Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03216837 |
| Other study ID # |
REB16-2535 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
July 21, 2017 |
| Est. completion date |
March 18, 2023 |
Study information
| Verified date |
March 2024 |
| Source |
University of Calgary |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Perinatal stroke causes lifelong neurological disability and most hemiparetic cerebral palsy
(CP). With morbidity spanning diverse aspects of a child's life and lasting for decades,
global impact is large, including 10000 Canadian children. With pathophysiology poorly
understood and prevention strategies non-existent, the burden of hemiparetic CP will persist.
Limited treatments lead to loss of hope for children and families, necessitating exploration
of new therapies. The investigators have evidence that the investigators have a durable new
treatment for perinatal stroke, combining non-invasive neurostimulation and child-centred
intensive rehabilitation. Via the CHILD-BRIGHT SPOR national network, the investigators will
execute a multicentre trial to prove this treatment can improve function in children with
perinatal stroke and hemiparetic CP. Using novel advanced technologies not available
elsewhere in the world, the investigators will explore how developmental plasticity
determines function and response to neuromodulation therapy. This patient oriented effort
will advance personalized, precision medicine in pediatric neurorehabilitation to improve
outcomes for disabled children and their families.
Description:
Aim 1: Establish the ability of tDCS to enhance motor function in children with perinatal
stroke.
Hypothesis: Addition of tDCS to intensive motor learning therapy in children with perinatal
stroke and hemiparesis will increase the probability of achieving clinically significant
gains in function.
Aim 2: Understand the developmental motor neurophysiology of perinatal stroke and the changes
that occur during intensive motor learning and the effects of tDCS.
Hypothesis: Therapy-induced functional improvements are associated with increased motor
control in the lesioned (stroke) hemisphere as measured by: (a) enlargement of lesioned
hemisphere motor maps (robotic TMS), (b) increased functional connectivity between lesioned
motor and sensory cortices (rsfMRI), (c) strengthened correlations between lesioned motor
cortex NAA and clinical function (MRS), and (d) improved position sense of the affected upper
extremity (KINARM robot)
Methods This is a multicentre, randomized, sham-controlled, double blind, phase III clinical
trial.
Population. Participants will be recruited through established programs by expert
investigative teams at 4 sites. For Calgary (Alberta Children's Hospital) and Edmonton
(Stollery Children's Hospital and Glenrose Rehabilitation Hospital), subjects will be
identified via the Alberta Perinatal Stroke Project (APSP); a population-based research
cohort of >1000 MRI-confirmed perinatal stroke subjects with a proven track record of
recruitment to clinical trials71. Toronto subjects will be recruited from established CP
research cohorts at Holland Bloorview Kids Rehabilitation Hospital. All sites have
established clinical research programs in childhood CP and experience running relevant
interventions including camp-based intensive motor learning programs.
Intensive Motor Learning Camp. Participants will complete child-centered, age-appropriate,
goal-directed 2-week intensive motor learning camps (summers of 2017, 2018, and 2019). These
will be full day programs in peer-supported environments. All sites are experienced in such
motor learning interventions. Fidelity of all interventions will be facilitated by
standardized operating procedures, videotaping, and scheduled site visits. CIMT during the
first week will be followed by bimanual therapy during the second. Tasks will be graded and
selected according to relative function with increasing complexity across the spectrum. Tasks
will be both symmetrical and asymmetrical, geared to pre-set goals and age-appropriate
activities of daily living and individual interests. Intensive motor learning will be focused
within 2 hours each day of goal-directed therapy working 1:1 with a dedicated OT. The
remaining hours will include gross motor (1.5), group motor (1.5), lunch (1), social snack
(0.5x2), and fun breaks (0.5). Total dose is therefore 7.5 hours per day (75 hours total).
These activities include upper limb motor activities focused on general activities of daily
living rather than individualized goals. Following the 10 day intervention, children will
receive a structured home program based on the same principles with ongoing therapist support
if needed in the form of phone calls, surveillance, and documentation (home program log) for
6 months.
Randomization and Blinding. Randomization will occur in permuted blocks of 2 to ensure even
distribution within sites. Concealment of randomization will be achieved using online
methods. After turning on tDCS, those randomized to sham will have their machine
automatically ramp down after 30 seconds while those randomized to active treatment will
remain at 1.0mA. All subjects will experience the same sensations and such shaming has been
proven effective, including in children131. Treating therapists, outcome assessors, parents
and children are blinded to treatment allocation. Following day 1 and day 10 tDCS session,
participants will be asked first to guess which treatment they received: real, sham or no
idea and why. If they choose no idea, they will then be asked to choose only between real and
sham and give their reasons why.
