An Early Phase 1 interventional study of Tizanidine and Placebo in Stroke, sponsored by Northwestern University. Recruiting at 1 site in United States. Open to participants aged 18 Years to 80 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-09-30.
Sponsored by Northwestern University · Early Phase 1, Interventional, and Basic science
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.
Sixty-four individuals with stroke will be recruited. Efforts will be made to recruit the same participants for each protocol. A REDCap database for this study will be setup to manage every step involved in the protocol.
The experiment uses a two-arm, cross-over, double-blinded, pre-test-post-test, randomized controlled design. After confirming eligibility, all enrolled participants will be scheduled for one anatomic brain MRI data collection and 6 arm/ hand experiments: 2 for each aim, one with TIZ and the other with placebo. All experiments will take place on separate days at least one week apart. During each of the experimental sessions, the participant will complete the protocol both before and 1.5 hours after administration of either TIZ or a placebo. The order of using TIZ or a placebo will be double-blinded and randomized to balance the FMA of the participants who receive the TIZ or placebo during their first session. In Aim 1, individuals will perform various isometric tasks with their paretic upper limb while high-density surface electromyography is used to estimate the behavior of their motor units. In Aim 2, individuals will perform isometric shoulder abduction with their cortical activity estimated with electroencephalography and their muscle activity recorded with electromyography. In Aim 3, individuals will be placed in a novel robotic device and asked to produce various shoulder abduction torques while either being perturbed by the device to elicit stretch reflexes or asked to perform reaching and hand-opening tasks. For all aims, joint torque and surface electromyographic data will be obtained from each participant before and 1.5 hours after administration of placebo or Tizanidine. Additionally, electroencephalographic data will be obtained during the second aim and joint kinematics will be obtained in the third aim. In all aims, participants will be seated in a Biodex chair (System 3 ProTM; Shirley, New York, USA) with their paretic limb interfaced to a novel haptic device (NACT-3D, Plaisier et. al., 2023) to measure and manipulate the forces/torques experienced by the participant. Throughout each session, straps will be placed across the chest and waist to prevent unwanted movement. The total time from enrollment to completion of participants is expected to be 8-12 weeks, during which participants will be instructed to keep performing routine daily activities.
AE and SAE reporting Adverse event (AE) report form has been implemented in the RedCap database, which can be used at any time. The investigators will report all AEs to the Northwestern Institutional Review Board (IRB) per established policies and requirements. The investigators will create AE reports every six months to review for trends and troubleshoot any issues that arise and require study protocol revision. If any AEs are reported that require follow-up medical care, the investigators will immediately refer the participant back to his/her physician team.
Serious adverse events (SAEs) that are unanticipated, serious, and possibility related to the study intervention will be reported to the Independent Monitor(s), IRB, and National Institute of Child Health and Human Development (NICHD) in accordance with requirements. Unexpected fatal or life-threatening AEs related to the intervention will be reported to the Northwestern IRB in accordance with IRB requirements within 24 hours, and to the NICHD program Officer with 7 days. Other serious and unexpected AEs related to the intervention will also be reported to the Northwestern IRB in accordance with IRB requirements within 24 hours, and to the NICHD program Official within 15 days. Anticipated or unrelated SAEs will be handled in a less urgent manner but will be reported to the PIs, IRB, NICHD, and other oversight organizations in accordance with their requirements. In the annual AE summary, the PIs Report will state that they have reviewed all AE reports.
Exclusion Criteria:
Additionally, each participant will be asked to provide a list of their current medications and a medical screening questionnaire will be sent to their primary physician. Each participant's list of medications will be reviewed for possible interactions with the study drugs and, at the study physician's advice, will be excluded from the study or asked to withhold medications when applicable. A full list of potential drug interactions can be seen in "Medication Interactions", but concisely includes the following: medications with dopaminergic, serotonergic, or noradrenergic actions; central nervous system (CNS) depressants; antihypertensive/ antiarrhythmic agents; and hormonal medications/contraceptives.
One lactose pill will be administered as a control.
Drug: Placebo
4 mg Tizanidine
Drug: Tizanidine
Tizanidine (TIZ) (Zanaflex®) is a centrally acting noradrenergic α-2 agonist and a ligand of I3 (non-I1/I2) imidazoline receptors. It is currently indicated for the management of spasticity.
Also known as: Zanaflex®
Administered as control
Brace Height
Brace height quantifies the amplification in motor unit discharge rate generated by PICs. Brace height is sensitive to the level of neuromodulatory drive received by motoneurons.
Time frame: Before and 1.5 hours after administration of TIZ
Cortico-muscular-coherence in beta band
Cortico-muscular coherence (CMC) is a commonly used method to measure the synchronized activity between cortex and muscles. Specifically, betaband CMC has been reported to be linked to the use of corticospinal tract.
Time frame: Before and 1.5 hours after administration of TIZ
Difference in reaching distance under shoulder abduction load
The difference in reaching distance under shoulder abduction (SABD) load measures the strength of flexion synergy.
Time frame: Before and 1.5 hours after administration of TIZ
Reflexive electromyograph activity prior to movement
Reflexive electromyograph (EMG) activity will be calculated as the difference between perturbation-induced EMG amplitude and baseline EMG, averaged during three-time windows 1) before the perturbation -100- 0 ms pre-perturbation; 2) 25 - 75 ms (shortlatency stretch reflex) and 2) 75 - 125 ms (long latency stretch reflex) after the perturbation onset. Perturbations occur at rest before the onset of a regular ballistic reaching trial. EMG is then normalized by the maximal EMG of the corresponding muscle.
Time frame: Before and 1.5 hours after administration of TIZ
Delta-F
Delta-F quantifies hysteresis (i.e., prolongation, or persistence) in motor unit firing induced by persistent inward currents (PICs). Delta-F is less selective to the level of neuromodulatory drive, but also accounts for inhibitory synaptic inputs to motoneurons.
Time frame: Before and 1.5 hours after administration of TIZ
Cortico-muscular-coherence in alpha band
Alpha-band cortico-muscular-coherence (CMC) has been reported to be linked to the use of cortico-reticulospinal tract. A decreased use of cortico-reticulospinal tract will indirectly reflect an increased use of corticospinal tract, when the require motor task is still performed successfully.
Time frame: Before and 1.5 hours after administration of TIZ
Cortical Laterality Index (LI)
LI measures the relatively higher (close to 1) or lower (close to -1) cortical activity between the lesioned vs non-lesioned motor cortices. An increase in LI indicates a shift of cortical activity towards the lesioned motor cortices, and thus reflecting an increased use of corticospinal tract. Minimum value is -1 and maximum value is 1. Higher scores indicate increased use of corticospinal tract.
Time frame: Before and 1.5 hours after administration of TIZ
Difference in Hand hexagon area under SABD load
Hand hexagon area (HHA), i.e. the polygon created by connecting the five fingers of the hand with the base of the palm together in a plane, measures hand opening ability. The difference in HHA under SABD load also measures the strength of flexion synergy, but more distally. The investigators hypothesize that the difference under load will become less following tizanidine administration.
Time frame: Before and 1.5 hours after administration of TIZ
Reflexive EMG activity during movement
The investigators will calculate the reflexive EMG activity as in Hypothesis 3.2, but with the perturbation occurring during the onset of a ballistic reach.
Time frame: Before and 1.5 hours after administration of TIZ
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