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StrokeEarly Phase 1NCT03868410

A Novel Approach for Brain Stimulation in Severe Stroke

A Early Phase 1 study testing New Repetitive Magnetic Stimulation (rTMS) Approach and Conventional Repetitive Magnetic Stimulation (rTMS) Approach in people with Stroke, run by The Cleveland Clinic at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The long-term goal of this project is to develop upper limb rehabilitation interventions that can be utilized for stroke survivors, specifically survivors with more severe limitations in use of their affected upper limb. Read more about this study

Who is it for?
Ages 18 to 90 years
Conditions the study is for
Stroke
What is being tested?
New Repetitive Magnetic Stimulation (rTMS) Approach and Conventional Repetitive Magnetic Stimulation (rTMS) Approach
Type of treatment
Medical device
Could I receive a placebo?
No, everyone receives an active treatment
How many people
16 participants
Where
1 siteUnited States
Study dates
1 Apr 2019to 13 Jul 2023
Phase
Early Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 90 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • chronic phase (≥6 months) after index stroke
  • moderate or severely impaired (UEFM ≤42)
  • have either extensive damage to ipsilesional pathways (MEP-), or, have one of the following: less than 10 degrees active wrist extension, less than 10 degrees active thumb extension/abduction, less than 10 degrees active extension in at least 2 additional digits (i.e. will not meet minimum Constraint-Induced Movement Therapy [CIMT] criteria).
  • medically stable

Who cannot join

  • cerebellar stroke
  • brainstem stroke
  • bilateral strokes affecting sensorimotor structures
  • severe cognitive impairment
  • substantially elevated tone/spasticity in wrist/hand (Modified Ashworth Scale >3)
  • severe contracture
  • participation in outpatient or Botox therapy within 2 months
  • exclusion criteria for TMS and MRI (metal implant in head, H/O seizures, alcohol or substance abuse, intake of medications contraindicated with TMS, cardiac pacemaker or programmable implant).

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Lerner Research Institute; Cleveland Clinic Foundation

    Cleveland, Ohio, 44195

Other trials in United States

About this study

The long-term goal of this project is to develop upper limb rehabilitation interventions that can be utilized for stroke survivors, specifically survivors with more severe limitations in use of their affected upper limb.

This study will utilize a novel method of non-invasive brain stimulation in conjunction with upper limb training given for 12 visits over a period of 6 weeks.

Read more

The study will include the following site visits:

  • Eligibility Screening and Informed Consent Visit
  • An MRI visit
  • Two testing visits in which motor function of the upper limb and neurophysiology will be measured
  • 12 intervention visits during which patients will receive upper limb training in conjunction with non-invasive brain stimulation
  • Repeat testing of motor function of the upper limb and neurophysiology
  • Repeat MRI testing
  • A follow-up visit completed 3 months after the completion of interventions
Read the detailed description

In a pilot, randomized clinical trial, 24 stroke patients with moderate/severe impairments will receive non-invasive brain stimulation (repetitive Transcranial Magnetic Stimulation or rTMS) to one of two targets in the brain in conjunction with upper limb training for 2 days a week for 6 weeks. The primary outcome will be upper limb motor impairment, and secondary outcomes will be tests of functional abilities, proximal motor control, and patient-reported disability. Associated neural mechanisms will also be studied using neurophysiological and functional connectivity MRI techniques. Damage to ipsilesional corticospinal pathways will be indexed with diffusion tensor imaging (DTI).

Conditions
Stroke
Being tested
New Repetitive Magnetic Stimulation (rTMS) Approach, Conventional Repetitive Magnetic Stimulation (rTMS) Approach
Keywords
stroke, brain stimulation, TMS, Upper Limb, MRI, CVA, Rehabilitation
Medical subject headings
Stroke

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • New Repetitive Magnetic Stimulation (rTMS) ApproachDevice

    Also called Contralesional dorsal premotor cortex (cPMD) rTMS + Training

    Participants in this arm will receive rTMS-based facilitation of the contralesional dorsal premotor cortex (cPMd) located in the non-stroke hemisphere before start of each session. High-frequency rTMS (5-Hz) will be delivered using 42 10-sec trains of 50 pulses each (total 2100 pulses) for a period of 24 minutes. Immediately after the completion of rTMS, participants will undergo upper limb training for a total of one hour. Participants will receive these interventions 2 days a week for 6 weeks, i.e., for a total of 12 sessions.