Intervention: tDCS. The primary intervention will be cathodal (inhibitory) tDCS over the
contralesional M1. Rationale includes evidence from a phase 1 trial (Kirton 2016, submitted),
phase 2 rTMS trial, pediatric tDCS motor learning trial as well as adult stroke rTMS and tDCS
trials and developmental animal studies. Inhibitory stimulation over intact, contralesional
brain also maximizes safety with more predictable distribution of tDCS currents. Based on
previous studies of cathodal tDCS in motor learning, adult stroke rehabilitation and studies
of electrode montages in stroke and children140, the following methods will be employed.
Soft, replaceable 25cm2 electrodes (Soterix, NYC) will be placed on clean, dry areas of the
scalp. The cathode will be placed over the contralesional M1, precisely mapped for each
patient using neuronavigated (Brainsight2, Rogue Research, Montreal QU) MRI-TMS
co-registration over the hotspot for the contralateral first dorsal interosseous muscle.
Consistent with previous tDCS stroke studies, the reference electrode will be placed over the
contralateral orbit. The current-controlled model stimulator (Soterix, NYC) will
automatically ramp up slowly over 30 seconds to the treatment current of 1.0 mA. tDCS or sham
will be administered each day during the first 30 minutes of the daily 1:1 therapy sessions.
Co-investigators experienced in pediatric tDCS will perform on-site training and ongoing
quality assurance according to standard operating procedures.
Clinical Outcomes: Motor Function. Expert co-investigators have designed a rigorous approach
to motor outcome assessment, overcoming some of the limitations of existing hemiparetic CP
trials. Multidimensional evaluations will assess body structure and function, activity and
participation domains of the WHO International Classification of Functioning, Disability and
Health (ICF). Tools with established clinimetric properties were selected to evaluate diverse
upper extremity functions relevant to daily living in children. Measures had to be both
child/family friendly and time sensitive. The investigators will measure uni- and bi-lateral
function for normative data, evaluation of bimanual functions, and safety (including
screening for changes in unaffected hand function). Tests will be performed by the same
experienced, blinded, non-treating site OT and video-taped for quality assurance and offline
analysis. Motor outcomes are measured at baseline, and 1 week, 2 months and 6 months
post-intervention.
A. Primary Objective Motor Outcome: Assisting Hand Assessment (AHA). This is the established
standard for the objective quantification of bilateral hand function in children with
hemiparetic CP. This Rasch-built evaluation carries the strongest evidence of inter-rater,
intra-rater, and test-retest reliabilities, test-validity, and responsiveness to change for
bimanual tasks in hemiparetic CP children within this age range. Sensitivity to change and
excellent clinimetric properties have been established in multiple pediatric hemiparetic CP
clinical trials. Trained therapists have successfully executed >100 AHA measurements in
previous trials with no limitations and robust data.
B. Primary Subjective Motor Outcome: Canadian Occupational Performance Measure (COPM).
Individualized, family-centered tool identifying child and family-perceived difficulties in
self-care, productivity (school), and activities. Such subjective measures are essential in
hemiparetic CP trials. Validated for these ages and such trials, the COPM was a robust
measure in previous perinatal stroke trials. The investigators have recently characterized
how COPM goals are set in this population and their relationship to success (Haspels et al,
unpublished).
C. Novel real-life motor outcome: Actigraphy. No existing motor outcome measure can quantify
continuous use of the upper extremities during normal activities. The investigators propose
to overcome this limitation using actigraphy. Lightweight wrist accelerometers can constantly
measure and store subtle movements. Such systems can track movements in disabled persons
including those with CP145. Participants will be fitted bilaterally with actiwatches
(MotionWatch) to record mean movements every 2 seconds for 48 hour epochs of time (baseline,
1 week, 2 months, 6 months) as well as continuously during the 2 week intervention phase. A
standard diary will record sleep/wake patterns and activities. Importantly, The investigators
will do this bilaterally (2 watches) to generate the primary outcome of an actigraphic
asymmetry index (AAI) calculated between the affected and unaffected limbs.
Secondary Clinical Outcomes summarized include: Mirror movements, Children's Hand-Use
Experience Questionnaire (CHEQ), Jebsen Taylor Test of Hand Function, Box and Blocks Test
(BBT), Stanford Expectations of Treatment Scale (SETS), Child and Adolescent Social Support
Scale (CASSS), Loneliness and Social Dissatisfaction Questionnaire (LSDQ), PedsQL-CP, CNS
Vital signs, Child and Adolescent Scale of Participation (CASP), APSP parental outcome
measure (POM), and Health Utilities Index (HUI).
Safety and Tolerability. An experienced data safety and monitoring board will be established.
Primary adverse outcome for tDCS is any decrease in function of either upper extremity,
screened for by both uni- and bi-manual measures. An established tDCS Safety and Tolerability
evaluation (TST) will be performed on days 1, 5, and 10 on all subjects. Only trained
personnel will administer treatments under the approval and certification from experienced
brain stimulation team members. All tDCS interventions will occur within a hospital setting
with immediate access to medical care in the unlikely event care is required. Any potential
adverse events are immediately reported to the site and principal investigators, DSMB safety
monitor, and ethics boards. For any potentially serious adverse events, treatments will be
suspended pending decisions of the above.
