SRT4: Neurophysiological and Kinematic Predictors of Response in Chronic Stroke

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT02658630
• Collaborator: VA Maryland Health Care System (U.S. Fed)
• Enrollment: 68
• Locations: 2
• Arm: 1
• Actual Duration (Months): 44.8
• Patients Per Site: 34
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The purpose of this study is to design a predictive model of stroke recovery based on baseline measurements of arm movement and brain physiology. The expectation is the development of a formula to predict a person's response to an arm rehabilitation program provided in the chronic phase (6 months or greater post stroke) of recovery. The study will include magnetic resonance imaging (MRI), transcranial magnetic stimulation (TMS), genetic testing using blood and saliva, and an arm exercise program consisting of robot-assisted exercise combined with functional arm exercise called transition to task training (TTT).

Condition or Disease	Intervention/Treatment	Phase
Stroke	Device: Robot + TTT exercise	N/A

Detailed Description

After informed consent, a baseline neurological exam, medical records review, MRI of the brain, TMS, questionnaires, cognitive testing, robot evaluations, and arm function testing will occur. Baseline testing will occur in the first 4-6 weeks of participation including two separate sessions approximately 1 week a part to examine arm strength, range of motion, and ability to perform functional tasks, with one additional session if needed to verify stability between results. Additionally, one robot evaluation, one MRI, and one TMS session will be completed. We will also collect genetic data using blood and saliva samples to examine potential RNA expression and genetic polymorphisms that might influence response to therapy.

The intervention phase consists of 12 weeks of robot and transition to task arm exercise training (TTT). Interventions will occur approximately 3 times per week for 12 weeks for a total of 36 visits. Additional time and visits will be allowed with visits occurring 4 times per week or up to 6 additional weeks (not to exceed 18 weeks) if scheduling conflicts arise. The intervention sessions will be one hour in duration.

During the hour-long intervention, 45 minutes of robotic intervention will be followed by 15 minutes of TTT. Two separate robots targeting different movements will be used for the 3 phases of the robot training. The training will be sequential with 12 sessions completed on the wrist robot, followed by 12 sessions on the shoulder-elbow robot and the final 12 sessions alternating between the wrist and elbow-shoulder robot.

After the final training session, subjects will return after a 12 week retention period. At various time points during and after the intervention phase there will be additional arm function testing, robot evaluations, questionnaires, blood draws, and TMS sessions to re-assess ability.

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Masking Description: The outcomes assessor is masked as to the prediction model and to particulars of performance during the intervention, but knows that there is a single group design.
• Primary Purpose: Treatment
• Official Title: Neurophysiological and Kinematic Predictors of Response in Chronic Stroke
• Actual Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: Oct 28, 2019
• Actual Study Completion Date: Oct 28, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Device: Robot + TTT Exercise All participants will be enrolled in this group to receive the same 60 minute study intervention consisting of wrist and shoulder-elbow robot training and TTT arm exercises.

Device: Robot + TTT exercise; The intervention will be completed 36 visits approximately 3x/week for 12-18 weeks. The training progression will be sequential with 12 visits completed on the wrist robot, followed by 12 visits on the shoulder-elbow robot and completing with 12 visits alternating sessions on the wrist and shoulder-elbow robot. Participants will perform robot training for 45 minutes with each robot followed by 15 minutes of TTT practice to complete their 60 minute intervention session.

Outcome Measures

Primary Outcome Measures

1. Stroke Impact Scale: Hand [Baseline, after visit 36, and 12 week retention]

   The Stroke Impact Scale (SIS) is one of the primary outcome measures assessing change in hand use from baseline testing to mid-training after visits 12 and 24, and post-training after visit 36 and the 12 week retention period. It is a self-report structured interview consisting of eight domains designed to assess physical, mental and emotional changes following stroke that contribute to quality of life. It has been tested and found to be reliable, valid, and sensitive to change in the stroke population. It has four physical domain subscales that can be analyzed separately. The SIS hand subscale will be the focus for our outcome measure. Higher scores indicate greater function and life satisfaction. The minimum and maximum for the subscale is 0 and 100 respectively.

