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Remote Ischemic Conditioning, Bimanual Skill Learning, and Corticospinal Excitability

Primary Purpose

Unilateral Cerebral Palsy, Hemiplegic Cerebral Palsy, Remote Ischemic Conditioning

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Remote Ischemic Conditioning (RIC)
Sham conditioning
Hand Arm Bimanual Intensive Therapy (HABIT)
Bimanual Cup Stacking Training
Balance training
Sponsored by
East Carolina University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Unilateral Cerebral Palsy focused on measuring Cerebral palsy, Bimanual coordination, Corticospinal excitability

Eligibility Criteria

6 Years - 16 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Children diagnosed with unilateral cerebral palsy, ages 6-16 years

  • Manual Ability Classification System (MACS) levels I-III
  • Ability to complete a stack of 3 cups in 2 minutes
  • Mainstream in school and has sufficient cognition to follow the experiment instructions

Exclusion Criteria:

  • Children with other developmental disabilities such as autism, developmental coordination disorders, etc.

    • Children with absent active motor threshold
    • Children with cognitive deficits or communication problem
    • Children with known cardiorespiratory and vascular dysfunctions
    • Children with metabolic disorders, neoplasm, hydrocephalus
    • Children who are receiving other adjunct therapies such as rTMS and tDCS
    • Children with seizures and on anti-seizure medications
    • Children with metal implants and incompatible medical devices for MRI scans

Sites / Locations

  • Dept. of Physical Therapy, East Carolina UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Remote Ischemic Conditioning (RIC)

Sham Conditioning

Arm Description

RIC is achieved via blood pressure cuff inflation to at least 20 mmHg above systolic blood pressure to 250 mmHg on the more involved arm. RIC involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation and requires 45 minutes. RIC is performed on visits 2-6. Intervention Hand Arm Bimanual Intensive Therapy (HABIT) Bimanual cup stacking training Balance training

Sham conditioning is achieved via blood pressure cuff inflation to 25 mmHg on the more involved arm. RIC involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation and requires 45 minutes. RIC is performed on visits 2-6. Intervention Hand Arm Bimanual Intensive Therapy (HABIT) Bimanual cup stacking training Balance training

Outcomes

Primary Outcome Measures

Change in Assisting Hand Assessment
Assisting Hand Assessment assesses bimanual coordination and affected hand function. A 5-point change from pre- to post-intervention is considered a clinically meaningful improvement.
Change in Bimanual Task Performance
The time (seconds) to complete each trial of cup stack, which will be averaged across three trials. This will be measured at visit 1 (pre-) and visit 7 (post-intervention). Smaller time to complete the task indicates better performance.
Change in Resting and Active Motor Thresholds
The minimum intensity of the stimulator output required to produce an MEP of > 50 μV will be determined using maximum-likelihood parameter estimation by a sequential testing (ML-PEST) algorithm from the lesioned and non-lesioned cortex. Greater reduction in resting and active motor threshold from pre- to post-intervention indicates greater corticospinal excitability.
Change in Stimulus-response curves
Suprathreshold intensities of 110%, 120%, 130%, 140%, and 150% of resting motor threshold will be administered randomly on the lesioned and non-lesioned cortex. Greater motor evoked potential response at each of these intensities indicate greater corticospinal excitability.

Secondary Outcome Measures

Change in Box and Blocks Test (BBT)
BBT is a standard test to assess manual speed. Greater number of blocks transferred indicates greater manual speed.
Change in Nine Hole Peg Test (NHPT)
NHPT is a standard test to assess manual speed and dexterity. Smaller time to complete NHPT indicates greater speed and dexterity.
Change in Jebsen Hand Function Test (JHFT)
JHFT assesses fine and gross hand and arm movements. Smaller time to complete JHFT indicates better hand function.
Change in Balance performance
The average amount of time in seconds that a participant maintains the stability platform within ±5° of horizontal position during 15 trials of 30 seconds each. The total score will range between 0-30 seconds. Higher balance score indicates better balance performance. Greater average balance time indicates better balance performance.
Change in Hand grip and pinch strength
Hand grip and pinch strength assesses hand muscle strength. Greater hand and pinch strength indicates greater strength of hand muscles.
Change in Short-Interval Intracortical Inhibition (SICI)
For SICI, a subthreshold (80% RMT) conditioning pulse to the motor hotspot will be applied followed by a suprathreshold (120% RMT) test pulse 3 milliseconds later. Reduction in SICI indicates intracortical facilitation.
Change in Intracortical Facilitation (ICF)
For ICF, the interstimulus interval will increase to 12 milliseconds. Greater ICF indicates greater intracortical facilitation.
Change in accelerometry derived variables
Number of movements, use ratio, magnitude ratio, bilateral magnitude, and acceleration variability will be quantified using wrist worn accelerometers. Greater values indicate better bimanual performance.

