rTMS Plus CCFES-mediated Functional Task Practice for Severe Stroke

NCT03870672 | Recruiting DMC FDA Device

• 2 other identifiers: 19-286R01HD098073
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a necessary and important step in the development of a new therapy for upper limb functional recovery in patients with severe motor impairment. It is the first clinical trial of non-invasive brain stimulation (repetitive transcranial magnetic stimulation or rTMS) delivered to excite the undamaged hemisphere (specifically the contralesional higher motor cortices or cHMC) in stroke. Therefore, this study will determine whether the positive results obtained in our short-term pilot study can be made to last longer and produce functional benefits in severe patients with the application of brain stimulation in combination with long-term rehabilitation therapy. Rehabilitation therapy administered is called contralaterally controlled functional electrical stimulation (CCFES). Determining whether combining rTMS facilitating the cHMC with CCFES produces synergistic gains in functional abilities in severe patients is necessary for acceptance by the clinical community and to move this technology toward commercialization and widespread dissemination. The proposed study will determine whether the combination of rTMS facilitating the cHMC with CCFES produces greater improvements in upper extremity function in severe participants who are ≥6 months from stroke onset than the combination of rTMS facilitating the damaged hemisphere (specifically the ipsilesional primary motor cortex, iM1) and CCFES or the combination of sham rTMS and CCFES. The secondary purposes are to define which patients benefit most from the treatments, which may inform future device and treatment development and clinical translation, and to explore what distinct effects the three treatments have on the brain. To accomplish these purposes, we are conducting a clinical trial that enrolls severe stroke patients.

Conditions

Stroke; Hemiplegia; Cerebrovascular Accident (CVA); Hemiparesis

Keywords

Upper limb; Stroke; CVA; Rehabilitation; Brain Stimulation; CCFES; Motor Cortex; TMS; Motor Recovery

Outcome Measures

Primary Outcomes (1)

• Change in Upper Extremity Fugl-Meyer (UEFM)

  The UEFM is a reliable and valid measure of post-stroke upper limb motor impairment. The UEFM items take into account synergy patterns, isolated strength, coordination, and hypertonia. Volitional movement of the upper limb (shoulder, elbow, forearm, wrist, and hand) is examined in and out of synergies. Each item is graded on a 3-point ordinal scale (0, cannot perform; 1, perform partially; and 2, perform fully) and summed to provide a maximum score of 66. The UEFM is classified as a body structure/function impairment measure on the ICF domain.

  Change in UEFM will be assessed at at 6 weeks, 12 weeks (end of treatment), 24 weeks, and 36 weeks.

Other Outcomes (1)

• Change in Neurophysiologic Assessments

  Change in neurophysiologic indices will be measured at 12 weeks (end of treatment) and at 36 weeks, on a separate day from functional motor outcomes assessment.

Study Arms (3)

CCFES + rTMS facilitating cHMC

ACTIVE COMPARATOR

This rTMS paradigm is the "New Approach". Facilitation of the intact hemisphere target (cHMC) will be achieved using 5Hz rTMS. After rTMS, the participant will participate in one hour of CCFES-mediated functional task practice. The therapist will instruct and guide the participants in practicing functional tasks with their paretic hand with the assistance of CCFES. Tasks will involve using the paretic hand to pick up, manipulate, and release objects commonly used in daily life. Early sessions will focus on simpler tasks, such as practicing opening the hand adequately to acquire an object.

Device: Contralaterally Controlled Functional Electrical Stimulation; Device: New rTMS approach

CCFES + rTMS facilitating iM1

ACTIVE COMPARATOR

This rTMS paradigm is the "Conventional Approach".Facilitation of M1 will be achieved using 5Hz rTMS. After rTMS, the participant will participate in one hour of CCFES-mediated functional task practice. The therapist will instruct and guide the participants in practicing functional tasks with their paretic hand with the assistance of CCFES. Tasks will involve using the paretic hand to pick up, manipulate, and release objects commonly used in daily life. Early sessions will focus on simpler tasks, such as practicing opening the hand adequately to acquire an object.

Device: Contralaterally Controlled Functional Electrical Stimulation; Device: Conventional rTMS approach

CCFES + Sham rTMS

SHAM COMPARATOR

This rTMS paradigm is the "Sham Approach". Immediately after sham rTMS, the participant will participate in one hour of CCFES-mediated functional task practice. The therapist will instruct and guide the participants in practicing functional tasks with their paretic hand with the assistance of CCFES. Tasks will involve using the paretic hand to pick up, manipulate, and release objects commonly used in daily life. Early sessions will focus on simpler tasks, such as practicing opening the hand adequately to acquire an object.