2. Fugl-Meyer Upper Extremity Assessment [Baseline, after visits 12, 24, and 36, and 12 week retention]

   The Fugl-Meyer is one of the primary outcome measures assessing change in arm use from baseline testing to mid-training after visits 12 and 24, and post-training after visit 36 and the 12 week retention period. It is a stroke-specific measure of impairment of the upper extremity that has been shown to be valid and reliable with high inter-rater and test-retest reliability. It provides a direct-observational assessment of volitional movement and motor impairment related to reflexes, sensation, and abnormal synergies. Each item on the FM is rated on a three-point ordinal scale (0 = cannot perform, 1 = performs partially, 2 = performs fully). The scale ranges from 0-66 with higher scores representing less motor impairment.

Secondary Outcome Measures

1. Action Research Arm Test (ARAT) [Baseline, after visits 12, 24, and 36, and 12 week retention]

   The ARAT will be used to assess change from baseline testing to mid-training after visits 12 and 24, and post-training after visit 36 and the 12 week retention period. It is a stroke-specific measure of arm motor function and impairment of the upper extremity that has been shown to be valid and reliable with high inter-rater and test-retest reliability. It provides a direct-observational assessment of volitional movement. It includes 19 test activities and each test is given an ordinal score of 0, 1, 2, or 3, with higher values indicating better arm motor status. The total ARAT score is the sum of the 19 tests, and thus the maximum score is 57.

2. 6-Item Wolf Motor Function Test (WMFT) [Baseline, after visits 12, 24, and 36, and 12 week retention]

   The Streamlined 6-Item Wolf Motor Function Test (WMFT) will be used to assess change from baseline testing to mid-training after visits 12 and 24, and post-training after visit 36 and the 12 week retention period. It examines UE function based on task performance time, and quality of movement. Functional use and speed of movement are based on six timed activities. It has been examined in chronic stroke and has high inter-rater reliability, internal consistency, and test-retest reliability. Timed tasks that cannot be completed default to a time score of 120 seconds. Faster times or a lower score in seconds represent better function. The maximum score of 75 (minimum score 0) refers to perfect score on the full 15 item functional ability assessment (15 x 5.)

Other Outcome Measures

1. TMS Score: Three Muscle Responses to Transcranial Magnetic Stimulation of the Motor Cortex [Baseline, after visit 36, and 12 week retention]

   TMS stimulation of the motor cortex will be performed using MagStim 200 Magnetic Stimulators (MagStim Ltd., Wales, UK) at baseline and post training after visit 36 and the 12 week retention to assess change in the motor evoked potential (MEP) of the arm muscles. TMS testing is as follows: 1) Location of muscle hotspot (highest motor evoked potential), 2) Threshold (lowest stimulation strength that evokes an MEP at hotspot) 3) Ipsilateral silent period measured on both the affected and unaffected side. A score on the scale of 0-9, 9 indicating a greater nervous system response.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Clinically defined, unilateral, hemiparetic stroke with radiologic exclusion of other possible diagnosis

• Stroke onset at least 6 months before enrollment

• Present with Mild/Moderate to Severe arm dysfunction (based on Fugl-Meyer scores of 10 to 45)

• Be medically stable to participate in the study and not have contractures or other impairments that would interfere with the interventional training.

Exclusion Criteria:

• Unable to give informed consent

• Have a serious complicating medical illness that would preclude participation.