  • Conventional Repetitive Magnetic Stimulation (rTMS) ApproachDevice

    Also called Ipsilesional Primary Motor Cortex (iM1) rTMS + Training

    Participants in this arm will receive rTMS-based facilitation of the ipsilesional primary motor cortex (iM1) before the start of each session. iM1 will be stimulated with high-frequency rTMS (5-Hz) using 42 10-sec trains of 50 pulses each (total 2100 pulses) for a period of 24 minutes. Immediately after the completion of rTMS, participants will undergo upper limb training for a total of one hour. Participants will receive these interventions 2 days a week for 6 weeks, i.e., for a total of 12 sessions.

Study groups in NCT03868410
Study groupRoleWhat they receive
Contralesional dorsal premotor cortex (cPMD) rTMS + TrainingActive comparatorNew Approach
Receives: Device: New Repetitive Magnetic Stimulation (rTMS) Approach
Ipsilesional Primary Motor Cortex (iM1) rTMS + TrainingActive comparatorConventional Approach
Receives: Device: Conventional Repetitive Magnetic Stimulation (rTMS) Approach

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Upper Extremity Fugyl-Meyer Score (UEFM)

    Change between Baseline and Post-Test (average 6 weeks) is reported for the UEFM. Impairment will be measured using UEFM, one of the most widely used assessments in stroke. UEFM will serve as our primary outcome because it is sensitive to discerning the effects of rTMS/rehabilitation, and has excellent reliability (ICC= 0.97), consistency (Cronbach's α= 0.84) and validity. UEFM has a score ranging from 0-66 (0 meaning there is no movement of the paretic arm, and 66 meaning there is no functional limitation of the paretic arm.)

    Measured: Change between Baseline and Post-Test (average 6 weeks)

  2. Change in Inter-hemispheric Inhibition (IHI)

    Inter-hemispheric connectivity (IHI) will be collected with transcranial magnetic stimulation (TMS) and is assessed using ipsilateral silent period (ISP) method. TMS is delivered to the contralesional motor hotspot at supra-maximal intensity (100% maximum stimulator output) while participants maintain sub-maximal contraction (50% maximum volitional contraction) of the ipsilateral paretic extensor digitorum communis muscle for 40 trials. Ipsilateral TMS produces transient suppression of on-going EMG activity, called ISP. ISP is analyzed using an algorithm that compares psotstimulus average rectified EMG to mean consecutive difference (MCD) of background EMG. A threshold of MCD x1.77 below mean background EMG is used to define ISP onset and offset. ISP duration is then calculated as a difference between onset and offset of the ISP.

    Measured: Change between Baseline and Post-Test (average 6 weeks)

Secondary outcomes (9)

  1. Change in Wolf Motor Function Test (WMFT) Functional Ability

    Change in Functional Ability (FA) from Baseline to Post-Test (average 6 weeks) is reported for the Wolf Motor Function Test. Functional ability (FA) to use the paretic upper limb in a variety of tasks will be assessed using WMFT. FA is scored on a scale from 0-5 with 0 not attempting the task at all and 5 being completely normal movement compared to non paretic limb. 15 items of WMFT are given a FA for the Paretic limb and then the score is averaged to give an overall FA for each participant.

    Measured: Change between Baseline and Post-Test (average 6 weeks)

  2. Change in Wolf Motor Function Test (WMFT) Rate Paretic Limb

    Change in Rate of the Paretic limb from Baseline to Post-Test (average 6 weeks) is reported for the Wolf Motor Function Test. Time to complete each task will be noted and converted to rate (60/Performance Time (sec)), optimized for measurement in moderately/severely-impaired patients. The rate will be calculated for the Paretic limb [WMFT Rate (P)]. The higher the rate the quicker they were able to complete the task.

