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A Novel Approach for Brain Stimulation in Severe Stroke

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ClinicalTrials.gov Identifier: NCT03868410
Recruitment Status : Recruiting
First Posted : March 11, 2019
Last Update Posted : March 11, 2019
Sponsor:
Collaborator:
American Heart Association
Information provided by (Responsible Party):
Ela B Plow, PhD, PT, The Cleveland Clinic

Brief 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.

This study will utilize a novel method of non-invasive brain stimulation in conjunction with upper limb training given for 15 visits over a period of 5 weeks.

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
  • Fifteen 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

Condition or disease Intervention/treatment Phase
Stroke Device: New rTMS Approach Device: Conventional rTMS Approach Early Phase 1

Detailed Description:
In a pilot, randomized controlled study, 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 3 days a week for 5 weeks. The primary outcome will be upper limb motor impairment, and secondary outcomes will be tests of functional abilities, proximal reaching performance 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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: In a pilot, randomized-controlled, double-blind study, 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 3 days a week for 5 weeks.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Subjects will be told they will receive brain stimulation, but will be given no indication as to which target will be stimulated. Investigators analyzing functional outcome data, neurophysiology data and MRI data will receive coded data that conceals the identity of the subject.
Primary Purpose: Treatment
Official Title: A Novel Approach for Brain Stimulation in Severe Stroke
Estimated Study Start Date : April 1, 2019
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : September 30, 2021

Arm Intervention/treatment
Active Comparator: cPMD rTMS + Training
New Approach
Device: New rTMS Approach
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 five 1-min trains of 300 pulses each (total 1500 pulses) for a period of 10 minutes. Immediately after the completion of rTMS, participants will undergo upper limb training for a total of one hour. Participants will receive these interventions 3 days a week for 5 weeks, i.e., for a total of 15 sessions.
Other Name: cPMd rTMS + Training

Active Comparator: iM1 rTMS + Training
Conventional Approach
Device: Conventional rTMS Approach
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 facilitated using a widely-used approach of stimulation delivered to inhibit the contralesional motor cortices located in the non-stroke hemisphere. Low-frequency rTMS (1-Hz) can inhibit the excitability of targeted regions. Therefore, this low-frequency approach will be delivered to suppress the excitability of the non-stroke hemisphere. A total of 1500 pulses will be given for 25 minutes. Immediately after the completion of rTMS, participants will undergo upper limb training for a total of one hour. Participants will receive these interventions 3 days a week for 5 weeks, i.e., for a total of 15 sessions.
Other Name: iM1 rTMS + Training




Primary Outcome Measures :
  1. Change in Upper Extremity Fugyl-Meyer Score (UEFM) [ Time Frame: through study completion, on average 6 weeks ]
    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.)

  2. Change in Inter-hemispheric Inhibition (IHI) [ Time Frame: through study completion, on average 6 weeks ]
    Inter-hemispheric connectivity will be characterized using IHI collected with TMS.


Secondary Outcome Measures :
  1. Change in Wolf Motor Function Test (WMFT) [ Time Frame: through study completion, on average 6 weeks ]
    Functional ability to use the paretic upper limb in a variety of tasks will be assessed using WMFT. Time to complete each task will be noted and converted to rate (60/Performance Time (sec)), optimized for measurement in moderately/severely-impaired patients. Grip strength will also be recorded with WMFT.

  2. Change in Reaching Response Time [ Time Frame: through study completion, on average 6 weeks ]
    Proximal motor control will be assessed using the reaching response-time task, which, as the name suggests, measures the time required to reach forward and push a cued button. This task is used to characterize motor control in moderately/severely-impaired patients who typically lack adequate distal movements.

  3. Change in Stroke Impact Scale (SIS-16) [ Time Frame: through study completion, on average 6 weeks ]
    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 1-5 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).

  4. Change Resting State Functional Magnetic Resonance Imaging(rsfMRI) [ Time Frame: through study completion, on average 6 weeks ]
    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.

  5. Change in ipsilateral MEPs (motor evoked potentials) [ Time Frame: through study completion, on average 6 weeks ]
    Output of uncrossed pathways will be studied as ipsilateral MEPs elicited in the paretic-muscle with TMS.

  6. DTI [ Time Frame: Baseline ]
    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 TMS due to extensive damage (MEP-). Ipsilesional and contralesional corticospinal tracts will be reconstructed using probabilistic tractography. FA, a unit-less measure of white matter integrity, will be calculated.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • chronic phase (≥6 months) after index stroke
  • moderate or severely impaired (UEFM ≤42) with extensive damage to ipsilesional pathways (MEP-)
  • able to perform the reaching-response time task
  • medically stable

Exclusion Criteria:

  • cortical stroke affecting motor areas (identified using T1-weighted MRI)
  • brainstem stroke
  • bilateral strokes
  • severe cognitive impairment (Mini-Mental State Examination (MMSE) score ≤ 24)
  • substantially elevated tone/spasticity in wrist/hand (Modified Ashworth Scale >3)
  • severe contracture
  • participation in outpatient or Botox therapy within 3 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03868410


Contacts
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Contact: Kyle J. O'Laughlin, MS 216-445-6728 olaughk@ccf.org
Contact: Ela Plow, PhD 216-445-4589 plowe2@ccf.org

Locations
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United States, Ohio
Lerner Research Institute; Cleveland Clinic Foundation Recruiting
Cleveland, Ohio, United States, 44195
Contact: Kyle J O'Laughlin, MS    216-445-6728    olaughk@ccf.org   
Contact: Ela Plow, PhD    216-445-4589    plowe2@ccf.org   
Principal Investigator: Ela Plow, PhD         
Sponsors and Collaborators
The Cleveland Clinic
American Heart Association
Investigators
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Principal Investigator: Ela Plow, PhD Lerner Research Institute; Cleveland Clinic Foundation

Publications of Results:
Other Publications:
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Responsible Party: Ela B Plow, PhD, PT, Assistant Staff, The Cleveland Clinic
ClinicalTrials.gov Identifier: NCT03868410     History of Changes
Other Study ID Numbers: 18-861
First Posted: March 11, 2019    Key Record Dates
Last Update Posted: March 11, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No

Keywords provided by Ela B Plow, PhD, PT, The Cleveland Clinic:
stroke
brain stimulation
TMS
Upper Limb
MRI
CVA
Rehabilitation

Additional relevant MeSH terms:
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Stroke
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases