Tizanidine for Stroke

(SDMOAD Trial)

Overseen By Jun Yao, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Northwestern University

Must not be taking: CNS depressants, Antihypertensives, Hormonal medications, others

Disqualifiers: Cardiovascular disease, Seizure, Pregnancy, others

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 6-8 weeks

64 Participants Needed

Trial Summary

What is the purpose of this trial?

This study investigates the effects of Tizanidine on the voluntary movement controls of the arms of participants who have had a stroke and have not had a stroke by measuring medication-induced changes in upper extremity kinematics, pupillometry, and brain activity. Tizanidine is approved by the U.S. Food and Drug Administration. Understanding how different areas of the brain are involved in movement impairments may help rehabilitation efforts and assist in restoring healthy movement in individuals who have had a stroke.

Will I have to stop taking my current medications?

The trial may require you to stop taking certain medications if they interact with Tizanidine. These include medications affecting dopamine, serotonin, or norepinephrine, as well as those that depress the central nervous system, control blood pressure or heart rhythm, and hormonal medications. Your current medications will be reviewed, and you may be asked to withhold some if necessary.

How does the drug Tizanidine differ from other treatments for stroke?

Tizanidine is unique for stroke treatment as it is primarily a muscle relaxant used for conditions like muscle spasticity, whereas other stroke treatments often focus on neuroprotection or thrombolysis. Its use in stroke may offer a novel approach by potentially addressing muscle-related symptoms, which is different from the typical focus on brain protection or blood flow restoration. ^{1 2 3 4 5}

Research Team

Julius Dewald, DPT, PhD

Principal Investigator

Northwestern University

Jun Yao, PhD

Principal Investigator

Northwestern University

Eligibility Criteria

This trial is for adults aged 18-80 who've had a stroke at least six months ago, can move their arm voluntarily but with significant impairment, and can sit for three hours. They must not have other neurological disorders affecting the arms, untreated heart disease, severe pain in limbs or spine, recent injections for muscle control in the affected arm, or be on certain medications.

Inclusion Criteria

I can communicate, understand information, and give informed consent.

I had a stroke in the upper part of my brain more than 6 months ago.

MRI compatible

Exclusion Criteria

I have weakness or numbness in my limb that was not affected by my condition.

Current use of a pacemaker

I have had seizures in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a two-arm, cross-over, double-blinded, pre-test-post-test, randomized controlled design with Tizanidine and placebo, including MRI and 6 arm/hand experiments

6-8 weeks

7 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Tizanidine

Trial Overview The study tests Tizanidine's effects on arm movement control in people who've had a stroke by observing changes in limb motion dynamics, pupil response to light (pupillometry), and brain activity. Participants will receive either Tizanidine or a placebo to compare outcomes.

Participant Groups

Group I: Drug Probe Active Control 1 Intervention

8 mg Tizanidine

Group II: Placebo Placebo Group 1 Intervention

One lactose pill will be administered as a control.

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

Approved in United States as Zanaflex for:

• Muscle spasticity

Approved in European Union as Zanaflex for:

• Muscle spasticity

Approved in Canada as Zanaflex for:

• Muscle spasticity

Approved in Japan as Zanaflex for:

• Muscle spasticity

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Findings from Research

In a review of six double-blind, placebo-controlled trials involving 1757 patients with acute ischaemic stroke, tirilazad mesylate did not reduce early or end-of-trial case fatality rates, indicating it may not be effective in improving survival outcomes.

However, tirilazad was associated with a significant increase in the odds of death or disability by about 20%, and it also raised the risk of infusion site phlebitis, suggesting potential safety concerns with its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirilazad for acute ischaemic stroke. Bath, PM., Iddenden, R., Bath, FJ., et al.[2018]

TBN, a novel dual-functional agent, demonstrated significant therapeutic effects in rat models of ischemic stroke, effectively crossing the blood-brain barrier and showing a therapeutic time window of up to 8 hours after stroke onset.

The compound works through multiple mechanisms, including scavenging harmful free radicals and inhibiting calcium influx, which are crucial for protecting neurons from damage during ischemic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic effects of tetramethylpyrazine nitrone in rat ischemic stroke models. Sun, Y., Yu, P., Zhang, G., et al.[2012]

Tetramethylpyrazine nitrone (TBN) demonstrated significant neuroprotective effects in a rat model of ischaemic stroke, reducing cerebral infarction and improving neurological function when administered shortly after the stroke.

TBN also promoted the growth of new neurons and oligodendrocytes, with its pro-neurogenic effects linked to the activation of specific signaling pathways involving brain-derived neurotrophic factor (BDNF), suggesting it could be a dual-action treatment for stroke recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tetramethylpyrazine nitrone activates the BDNF/Akt/CREB pathway to promote post-ischaemic neuroregeneration and recovery of neurological functions in rats. Zhang, G., Zhang, T., Li, N., et al.[2021]

In an embolic stroke model, the combination of the glutamate antagonist MK-801 with tissue plasminogen activator (t-PA) significantly reduced neurological damage compared to t-PA alone, suggesting enhanced efficacy of this treatment approach.

The calcium channel blocker nimodipine did not improve outcomes when used with t-PA, indicating that not all combination therapies are beneficial, and highlighting the potential of glutamate antagonists in improving stroke treatment safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tissue plasminogen activator plus glutamate antagonist improves outcome after embolic stroke. Zivin, JA., Mazzarella, V.[2019]

Tirilazad demonstrated a significant reduction in infarct volume by 29.2% and improved neurobehavioral scores by 48.1% in a systematic review of 18 studies involving 544 animals, indicating its potential neuroprotective efficacy in stroke models.

Despite these promising results in animal studies, the overall quality of the studies was moderate, and potential biases may affect the reliability of these findings, suggesting caution in translating these results to clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke. Sena, E., Wheble, P., Sandercock, P., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Tirilazad for acute ischaemic stroke. [2018]

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

Therapeutic effects of tetramethylpyrazine nitrone in rat ischemic stroke models. [2012]

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

Tetramethylpyrazine nitrone activates the BDNF/Akt/CREB pathway to promote post-ischaemic neuroregeneration and recovery of neurological functions in rats. [2021]

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

Tissue plasminogen activator plus glutamate antagonist improves outcome after embolic stroke. [2019]

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

Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke. [2020]