    Measured: Change between Baseline and Post-Test (average 6 weeks)

  3. Change in Wolf Motor Function Test (WMFT) Rate Non-paretic Limb

    Change in Rate of the Non-paretic limb from Baseline to Post-Test (average 6 weeks) is reported for the Wolf Motor Function Test. Time to complete each task will be noted and converted to rate (60/Performance Time (sec)), optimized for measurement in moderately/severely-impaired patients. The rate will be calculated for the Non-paretic limb [WMFT Rate (NP)]. The higher the rate the quicker they were able to complete the task.

    Measured: Change between Baseline and Post-Test (average 6 weeks)

  4. Change in Wolf Motor Function Test (WMFT) Rate Paretic Limb Normalized to the Non-paretic Limb

    Change in the normalized Rate of the Paretic limb to the Non-paretic limb from Baseline to Post-Test (average 6 weeks) is reported for the Wolf Motor Function Test. Time to complete each task will be noted and converted to rate (60/Performance Time (sec)), optimized for measurement in moderately/severely-impaired patients. The rate will be calculated for the Paretic limb normalized to the Non-paretic limb [WMFT Rate (P/NP)]. The higher the rate the quicker they were able to complete the task.

    Measured: Change between Baseline and Post-Test (average 6 weeks)

  5. Change in Stroke Impact Scale (SIS-16)

    Change in total score between Baseline and Post-Test (average 6 weeks) is reported for the Stoke Impact Scale (SIS-16) for each group. Patient's perceived disability related to physical function will be indexed using the Stroke Impact Scale (SIS-16) which a subjective questionnaire asked to the subject pertaining of 16 questions. Each question is rated on scale from 1 to 5 and then the scores are totaled. Total scores can range from 16-80 (16 means that none of the functional tasks asked can be performed, a score of 80 means the subject has no issues at all performing any of the tasks asked).

    Measured: Change between Baseline and Post-Test (average 6 weeks)

  6. Change Resting State Functional Magnetic Resonance Imaging(rsfMRI)

    Functional connectivity will complement IHI measurement as a secondary outcome because while IHI records neurophysiologic interactions between a contralesional and a weak ipsilesional region, functional connectivity defines "global" interactions across multiple regions.

    Measured: Change between Baseline and Post-Test (average 6 weeks)

  7. Change in Ipsilateral MEPs (Motor Evoked Potentials)

    Output of uncrossed pathways will be studied as ipsilateral MEPs elicited in the paretic-muscle with TMS.

    Measured: Change between Baseline and Post-Test (average 6 weeks)

  8. Diffusion Tensor Imaging (DTI)

    Diffusion Tensor Imaging (DTI) enables the investigation of structural integrity and orientation of pathways in vivo through the estimation of magnitude and directionality of water diffusion. DTI metrics can help quantitate damage even when patients show no response to Transcranial Magnetic Stimulation (TMS) due to extensive damage (MEP-). Ipsilesional and contralesional corticospinal tracts will be reconstructed using probabilistic tractography. Fractional Anisotropy (FA), a unit-less measure of white matter integrity, will be calculated.

    Measured: Baseline

  9. Change in SULCS

    Change in total score between Baseline and Post-Test (average 6 weeks) is reported for the Stroke Upper Limb Capacity Scale (SULCS). SULCS is a stroke-specific assessment instrument that evaluates functional capacity of the upper limb based on the execution of 10 tasks. Score ranges from 0-10 where 0 is the lowest level of function in which the participant cannot perform any of the tasks as instructed and 10 is the highest level of function in which all 10 tasks are completed as instructed.