Device: Contralaterally Controlled Functional Electrical Stimulation; Device: Sham rTMS approach

Interventions

Contralaterally Controlled Functional Electrical Stimulation DEVICE

Contralaterally Controlled Functional Electrical Stimulation (CCFES) uses electrical stimulation to open the weak hand. Sticky patches called electrodes are placed on the participant's affected arm to stimulate the hand muscles, and a special glove is worn on the participant's strong hand and controls the stimulator. When the participant opens the gloved hand, stimulation opens the weak hand; when they close the gloved hand, stimulation turns off and the weak hand relaxes. During the clinic visits, participants will use CCFES to assist hand opening during functional training. During participant home sessions, they will use CCFES to perform hand opening exercise.

Also known as: CCFES

CCFES + Sham rTMS; CCFES + rTMS facilitating cHMC; CCFES + rTMS facilitating iM1

New rTMS approach DEVICE

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 + CCFES for a total of one hour. Participants will receive these interventions 2 days a week for 12 weeks.

Also known as: cHMC rTMS + CCFES and upper limb training

CCFES + rTMS facilitating cHMC

Conventional rTMS approach DEVICE

Facilitation of M1 will be achieved using 5Hz rTMS. 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 + CCFES for a total of one hour. Participants will receive these interventions 2 days a week for 12 weeks.

Also known as: iM1 rTMS + CCFES and upper limb training

CCFES + rTMS facilitating iM1

Sham rTMS approach DEVICE

In the sham rTMS group, ipsilesional motor hotspot will be targeted in half the patients and cHMC location will be targeted in the other half (based on random assignment). Immediately after the completion of rTMS, participants will undergo upper limb training + CCFES for a total of one hour. Participants will receive these interventions 2 days a week for 12 weeks.

Also known as: Sham rTMS + CCFES and upper limb training

CCFES + Sham rTMS

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• age 18 to 90 years old at time of randomization
• greater than 6 months since a first clinical cortical or subcortical, ischemic or hemorrhagic stroke
• severe upper limb hemiparesis defined as less than 10° active wrist extension or less than 10° active thumb abduction/extension or less than 10° active extension in at least two additional digits (i.e., will not meet minimum CIMT criteria)
• ability to follow 3-stage commands and can remember 2 items from a list of 3 items after 3 minutes
• adequate active movement of shoulder and elbow to position the paretic hand on one's lap for performance of functional task practice and CCFES-assisted hand opening exercises
• skin intact on hemiparetic arm
• surface electrical stimulation of the paretic finger and thumb extensors produces functional hand opening without pain
• able to hear and respond to cues from stimulator
• completed occupational therapy at least 2 months prior to enrollment (no concomitant OT)
• full volitional hand opening/closing of the non-paretic hand
• ability to follow instructions for putting on and operating the CCFES stimulator or a caregiver available to provide assistance

You may not qualify if:

• metal implant in the head
• history of seizures as an adult
• history of alcohol or substance abuse less than 10yrs prior to enrollment
• intake of anticonvulsants or anti-depressants contraindicated with TMS
• cardiac pacemaker or other programmable implant

Sponsors & Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• The Cleveland Clinic: lead

Study Sites (1)

Lerner Research Institute; Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

RECRUITING

Related Publications (1)

• Mohan A, Knutson JS, Cunningham DA, Widina M, O'Laughlin K, Arora T, Li X, Sakaie K, Wang X, Uchino K, Plow EB. Contralaterally Controlled Functional Electrical Stimulation Combined With Brain Stimulation for Severe Upper Limb Hemiplegia-Study Protocol for a Randomized Controlled Trial. Front Neurol. 2022 Apr 29;13:869733. doi: 10.3389/fneur.2022.869733. eCollection 2022.

  PMID: 35599736 DERIVED

MeSH Terms

Conditions

Stroke; Hemiplegia; Paresis

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Paralysis; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Ela B Plow, PhD PT

  Lerner Research Institute; Cleveland Clinic Foundation

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kyle J. O'Laughlin, MS

CONTACT

866-449-1394; olaughk@ccf.org

Ela B. Plow, PhD PT

CONTACT

216-445-4589; plowe2@ccf.oeg

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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. Therapists involved in training patients will not know which type of rTMS the participant receives.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Porfessor

Model Details: In a randomized-controlled, assessor-blinded clinical trial, an anticipated 72 patients will be assigned to receive 12 weeks of CCFES + cHMC facilitation, or CCFES + iM1 facilitation, or CCFES + sham rTMS. Assessments of upper limb motor function and neurophysiology will be completed at baseline, 6, 12, 24, and 36 weeks. This study will 1) determine whether cHMC facilitation augments the effects of CCFES to produce greater improvements in upper limb function in severe patients, 2) investigate the underlying neurophysiologic mechanisms contributing to restored paretic limb motor control, and 3) evaluate and identify patient factors that affect efficacy of CCFES + cHMC facilitation.

Study Record Dates

• First Submitted: March 6, 2019
• First Posted: March 12, 2019
• Study Start: May 14, 2019
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: March 24, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)