effects of medications
• Postherpetic neuralgia

Approved in Canada as Amantadine Hydrochloride for:

• Parkinson's disease
• Influenza A viral infection

Who Is Running the Clinical Trial?

SHINKEI Therapeutics, Inc

Lead Sponsor

Trials

1

Recruited

50+

Duke Clinical Research Institute

Collaborator

Trials

69

Recruited

242,000+

Published Research Related to This Trial

In a study of 39 children with autism, amantadine hydrochloride showed statistically significant improvements in clinician-rated measures of hyperactivity and inappropriate speech, suggesting it may be effective for managing certain behavioral disturbances.

While parents did not report significant changes in behavior, the overall safety profile of amantadine was good, indicating it was well tolerated, and highlighting the need for further research into its effects and the potential for large placebo responses in such trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. King, BH., Wright, DM., Handen, BL., et al.[2013]

Amantadine may help improve cognitive function and reduce agitation in patients after a non-penetrating traumatic brain injury (TBI), based on a review of five clinical trials and additional case reports.

While most patients showed improved neuropsychological test scores with amantadine therapy, the evidence is still inconclusive, indicating a need for further studies to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amantadine for traumatic brain injury: does it improve cognition and reduce agitation? Leone, H., Polsonetti, BW.[2013]

Amantadine, a dopamine agonist, has been shown to improve cognitive function in individuals with traumatic brain injury (TBI), particularly in areas like arousal, memory, and aggression, based on literature reviewed from 1994 to present.

The review indicates that amantadine can be effective even when started days to months after the injury, suggesting its potential as a treatment option for cognitive dysfunction following TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amantadine to Treat Cognitive Dysfunction in Moderate to Severe Traumatic Brain Injury. Stelmaschuk, S., Will, MC., Meyers, T.[2017]

In a study of 22 subjects with chronic traumatic brain injury (TBI), treatment with amantadine for 12 weeks led to significant improvements in executive function, indicating its potential efficacy in cognitive rehabilitation.

PET scans showed increased glucose metabolism in the left pre-frontal cortex, correlating positively with improvements in executive function, suggesting a mechanism of action related to enhanced brain activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of the dopaminergic agent and NMDA receptor antagonist amantadine on cognitive function, cerebral glucose metabolism and D2 receptor availability in chronic traumatic brain injury: a study using positron emission tomography (PET). Kraus, MF., Smith, GS., Butters, M., et al.[2022]

In a double-blind, randomized controlled trial involving 40 patients with traumatic brain injury (TBI), amantadine showed a significant improvement in the Glasgow Coma Scale (GCS) scores from the first to the seventh day of treatment, indicating a potential short-term benefit in consciousness levels.

However, after 6 months of follow-up, amantadine did not demonstrate any significant long-term effects on cognitive function, memory, disability, or overall performance in patients, suggesting limited efficacy in the recovery process after TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of amantadine on traumatic brain injury outcome: a double-blind, randomized, controlled, clinical trial. Ghalaenovi, H., Fattahi, A., Koohpayehzadeh, J., et al.[2019]

In a study of 42 patients with Parkinson's disease, amantadine significantly improved symptoms and activity impairment scores by 92% and 95% respectively, compared to only 4% and 18% improvements with placebo, demonstrating its efficacy when combined with levodopa and carbidopa.

The side effects of amantadine were generally similar to those of placebo, with only a few mild cases reported, indicating that it is a safe addition to existing Parkinson's treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amantadine and a fixed combination of levodopa and carbidopa in the treatment of Parkinson's disease. Savery, F.[2013]

In a triple-blinded, placebo-controlled trial involving 57 severe TBI patients, amantadine hydrochloride significantly improved functional ability as measured by the Disability Rating Scale (DRS) compared to placebo, indicating its potential efficacy in enhancing recovery.