• Contractures or orthopedic problems limiting range of joint motion in the potential study arm

• Visual loss such that the subject would not be able to see the test patterns on the robot computer monitor

• Botulinum toxin to study arm within four months of study enrollment or if received during the study period

• Unable to comply with requirements of the study

• Participants with a history of a seizure will not be precluded from the study, but will not be enrolled in the TMS portions

• Participants with electromagnetic exclusions (metal implants in the cranium, implanted electronic devices etc.) will not be precluded from the study but will be excluded from the MRI and TMS portions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD	Baltimore	Maryland	United States	21201
2	VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA	Pittsburgh	Pennsylvania	United States	15240

Sponsors and Collaborators

• VA Office of Research and Development
• VA Maryland Health Care System

Investigators

• Principal Investigator: George F. Wittenberg, MD PhD, VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 12, 2020

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT02658630
• Other Study ID Numbers: N1667-R; HP-00062868
• First Posted: Jan 20, 2016
• Last Update Posted: Mar 2, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by VA Office of Research and Development: arm rehabilitation; recovery of function
• Additional relevant MeSH terms: Stroke

Study Results

Participant Flow

Recruitment Details	There were 68 participants consented. Of these 46 were eligible and entered the intervention. Four did not complete due to transportation issues, scheduling conflicts or lack of communication.

Arm/Group Title	Device: Robot + TTT Exercise
Arm/Group Description	All participants will be enrolled in this group to receive the same 60 minute study intervention consisting of wrist and shoulder-elbow robot training and TTT arm exercises. Robot + TTT exercise: The intervention will be completed 36 visits approximately 3x/week for 12-18 weeks. The training progression will be sequential with 12 visits completed on the wrist robot, followed by 12 visits on the shoulder-elbow robot and completing with 12 visits alternating sessions on the wrist and shoulder-elbow robot. Participants will perform robot training for 45 minutes with each robot followed by 15 minutes of TTT practice to complete their 60 minute intervention session.
Period Title: Overall Study
STARTED	46
COMPLETED	42
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Device: Robot + TTT Exercise
Arm/Group Description	All participants will be enrolled in this group to receive the same 60 minute study intervention consisting of wrist and shoulder-elbow robot training and TTT arm exercises. Robot + TTT exercise: The intervention will be completed 36 visits approximately 3x/week for 12-18 weeks. The training progression will be sequential with 12 visits completed on the wrist robot, followed by 12 visits on the shoulder-elbow robot and completing with 12 visits alternating sessions on the wrist and shoulder-elbow robot. Participants will perform robot training for 45 minutes with each robot followed by 15 minutes of TTT practice to complete their 60 minute intervention session.
Overall Participants	42
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	27 64.3%
>=65 years	15 35.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.80952381 (11.2818397)
Sex: Female, Male (Count of Participants)
Female	15 35.7%
Male	27 64.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	42 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	23 54.8%
White	19 45.2%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	42 100%

Outcome Measures

1. Primary Outcome

Title	Stroke Impact Scale: Hand
Description	The Stroke Impact Scale (SIS) is one of the primary outcome measures assessing change in hand use from baseline testing to mid-training after visits 12 and 24, and post-training after visit 36 and the 12 week retention period. It is a self-report structured interview consisting of eight domains designed to assess physical, mental and emotional changes following stroke that contribute to quality of life. It has been tested and found to be reliable, valid, and sensitive to change in the stroke population. It has four physical domain subscales that can be analyzed separately. The SIS hand subscale will be the focus for our outcome measure. Higher scores indicate greater function and life satisfaction. The minimum and maximum for the subscale is 0 and 100 respectively.
Time Frame	Baseline, after visit 36, and 12 week retention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Device: Robot + TTT Exercise
Arm/Group Description	All participants will be enrolled in this group to receive the same 60 minute study intervention consisting of wrist and shoulder-elbow robot training and TTT arm exercises. Robot + TTT exercise: The intervention will be completed 36 visits approximately 3x/week for 12-18 weeks. The training progression will be sequential with 12 visits completed on the wrist robot, followed by 12 visits on the shoulder-elbow robot and completing with 12 visits alternating sessions on the wrist and shoulder-elbow robot. Participants will perform robot training for 45 minutes with each robot followed by 15 minutes of TTT practice to complete their 60 minute intervention session.
Measure Participants	42
Baseline	20.4 (27.13)
After visit 36	22.2 (24.26)
12-week retention visit	30.0 (30.57)