Full Information

First Posted
January 15, 2022
Last Updated
April 30, 2022
Sponsor
East Carolina University
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1. Study Identification

Unique Protocol Identification Number
NCT05355883
Brief Title
Remote Ischemic Conditioning, Bimanual Skill Learning, and Corticospinal Excitability
Official Title
Effects of Remote Ischemic Conditioning on Bimanual Skill Learning, Bimanual Coordination, and Corticospinal Excitability in Children With Unilateral Cerebral Palsy
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
December 18, 2021 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
East Carolina University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Unilateral cerebral palsy (UCP) is a leading cause of childhood disability. An early brain injury impairs the upper extremity function, bimanual coordination, and impacts the child's independence. The existing therapeutic interventions have higher training doses and modest effect sizes. Thus, there is a critical need to find an effective priming agent to enhance bimanual skill learning in children with UCP. This study aims to determine the effects of a novel priming agent, remote ischemic conditioning (RIC), when paired with intensive bimanual skill training to enhance bimanual skill learning and to augment skill dependent plasticity in children with UCP.
Detailed Description
Ischemic conditioning (IC) is a phenomenon of protecting the target organ from ischemia by directly exposing it to brief episodes of sublethal ischemia. RIC is a clinically feasible way of performing IC where episodes of ischemia and reperfusion are delivered with cyclic inflation and deflation of a blood pressure cuff on the arm or leg. Pre-clinical and preliminary clinical trials in humans show neuroprotective effects of RIC. Investigators prior work has shown that when paired with motor training, RIC enhances motor learning in healthy individuals. Based on these diversified benefits of RIC, the central hypothesis is that the multifactorial mechanisms of RIC can be harnessed as a priming agent to enhance motor learning and augment neuroplasticity in children with UCP. The Specific Aims are: 1) to determine the effects of RIC + training on bimanual skill performance, and 2) to determine the effects of RIC + training on corticospinal excitability in children with UCP. In this triple blind, randomized controlled trial, 30 children with UCP, ages 6-16 years will first undergo bimanual speed stack performance, functional upper extremity, and Transcranial Magnetic Stimulation assessments. Children will then undergo RIC/Sham conditioning plus training. Investigators will deliver RIC/sham conditioning via cyclic inflation and deflation of a pressure cuff on the paretic arm using a standard protocol. Training will involve 5 days (15 trials/day) of bimanual speed stack training and intensive bimanual training using hand arm bimanual intensive therapy (HABIT) with a standard dose of 6 hours/day for 5 days. The children will perform the same baseline assessments post-intervention. Investigators hypothesize that compared to sham conditioning + training, RIC + training will significantly enhance: 1) bimanual skill performance (decrease in movement time (sec) to complete bimanual speed stack task), 2) bimanual function (increase in the Assisting Hand Assessment scores), 3) cortical excitability in the ipsilesional primary motor cortex (M1) (larger amplitude of motor evoked potentials and lower resting or active motor thresholds), and 4) reduce motor cortex inhibition (reduced short-interval intracortical inhibition and increase in intracortical facilitation in ipsilesional M1). The long-term goal is to develop effective interventions to improve function of children with UCP. Outcomes of this project will provide critical ingredients for designing Phase II trials that will determine the effects of RIC combined with different dose of intensive behavioral interventions to improve functional outcomes in children with UCP.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Unilateral Cerebral Palsy, Hemiplegic Cerebral Palsy, Remote Ischemic Conditioning
Keywords
Cerebral palsy, Bimanual coordination, Corticospinal excitability