While both groups showed improvement, the amantadine group had a greater change from baseline in DRS scores (10.88 vs. 8.04), and the treatment was well tolerated, suggesting it could be a safe option for enhancing recovery in severe TBI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A placebo-controlled randomized clinical trial of amantadine hydrochloride for evaluating the functional improvement of patients following severe acute traumatic brain injury. Shimia, M., Iranmehr, A., Valizadeh, A., et al.[2023]

In a study of 184 patients with prolonged disorders of consciousness after traumatic brain injury, amantadine significantly accelerated functional recovery compared to placebo during a 4-week treatment period, as indicated by a faster improvement in Disability Rating Scale scores.

Although the rate of improvement slowed after treatment ended, there were no significant differences in serious adverse events between the amantadine and placebo groups, suggesting that amantadine is a safe option for promoting recovery in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-controlled trial of amantadine for severe traumatic brain injury. Giacino, JT., Whyte, J., Bagiella, E., et al.[2022]

A multicenter, double-blind, placebo-controlled trial involving 184 patients with severe traumatic brain injury (TBI) showed that amantadine hydrochloride significantly accelerates recovery, with a notable improvement in the Disability Rating Scale score over 4 weeks.

Patients receiving amantadine had a recovery rate that was statistically better than those on placebo, indicating its potential therapeutic value in managing severe TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amantadine for patients with severe traumatic brain injury: a critically appraised topic. Spritzer, SD., Kinney, CL., Condie, J., et al.[2022]

A 65-year-old woman with Parkinsonism who did not respond to standard treatments like levodopa and bromocriptine showed significant improvement in motor and mental function after being treated with amantadine (200 mg/day).

This case highlights amantadine's potential as an effective alternative therapy for patients with Parkinsonism who are resistant to conventional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amantadine for levodopa resistant parkinsonism. Sandyk, R., Iacono, RP., Snider, SR.[2019]

In a double-blind, placebo-controlled study involving one patient with severe amotivation after traumatic brain injury, amantadine (100 mg three times daily) significantly improved motivation scores from an average of 0.86 on placebo to 1.74 on amantadine.

The study found no side effects associated with amantadine, suggesting it may be a safe option for enhancing rehabilitation in patients with amotivational syndrome, warranting further randomized clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N of 1 study: amantadine for the amotivational syndrome in a patient with traumatic brain injury. Van Reekum, R., Bayley, M., Garner, S., et al.[2019]

In a study of 55 patients with severe traumatic brain injury, those treated with amantadine showed a significant improvement in cognitive function, as measured by the Disability Rating Scale, compared to those who did not receive the medication (7.8 vs 3.6 improvement, P = .001).

Patients receiving amantadine were also more likely to be discharged to traumatic brain injury rehabilitation (73.9% vs 21.9%, P = .0002), suggesting that amantadine may enhance recovery outcomes in the acute postinjury period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of amantadine on acute cognitive disability after severe traumatic brain injury: An institutional pilot study. Tracy, BM., Srinivas, S., Nahum, KD., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10924175/

Amantadine for functional improvement in patients with ... Evidence of this review show that the use of Amantadine may have a beneficial effect on functional outcome in moderate to severe traumatic brain injuries among ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT00970944

Effectiveness of Amantadine Hydrochloride for Treatment ... This is a controlled trial of amantadine to improve level of function following severe traumatic brain injury. The purpose of this study is:.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1102609

Placebo-Controlled Trial of Amantadine for Severe ... During the 4-week treatment period, recovery was significantly faster in the amantadine group than in the placebo group, as measured by the DRS ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/24263176/

Effectiveness of amantadine hydrochloride in the reduction ... Conclusions: : Amantadine 100 mg every morning and at noon appears an effective and safe means of reducing frequency and severity of irritability and aggression ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0303846725003671

Efficacy and safety of amantadine for functional recovery in ... Amantadine accelerates functional recovery in patients with traumatic brain injury. •. Amantadine use does not impact mortality rates. •. Amantadine use is not ...

6. biausa.org biausa.org/professionals/research/tbi-model-systems/amantadine-did-not-positively-impact-cognition-in-chronic-traumatic-brain-injury

Amantadine did not Positively Impact Cognition in Chronic ... The results of this large scale study suggest that the application of amantadine may even have some very small negative effects on thinking skills after a TBI.