2. Primary Outcome

Title	Fugl-Meyer Upper Extremity Assessment
Description	The Fugl-Meyer is one of the primary outcome measures assessing change in arm use from baseline testing to mid-training after visits 12 and 24, and post-training after visit 36 and the 12 week retention period. It is a stroke-specific measure of impairment of the upper extremity that has been shown to be valid and reliable with high inter-rater and test-retest reliability. It provides a direct-observational assessment of volitional movement and motor impairment related to reflexes, sensation, and abnormal synergies. Each item on the FM is rated on a three-point ordinal scale (0 = cannot perform, 1 = performs partially, 2 = performs fully). The scale ranges from 0-66 with higher scores representing less motor impairment.
Time Frame	Baseline, after visits 12, 24, and 36, and 12 week retention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Device: Robot + TTT Exercise
Arm/Group Description	All participants will be enrolled in this group to receive the same 60 minute study intervention consisting of wrist and shoulder-elbow robot training and TTT arm exercises. Robot + TTT exercise: The intervention will be completed 36 visits approximately 3x/week for 12-18 weeks. The training progression will be sequential with 12 visits completed on the wrist robot, followed by 12 visits on the shoulder-elbow robot and completing with 12 visits alternating sessions on the wrist and shoulder-elbow robot. Participants will perform robot training for 45 minutes with each robot followed by 15 minutes of TTT practice to complete their 60 minute intervention session.
Measure Participants	42
Baseline	19.8 (9.62)
After visit 12	22.2 (11.23)
After visit 24	24.0 (13.08)
After visit 36	24.4 (13.15)
12-week retention	25.2 (13.36)

3. Secondary Outcome

Title	Action Research Arm Test (ARAT)
Description	The ARAT will be used to assess change from baseline testing to mid-training after visits 12 and 24, and post-training after visit 36 and the 12 week retention period. It is a stroke-specific measure of arm motor function and impairment of the upper extremity that has been shown to be valid and reliable with high inter-rater and test-retest reliability. It provides a direct-observational assessment of volitional movement. It includes 19 test activities and each test is given an ordinal score of 0, 1, 2, or 3, with higher values indicating better arm motor status. The total ARAT score is the sum of the 19 tests, and thus the maximum score is 57.
Time Frame	Baseline, after visits 12, 24, and 36, and 12 week retention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Device: Robot + TTT Exercise
Arm/Group Description	All participants will be enrolled in this group to receive the same 60 minute study intervention consisting of wrist and shoulder-elbow robot training and TTT arm exercises. Robot + TTT exercise: The intervention will be completed 36 visits approximately 3x/week for 12-18 weeks. The training progression will be sequential with 12 visits completed on the wrist robot, followed by 12 visits on the shoulder-elbow robot and completing with 12 visits alternating sessions on the wrist and shoulder-elbow robot. Participants will perform robot training for 45 minutes with each robot followed by 15 minutes of TTT practice to complete their 60 minute intervention session.
Measure Participants	42
Baseline	14.4 (14.67)
After visit 12	14.9 (15.33)
After visit 24	16.2 (16.82)
After visit 36	16.4 (16.57)
12-week retention	16.8 (17.73)