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Double blinded, randomized controlled trial
Masking
ParticipantOutcomes Assessor
Masking Description
Participants are masked to group assignment (RLIC vs. Sham conditioning) and the assessor will be masked to group assignment of the participants.
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Remote Ischemic Conditioning (RIC)
Arm Type
Experimental
Arm Description
RIC is achieved via blood pressure cuff inflation to at least 20 mmHg above systolic blood pressure to 250 mmHg on the more involved arm. RIC involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation and requires 45 minutes. RIC is performed on visits 2-6. Intervention Hand Arm Bimanual Intensive Therapy (HABIT) Bimanual cup stacking training Balance training
Arm Title
Sham Conditioning
Arm Type
Sham Comparator
Arm Description
Sham conditioning is achieved via blood pressure cuff inflation to 25 mmHg on the more involved arm. RIC involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation and requires 45 minutes. RIC is performed on visits 2-6. Intervention Hand Arm Bimanual Intensive Therapy (HABIT) Bimanual cup stacking training Balance training
Intervention Type
Behavioral
Intervention Name(s)
Remote Ischemic Conditioning (RIC)
Other Intervention Name(s)
Remote limb ischemic conditioning
Intervention Description
See descriptions under arm/group descriptions. RIC is delivered for 5 intervention visits. Visits 1 is the pre-training assessment visit, visits 2-6 are RIC plus training visits, visit 7 is a post-training assessment visit.
Intervention Type
Behavioral
Intervention Name(s)
Sham conditioning
Other Intervention Name(s)
Sham
Intervention Description
See descriptions under arm/group descriptions. Sham conditioning is delivered for 5 intervention visits. Visits 1 is the pre-training assessment visit, visits 2-6 are RIC plus training visits, visit 7 is a post-training assessment visit.
Intervention Type
Behavioral
Intervention Name(s)
Hand Arm Bimanual Intensive Therapy (HABIT)
Other Intervention Name(s)
Bimanual skill training
Intervention Description
HABIT is a child-friendly, intensive intervention directed at improving bimanual coordination and function of the affected arm. The intervention employed in this study includes various age-appropriate fine and gross motor bimanual activities that will be delivered in a play context. Children practice bimanual activities for 6 hours per day, 5 days per week, for 1 week.
Intervention Type
Behavioral
Intervention Name(s)
Bimanual Cup Stacking Training
Other Intervention Name(s)
Cup stacking task
Intervention Description
Children practices bimanual cup stacking, 15 trials/day for 5 consecutive day.
Intervention Type
Behavioral
Intervention Name(s)
Balance training
Intervention Description
All children undergo training on a balance board, learning to hold the board level with equal weight on each leg and using various bilateral upper extremity strategies. Participants perform the balance task for 15, 30-second trials per day at visits 2-6.
Primary Outcome Measure Information:
Title
Change in Assisting Hand Assessment
Description
Assisting Hand Assessment assesses bimanual coordination and affected hand function. A 5-point change from pre- to post-intervention is considered a clinically meaningful improvement.
Time Frame
Baseline and 1 week
Title
Change in Bimanual Task Performance
Description
The time (seconds) to complete each trial of cup stack, which will be averaged across three trials. This will be measured at visit 1 (pre-) and visit 7 (post-intervention). Smaller time to complete the task indicates better performance.
Time Frame
Baseline and 1 week
Title
Change in Resting and Active Motor Thresholds
Description
The minimum intensity of the stimulator output required to produce an MEP of > 50 μV will be determined using maximum-likelihood parameter estimation by a sequential testing (ML-PEST) algorithm from the lesioned and non-lesioned cortex. Greater reduction in resting and active motor threshold from pre- to post-intervention indicates greater corticospinal excitability.
Time Frame
Baseline and 1 week
Title
Change in Stimulus-response curves
Description
Suprathreshold intensities of 110%, 120%, 130%, 140%, and 150% of resting motor threshold will be administered randomly on the lesioned and non-lesioned cortex. Greater motor evoked potential response at each of these intensities indicate greater corticospinal excitability.
Time Frame
Baseline and 1 week
Secondary Outcome Measure Information:
Title
Change in Box and Blocks Test (BBT)
Description
BBT is a standard test to assess manual speed. Greater number of blocks transferred indicates greater manual speed.
Time Frame
Baseline and 1 week
Title
Change in Nine Hole Peg Test (NHPT)
Description
NHPT is a standard test to assess manual speed and dexterity. Smaller time to complete NHPT indicates greater speed and dexterity.
Time Frame
Baseline and 1 week
Title
Change in Jebsen Hand Function Test (JHFT)
Description
JHFT assesses fine and gross hand and arm movements. Smaller time to complete JHFT indicates better hand function.
Time Frame
Baseline and 1 week
Title
Change in Balance performance
Description
The average amount of time in seconds that a participant maintains the stability platform within ±5° of horizontal position during 15 trials of 30 seconds each. The total score will range between 0-30 seconds. Higher balance score indicates better balance performance. Greater average balance time indicates better balance performance.
Time Frame
Baseline and 1 week
Title
Change in Hand grip and pinch strength
Description
Hand grip and pinch strength assesses hand muscle strength. Greater hand and pinch strength indicates greater strength of hand muscles.
Time Frame
Baseline and 1 week
Title
Change in Short-Interval Intracortical Inhibition (SICI)
Description
For SICI, a subthreshold (80% RMT) conditioning pulse to the motor hotspot will be applied followed by a suprathreshold (120% RMT) test pulse 3 milliseconds later. Reduction in SICI indicates intracortical facilitation.
Time Frame
Baseline and 1 week
Title
Change in Intracortical Facilitation (ICF)
Description
For ICF, the interstimulus interval will increase to 12 milliseconds. Greater ICF indicates greater intracortical facilitation.
Time Frame
Baseline and 1 week
Title
Change in accelerometry derived variables
Description
Number of movements, use ratio, magnitude ratio, bilateral magnitude, and acceleration variability will be quantified using wrist worn accelerometers. Greater values indicate better bimanual performance.
Time Frame
Baseline and 1 week