    Measured: Change between Baseline and Post-Test (average 6 weeks)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Mar 2019
  2. Study start1 Apr 2019
  3. Primary completion21 Apr 2023
  4. Study completion13 Jul 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
In a pilot, randomized, assessor-blind clinical trial, an anticipated 24 patients will be assigned to either receive stimulation to a new brain target- contralesional dorsal premotor cortex (cPMd) located in the non-stroke hemisphere- or the conventional brain target- ipsilesional primary motor cortex (iM1) located in the stroke hemisphere. Stimulation will be delivered in conjunction with rehabilitation for 2 days a week for 6 weeks.
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
16 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03868410
Sponsor's protocol ID
18-861
Status last verified
May 2025
First submitted
24 Sep 2018
Last updated
5 Jun 2025
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
Yes
Individual data sharing
No

Publications

  • Cunningham DA, Varnerin N, Machado A, Bonnett C, Janini D, Roelle S, Potter-Baker K, Sankarasubramanian V, Wang X, Yue G, Plow EB. Stimulation targeting higher motor areas in stroke rehabilitation: A proof-of-concept, randomized, double-blinded placebo-controlled study of effectiveness and underlying mechanisms. Restor Neurol Neurosci. 2015;33(6):911-26. doi: 10.3233/RNN-150574.

    PubMed 26484700

  • Potter-Baker KA, Lin YL, Machado AG, Conforto AB, Cunningham DA, Sankarasubramanian V, Sakaie K, Plow EB. Variability of motor evoked potentials in stroke explained by corticospinal pathway integrity. Brain Stimul. 2018 Jul-Aug;11(4):929-931. doi: 10.1016/j.brs.2018.03.004. Epub 2018 Mar 9. No abstract available.

    PubMed 29563050

  • Plow EB, Cunningham DA, Varnerin N, Machado A. Rethinking stimulation of the brain in stroke rehabilitation: why higher motor areas might be better alternatives for patients with greater impairments. Neuroscientist. 2015 Jun;21(3):225-40. doi: 10.1177/1073858414537381. Epub 2014 Jun 20.

    PubMed 24951091

  • Sankarasubramanian V, Machado AG, Conforto AB, Potter-Baker KA, Cunningham DA, Varnerin NM, Wang X, Sakaie K, Plow EB. Inhibition versus facilitation of contralesional motor cortices in stroke: Deriving a model to tailor brain stimulation. Clin Neurophysiol. 2017 Jun;128(6):892-902. doi: 10.1016/j.clinph.2017.03.030. Epub 2017 Mar 21.

    PubMed 28402865

  • Li X, Widina M, Liu J, O'Laughlin K, Barden E, Lin YL, Sakaie K, Cunningham DA, Wang X, Uchino K, Wolf SL, Conforto AB, Plow EB. Repetitive Transcranial Magnetic Stimulation of the Contralesional Dorsal Premotor Cortex for Upper Extremity Motor Improvement in Severe Stroke: A Pilot Randomized Clinical Trial. Am J Phys Med Rehabil. 2026 Mar 1;105(3S Suppl 2):S64-S73. doi: 10.1097/PHM.0000000000002909.

    PubMed 41707126

  • Li X, Lin YL, Cunningham DA, Wolf SL, Sakaie K, Conforto AB, Machado AG, Mohan A, O'Laughlin K, Wang X, Widina M, Plow EB. Repetitive Transcranial Magnetic Stimulation of the Contralesional Dorsal Premotor Cortex for Upper Extremity Motor Improvement in Severe Stroke: Study Protocol for a Pilot Randomized Clinical Trial. Cerebrovasc Dis. 2022;51(5):557-564. doi: 10.1159/000521514. Epub 2022 Jan 20.

    PubMed 35051941

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing New Repetitive Magnetic Stimulation (rTMS) Approach and Conventional Repetitive Magnetic Stimulation (rTMS) Approach in people with Stroke, run by The Cleveland Clinic at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 5 Jun 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Upper Extremity Fugyl-Meyer Score (UEFM) (time frame: Change between Baseline and Post-Test (average 6 weeks)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03868410, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jun 2025; AzTrials last refreshed its copy on 6 Nov 2026.

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