Amantadine for Traumatic Brain Injury

Recruiting at 11 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

Trial Summary

What is the purpose of this trial?

The main goal of this clinical trial is to check if the treatment is safe and well-tolerated. Researchers will compare the MR-301 active drug group with the placebo group to evaluate the safety and tolerability of the drug. Other measurements include assessing the patient's overall outcome, neurological responses, time spent in the intensive care unit, time in the hospital, and mortality. Participants will receive either MR-301 BID IV dosing or a matching placebo for a total of 3 weeks.

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.

What data supports the effectiveness of the drug amantadine for traumatic brain injury?

Research suggests that amantadine can help improve cognitive function, such as memory and attention, in people with traumatic brain injury. Studies have shown that it may aid in recovery by enhancing brain activity and supporting neurological function. ^{1 2 3 4 5}

Is amantadine generally safe for humans?

Amantadine has been studied for various conditions, including Parkinson's disease and autism, and is generally considered safe. In studies, side effects were similar to placebo, with mild cases of skin discoloration and blurred vision reported. In a study on traumatic brain injury, no side effects were observed. ^{6 7 8 9 10}

How is the drug amantadine different from other treatments for traumatic brain injury?

Amantadine is unique because it acts as a dopamine receptor agonist, which means it can stimulate the nervous system and potentially aid in recovery after a traumatic brain injury. It is commonly used to improve cognitive function and promote functional recovery in patients with severe TBI. ^{1 2 5 11 12}

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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 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]

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]

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]

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]

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]

References

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

Placebo-controlled trial of amantadine for severe traumatic brain injury. [2022]

2. Italy 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. [2023]

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

Amantadine to Treat Cognitive Dysfunction in Moderate to Severe Traumatic Brain Injury. [2017]

4. England 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). [2022]

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

The effect of amantadine on acute cognitive disability after severe traumatic brain injury: An institutional pilot study. [2023]

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

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

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

Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Amantadine for levodopa resistant parkinsonism. [2019]

9. England pubmed.ncbi.nlm.nih.gov

N of 1 study: amantadine for the amotivational syndrome in a patient with traumatic brain injury. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Amantadine for traumatic brain injury: does it improve cognition and reduce agitation? [2013]

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

Amantadine for patients with severe traumatic brain injury: a critically appraised topic. [2022]

12. England pubmed.ncbi.nlm.nih.gov

The effects of amantadine on traumatic brain injury outcome: a double-blind, randomized, controlled, clinical trial. [2019]