Tizanidine for Stroke

(ENCMS 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effects of Tizanidine, a medication approved by the U.S. FDA, to determine its potential to improve arm movement in stroke survivors. Researchers examine how Tizanidine might alter brain activity, eye response, and arm movements. The trial includes two groups: one receiving Tizanidine and the other a placebo (a non-active pill). This trial may suit stroke survivors with substantial arm weakness on one side who can still move their shoulder and elbow. As an Early Phase 1 trial, this research aims to understand how Tizanidine works in stroke survivors, offering participants a chance to contribute to groundbreaking insights.

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.

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

Research has shown that Tizanidine, the treatment under study, is generally safe for people. It helps with muscle stiffness related to conditions like stroke without weakening the muscles.

The FDA has already approved Tizanidine for treating conditions like multiple sclerosis and spinal cord injury, indicating a well-understood safety profile. However, it can cause side effects, such as drowsiness, which is important to consider when joining the trial.

In summary, previous studies consider Tizanidine safe, but potential drowsiness should be noted. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for stroke?

Tizanidine is unique because it offers a new approach to stroke recovery by potentially enhancing muscle relaxation and reducing spasticity. Most current treatments for stroke focus on clot removal or rehabilitation therapies, but Tizanidine targets muscle tone directly, which could lead to improved motor function. Researchers are excited about Tizanidine's potential to work quickly and effectively in alleviating muscle stiffness, providing a novel option alongside current therapies.

What evidence suggests that Tizanidine might be an effective treatment for stroke?

Research has shown that Tizanidine effectively treats muscle stiffness in stroke patients. Studies have found that it reduces muscle tightness, improving movement and lessening pain. The medication relaxes overactive muscles without significantly weakening them. In this trial, participants will receive either Tizanidine or a placebo to evaluate its effectiveness. Comparisons with other treatments for muscle stiffness have demonstrated Tizanidine's effectiveness, making it a promising option for improving arm movement after a stroke. ^{1 2 4 6 7}

Who Is on the Research Team?

Julius Dewald, DPT, PhD

Principal Investigator

Northwestern University

Jun Yao, PhD

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/11486114/

Open-label dose-titration safety and efficacy study of ... Conclusions: Overall, the data suggest that tizanidine is safe and efficacious in the treatment of stroke-related spasticity, preserving muscle strength while ...

2. ahajournals.org ahajournals.org/doi/10.1161/01.str.32.8.1841

Open-Label Dose-Titration Safety and Efficacy Study of ... Conclusions— Overall, the data suggest that tizanidine is safe and efficacious in the treatment of stroke-related spasticity, preserving muscle strength while ...

3. biausa.org biausa.org/professionals/research/tbi-model-systems/first-study-tizanidine-medication-appears-to-reduce-abnormal-excessive-muscle-tone

First Study: Tizanidine Medication Appears to Reduce ... In this study, tizanidine appeared to be effective in decreasing spasticity associated with traumatic brain injury and stroke.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0885392404002155

Comparative efficacy and safety of skeletal muscle ... There is fair evidence that baclofen, tizanidine, and dantrolene are effective compared to placebo in patients with spasticity (primarily multiple sclerosis).

5. academic.oup.com academic.oup.com/ptj/article/84/10/973/2857578

Pharmacologic Management of Spasticity Following Stroke Tizanidine also has been shown to be effective in reducing spasticity as measured by the Modified Ashworth Scale, in reducing pain intensity, ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK519505/

Tizanidine - StatPearls - NCBI Bookshelf Tizanidine is a centrally acting alpha-2 agonist prescribed to manage spasticity caused by multiple sclerosis, stroke, and spinal cord injury. Tizanidine is ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT00047580?term=tizanidine&rank=8

Comparison of Safety and Efficacy of Tizanidine ... This study is being conducted to compare the impact of somnolence (sleepiness) on cognition (awareness) as well as the safety and effectiveness ...