Neuroplasticity Outcomes. For each component below, change in the primary outcome is
anticipated to favour increased motor control in the lesioned hemisphere associated with
functional improvements. All sites will capture neuroimaging data according to matched
protocols. Only Alberta sites will complete the TMS and KINARM robotic measures.
A. MRI: Connectivity and chemistry. Images will be acquired on dedicated 3T research scanners
across centres using standardized protocols within established neuroimaging networks.
Baseline imaging will be performed within 4 weeks of intervention. Post-intervention imaging
will be performed 5-7 days after the last day of treatment and at 6 months following
treatment. Scan time will be ~60 minutes. Anatomical imaging following established perinatal
stroke protocols includes T1- and T2-weighted 3D BRAVO anatomical sequences. For task fMRI,
subjects will perform contraction of affected hand and unaffected hand in an event-related
design. In response to a cue, participants will squeeze an air-filled bulb attached to a
pressure transducer that quantifies grip pressure. A static fixation cross will indicate to
stop and rest for 14 seconds. Brain activity in response to each hand movement will be
determined using SPM12 by employing a General Linear Model. Registration to each
participant's anatomical images will be performed using reverse deformation fields from SPM
segmentation. Outcomes include extent of blood-oxygen level dependent response (BOLD)
activation, peak locations and M1 laterality index (LI). For resting state MRI acquisition,
children will be instructed to lie still with eyes open. Resting-state fMRI BOLD signals will
be extracted from each M1 and other areas of interest as defined above with temporal
cross-correlation. Correlation coefficients will be Fisher transformed and entered into a
random effects General Linear Model consistent with validated methods. Outcomes include
intrahemispheric (M1-S1) and interhemispheric (M1-M1) connectivity. For white matter
connectivity, diffusion tensor imaging will include 60 directions (b-values= 0,2000s/mm2).
Voxel size is 2.5mm isotropic. Fractional anisotropy (FA), color coded-FA, ADC, and b0 maps
will all be generated in MRTrix3. A multi-ROI approach will generate tracts of interest using
probabilistic tractography. Outcomes will expand previous experience interrogating
corticospinal, somatosensory, and transcallosal tracts. Metabolite concentrations in
bilateral M1 will be measured via magnetic resonance spectroscopy (MRS), providing
information about neuronal and cell membrane health, energy metabolism, health of glial cells
and excitatory neurotransmitters. Preliminary data from the APSP has demonstrated the
feasibility of these methods in children with perinatal stroke. Established neuroimaging
experts will ensure optimal comparability between centres according to predefined protocols.
The centralized imaging repository system of the Stroke Imaging Lab for Children (SILC)
supported by Brain Canada will use established protocols and systems (BrainCode) for
anonymized online transfer of images to and from site investigators.
B. TMS: Robotic motor mapping. TMS studies will occur at the ACH Pediatric Brain Stimulation
Laboratory, a state-of-the-art, child-friendly facility that has completed >3 million
stimulations in >280 children (Zewdie, unpublished) without complication. The investigators
are the first pediatric centre in the world with the Axilum TMS Robot72 and have developed a
rapid motor mapping technique (see Figure 2). Using each subject's anatomical MRI and
neuronavigation (Brainsight2), a 10x10 grid with 7mm spacing will be placed over M1. A
recently developed rapid mapping protocol (4 stimulations per site) will obtain mean MEP
values for each active site. The robot allows precise targeting with real-time motion
correction and rapid mapping. The primary TMS outcome will be area-under-the-curve of
customized heat maps of contralesional motor cortex. Multiple upper extremity muscles will be
simultaneously mapped from both hemispheres including dedicated ipsilateral projections from
the contralesional hemisphere. Primary outcomes are motor map area, volume, and center of
gravity. Additional TMS measures will include corticospinal tract arrangement, motor
thresholds, MEP latency, and cortical silent period. The investigators have successfully
demonstrated these methods in children with stroke.
C. KINARM Robot: Sensorimotor function. The KINARM exoskeleton (Kinesiological Instrument for
Normal and Altered Reaching Movement) modified for children will assess limb movements at the
shoulder and elbow. A standardized, validated assessment of sensorimotor function will
include three tasks: position sense via a position matching task, kinesthesia, and visually
guided reaching. The investigators have demonstrated the ability of these assessments to
demonstrate specific elements of disordered sensorimotor function (50 perinatal stroke, 150
healthy children) including outcomes of position sense, kinesthesia, and motor dysfunction of
the "unaffected" limb. Primary outcomes will be position sense during a position-matching
task and bilateral motor impairment using a visually guided reaching task. The investigators
have just installed a dedicated pediatric KINARM at the Alberta Children's Hospital where all
Alberta subjects will attend.