4. Secondary Outcome

Title	6-Item Wolf Motor Function Test (WMFT)
Description	The Streamlined 6-Item Wolf Motor Function Test (WMFT) will be used to assess change from baseline testing to mid-training after visits 12 and 24, and post-training after visit 36 and the 12 week retention period. It examines UE function based on task performance time, and quality of movement. Functional use and speed of movement are based on six timed activities. It has been examined in chronic stroke and has high inter-rater reliability, internal consistency, and test-retest reliability. Timed tasks that cannot be completed default to a time score of 120 seconds. Faster times or a lower score in seconds represent better function. The maximum score of 75 (minimum score 0) refers to perfect score on the full 15 item functional ability assessment (15 x 5.)
Time Frame	Baseline, after visits 12, 24, and 36, and 12 week retention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Device: Robot + TTT Exercise
Arm/Group Description	All participants will be enrolled in this group to receive the same 60 minute study intervention consisting of wrist and shoulder-elbow robot training and TTT arm exercises. Robot + TTT exercise: The intervention will be completed 36 visits approximately 3x/week for 12-18 weeks. The training progression will be sequential with 12 visits completed on the wrist robot, followed by 12 visits on the shoulder-elbow robot and completing with 12 visits alternating sessions on the wrist and shoulder-elbow robot. Participants will perform robot training for 45 minutes with each robot followed by 15 minutes of TTT practice to complete their 60 minute intervention session.
Measure Participants	42
Baseline	1.7 (0.89)
After visit 12	1.8 (1.08)
After visit 24	1.9 (1.00)
After visit 36	2.0 (1.13)
12-week retention	2.0 (1.20)

5. Other Pre-specified Outcome

Title	TMS Score: Three Muscle Responses to Transcranial Magnetic Stimulation of the Motor Cortex
Description	TMS stimulation of the motor cortex will be performed using MagStim 200 Magnetic Stimulators (MagStim Ltd., Wales, UK) at baseline and post training after visit 36 and the 12 week retention to assess change in the motor evoked potential (MEP) of the arm muscles. TMS testing is as follows: 1) Location of muscle hotspot (highest motor evoked potential), 2) Threshold (lowest stimulation strength that evokes an MEP at hotspot) 3) Ipsilateral silent period measured on both the affected and unaffected side. A score on the scale of 0-9, 9 indicating a greater nervous system response.
Time Frame	Baseline, after visit 36, and 12 week retention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Device: Robot + TTT Exercise
Arm/Group Description	All participants will be enrolled in this group to receive the same 60 minute study intervention consisting of wrist and shoulder-elbow robot training and TTT arm exercises. Robot + TTT exercise: The intervention will be completed 36 visits approximately 3x/week for 12-18 weeks. The training progression will be sequential with 12 visits completed on the wrist robot, followed by 12 visits on the shoulder-elbow robot and completing with 12 visits alternating sessions on the wrist and shoulder-elbow robot. Participants will perform robot training for 45 minutes with each robot followed by 15 minutes of TTT practice to complete their 60 minute intervention session.
Measure Participants	35
Baseline	2.4 (2.80)
After visit 36	2.6 (3.03)
12-week retention	2.5 (3.09)

Adverse Events

Time Frame	36 weeks
Arm/Group Title	Device: Robot + TTT Exercise
Arm/Group Description	All participants will be enrolled in this group to receive the same 60 minute study intervention consisting of wrist and shoulder-elbow robot training and TTT arm exercises. Robot + TTT exercise: The intervention will be completed 36 visits approximately 3x/week for 12-18 weeks. The training progression will be sequential with 12 visits completed on the wrist robot, followed by 12 visits on the shoulder-elbow robot and completing with 12 visits alternating sessions on the wrist and shoulder-elbow robot. Participants will perform robot training for 45 minutes with each robot followed by 15 minutes of TTT practice to complete their 60 minute intervention session.
All Cause Mortality
	Device: Robot + TTT Exercise
	Affected / at Risk (%)	# Events
Total	0/42 (0%)
Serious Adverse Events
	Device: Robot + TTT Exercise
	Affected / at Risk (%)	# Events
Total	0/42 (0%)
Other (Not Including Serious) Adverse Events
	Device: Robot + TTT Exercise
	Affected / at Risk (%)	# Events
Total	0/42 (0%)

Limitations/Caveats

Total enrollment fell short of goals. There was some missing data in baseline measures, such as MRI or TMS.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.