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Children diagnosed with unilateral cerebral palsy, ages 6-16 years Manual Ability Classification System (MACS) levels I-III Ability to complete a stack of 3 cups in 2 minutes Mainstream in school and has sufficient cognition to follow the experiment instructions Exclusion Criteria: Children with other developmental disabilities such as autism, developmental coordination disorders, etc. Children with absent active motor threshold Children with cognitive deficits or communication problem Children with known cardiorespiratory and vascular dysfunctions Children with metabolic disorders, neoplasm, hydrocephalus Children who are receiving other adjunct therapies such as rTMS and tDCS Children with seizures and on anti-seizure medications Children with metal implants and incompatible medical devices for MRI scans
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Swati Surkar, PT, PhD
Phone
2527446244
Email
surkars19@ecu.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Swati Surkar
Organizational Affiliation
East Carolina University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dept. of Physical Therapy, East Carolina University
City
Greenville
State/Province
North Carolina
ZIP/Postal Code
27834
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Swati Surkar
Phone
402-714-2640
Email
surkars19@ecu.edu

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Data will be shared on NIH figshare network and will be made available on request.
IPD Sharing Time Frame
After publishing the results of the study
IPD Sharing Access Criteria
Data will be made available upon request to the principal investigator.
Citations:
PubMed Identifier
29578992
Citation
Surkar SM, Hoffman RM, Willett S, Flegle J, Harbourne R, Kurz MJ. Hand-Arm Bimanual Intensive Therapy Improves Prefrontal Cortex Activation in Children With Hemiplegic Cerebral Palsy. Pediatr Phys Ther. 2018 Apr;30(2):93-100. doi: 10.1097/PEP.0000000000000486.
Results Reference
background
PubMed Identifier
19296922
Citation
Dirnagl U, Becker K, Meisel A. Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol. 2009 Apr;8(4):398-412. doi: 10.1016/S1474-4422(09)70054-7.
Results Reference
background
PubMed Identifier
16715053
Citation
Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci. 2006 Jun;7(6):437-48. doi: 10.1038/nrn1927.
Results Reference
background
PubMed Identifier
24389580
Citation
Stetler RA, Leak RK, Gan Y, Li P, Zhang F, Hu X, Jing Z, Chen J, Zigmond MJ, Gao Y. Preconditioning provides neuroprotection in models of CNS disease: paradigms and clinical significance. Prog Neurobiol. 2014 Mar;114:58-83. doi: 10.1016/j.pneurobio.2013.11.005. Epub 2014 Jan 2.
Results Reference
background
PubMed Identifier
19880021
Citation
Kharbanda RK, Nielsen TT, Redington AN. Translation of remote ischaemic preconditioning into clinical practice. Lancet. 2009 Oct 31;374(9700):1557-65. doi: 10.1016/S0140-6736(09)61421-5.
Results Reference
background
Available IPD and Supporting Information:
Available IPD/Information Type
Informed Consent Form
Available IPD/Information URL
https://epirate.ecu.edu/App/app/portal/smartform/read?project=com.webridge.entity.Entity%5BOID%5B21688D0E003911ECFE80AAA590565000%5D%5D&projectEditorView=com.webridge.entity.Entity%5BOID%5BDB15548F56BE6942A0B8A537449C64C3%5D%5D

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Remote Ischemic Conditioning, Bimanual Skill Learning, and Corticospinal Excitability

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