Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03555474 |
| Other study ID # |
SR/SO/HS/0032/2010 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
October 5, 2009 |
| Est. completion date |
January 25, 2012 |
Study information
| Verified date |
June 2018 |
| Source |
Sree Chitra Tirunal Institute for Medical Sciences & Technology |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Approximately 50% of patients have persistent motor disability following stroke. Current
treatment approaches with conventional physiotherapy have limited efficacy. Repetitive
transcranial magnetic stimulation (rTMS) and Functional electrical stimulation (FES) have
been shown to improve the neuronal plasticity and motor control in few preliminary studies.
Their efficacy in human stroke subjects is unproven. We planned to study their efficacy in
improving the motor functions of stroke patients in a randomized trial. Sixty consecutive
haemodynamically stable adult patients with first ischemic stroke within last 7-30 days were
randomized into three treatment groups to receive either physiotherapy alone, or
physiotherapy combined with either FES or rTMS. Outcome was assessed using Fugl Meyer
assessment for physical performance of upper limb. Three groups were compared for the outcome
measures using intention to treat analysis.
Description:
Background
Present management strategies involving conventional physiotherapy (PT) have limited efficacy
in facilitating the motor recovery following stroke. Finding an effective intervention to
improve motor recovery in individuals with hemiplegia is very important for improving the
functional outcome and enabling independent living.
Following an injury, the brain undergoes significant reorganization of its functions
resulting in functional recovery, which occurs over a period of weeks to months. This
postlesional reorganization occurs mostly in the premotor cortex, dorsolateral prefrontal
cortex and supplementary motor area which are thought to play the most important role in
recovery following any type of brain injury. Treatment approaches which can facilitate this
reorganization process by enhancing the cortical plasticity might have a very important role
in improving the functional outcome following neuronal injury.
Both central and peripheral stimulation has potential to improve the cortical reorganization
and functional recovery following acute stroke. Previous studies have established that
following an acute stroke, the depressed excitability of the ipsilesional hemisphere can be
increased by stimulating the ipsilesional hemisphere or by inhibiting the contralesional
hemisphere.This happens because of the fact that one hemisphere has inhibitory effect on the
other hemisphere through transcallosal inhibition. In preliminary studies, application of
high frequency repetitive transcranial magnetic stimulation (rTMS) to motor cortex has been
shown to produce an increase in corticospinal excitability leading to enhancement of motor
functions. Theta Burst Stimulation (TBS), which is a novel method of delivering rTMS at lower
intensities without the risk of any major adverse effects, has been found to be safe in
chronic and acute stroke patients. In this regard, intermittent TBS (iTBS) has a stimulatory
effect on the brain and continuous TBS (cTBS) has inhibitory effect on the brain. In
preliminary studies, intermittent TBS (iTBS) applied to the ipsilesional hemisphere and
continuous TBS (cTBS) applied to the contralesional hemisphere have been shown to improve the
motor functions and corticospinal output in the paretic hands during experimental settings.
However, long term effects of this strategy on functional outcome have not been previously
studied. Similarly, functional electrical stimulation (FES), a form of peripheral
stimulation, when applied to the paretic upper limb muscles has been shown to improve the
upper limb functional activity in patients with acute or subacute stroke.
Thus both the TBS and FES has a potential of improving the motor functions and the functional
outcome following ischemic stroke. However, these strategies have not been used in clinical
setting and their usefulness in promoting motor recovery over and above that of conventional
PT has not been proven. If proven to be useful, these techniques have a potential of
improving the otherwise dismal functional outcome following stroke. The purpose of this study
is to determine efficacy of TBS or FES as an adjunctive to physical therapy for the
rehabilitation of stroke patients.
METHODS Study Setting and Participants This study is a single blind randomized controlled
trial to assess the efficacy of TBS and FES in improving motor functions over and above that
of standard PT following acute stroke. This study was carried out at the Department of
Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum,
Kerala, India. We recruited consecutive patients over a 28 months period from the outpatient
clinics and inpatient wards. Patients with first ever ischemic stroke in middle cerebral
artery territory who presented within 10 days to 30 days of onset and had ability to give
informed consent and comprehend instructions were included in this study. All the patients
underwent 1.5 T MRI and had documented single infarct in MCA territory with no other lesion.
All the patients received standard medical and rehabilitative care including passive and
active PT. The study was approved by the institutional ethics committee (SCT/IEC/223). All
the patients provided written informed consent to undergo the trial. Consecutive patients who
fulfilled the inclusion and exclusion criteria were randomized to one of the three groups:
(1) those who received TBS as per the predefined protocol along with standard PT (Group A);
(2) those who received FES as per the predefined protocol along with standard PT (Group B);
and (3) those who received PT (PT) alone (Group C).
Random allocation and sequence generation The patients were randomly allocated into three
groups by block randomization method. Concealed allocation was done by principle investigator
who blindly allocated the subjects into different groups according to the block randomization
table to receive the designated intervention
Blinding After providing the informed consent, a subject fulfilling the inclusion and
exclusion criteria was initially assessed by first co-investigator for all the outcome
measures and neurophysiological parameters. Patients who were eligible for the study were
allocated to different intervention groups by principle investigator. Interventions were done
by second co-investigator for all the subjects. Follow-up assessments were done by the first
co-investigator who was blinded to the allocation to intervention groups.
Outcome measures As we mainly wanted to assess upper extremity functions, we used Fugl Meyer
Assessment (FMA) scale as the primary outcome measure to assess the upper limb motor
functions. This is a 66-point scale to evaluate upper limb functions, a standard tool for
this purpose. In addition, we used Modified Rankin Scale (mRS) to assess global outcome,
National Institute of Health Stroke Scale (NIHSS) to assess stroke severity and Barthel Index
(BI) to assess activities of daily living. These three scales were used as secondary outcome
measures.
Outcome scales were applied at baseline (T1) and then subsequent assessments were done at one
month (T2), three months (T3), six months (T4) and at one year (T5) after the enrollment.
Sample size calculation Primary outcome measure for this study was the Fugl Meyer Assessment
of upper limb functions at one year. Previous studies have shown that FMA score increases by
16.5 ± 9.4 at one year in control subjects.21 We hypothesized that for a clinically
meaningful outcome, the intervention should produce an increase of 10 points over and above
the control group. To achieve this, a sample size of 14 patients in each arm was required for
a power of 80% with alpha fixed at 5%. In a previous study conducted at our institute, the
post stroke mortality was 27.2 % at one year, of these 72.1% died within 10 days after the
stroke.2 As have planned to include patients between 10 to 30 days of stoke onset, to account
for the mortality rate of 7.6% after 10 days, the required sample size was 16 in each group.
Considering a dropout rate of 20 %, we calculated a sample size of 20 patients in each group
as adequate.
TMS Protocol We assessed resting motor threshold (RMT) for both the hemispheres at baseline
using Magstim Rapid2 (Whitland, Wales, UK) stimulator with a figure-of-eight coil having an
external loop diameter of 9 cm. After making the patient seated comfortably in an armchair,
posterior-anterior orientation was used over the motor cortex (M1) to assume the optimal
scalp position to elicit MEP in the contralateral first dorsal interosseous (FDI) muscle. RMT
was assessed from ipsilesional hemisphere initially and followed by contralesional hemisphere
as per the standard techniques. Surface electromyograms (EMGs) were recorded from the FDI
muscles bilaterally using Ag-AgCl electrodes with a gain of 1-2 mv. Signals were filtered
(10Hz-10 KHz), and then stored for off-line analysis. Audio-visual feedback of the EMG signal
at high gain were given to assist subjects to maintain complete relaxation.
Patients in group A were subjected to TBS in addition to standard PT as described below.
Intermittent TBS (iTBS), which is facilitatory, was given to the ipsilesional hemisphere and
continuous TBS (cTBS), which is inhibitory, was given to contralesional hemisphere. The
stimulation was given at an intensity of 60% of RMT. The iTBS protocol of 10 bursts of
high-frequency stimulation (3 pulses at 50 Hz) was applied at 5 Hz every 10 s for a total of
600 pulses. When no MEP was elicited from the ipsilesional motor area (<0.05mV), 100%
stimulator intensity as that of contralesional hemisphere was applied at the mirror location
of the contralesional motor area.14 Continuous TBS was given with an intensity of 60% of RMT,
3 pulses at 50 Hz, repeated every 200 ms for a total of 600 pluses. Both iTBS and cTBS were
delivered for three times in a week for four weeks.
Functional Electrical Stimulation. Electrical stimulation was given with Mega XP (Cybermedic
Corporation, South korea). The patient received the electrical stimulation in sitting
position with affected arm positioned over the pillow and electrodes were positioned
according to pattern 3 [Grasp/Flexion/Extension, PATT (pattern movement)] of the FES (F) mode
of the instrument. The stimulator controller unit of the machine could deliver alternating
current at a frequency of 35 Hz, pulse width of 200 µs and intensity of 10~50 mA. The
stimulator was set to deliver interrupted trains of pulses with the contraction and
relaxation so as to simulate the lifting of upper limb in a functional position. The FES
group stimulation session was given for 30 minutes for each day, 3 times in a week (alternate
days) for 4 weeks and it was concurrently synchronized with the physical therapy.
Physical therapy treatment protocol The following physical therapy regimens were followed for
all the patients in the study: Passive/Active Range of Motion (ROM) at all joints; weight
bearing and supportive reaction; reaching activities; grasping, holding and release; and
upper extremity activities of daily living (ADL). Physical therapy intervention was given to
all the patients five days per week for one month. Modifications in the physical therapy was
made by second co-investigator for each patient so that he or she was able to practice
independently or with assistance from a family member after the intervention and was
instructed to practice one hour per day. In addition, all patients continued to receive
in-home physical therapy 1-2 times per week by a home care physical therapist who was guided
by second co-investigator. The investigators used a logbook to monitor the actual amount of
time that each patient exercised at home.
Statistical Methods We used descriptive statistics to summarize the data. Baseline
comparability of groups, in terms of demographic data and baseline measurements were assessed
with chi-square test and ANOVA. Non-normal data was subjected to reciprocal, logarithmic and
exponential transformation and Komogrov-Smirnov and Shapiro-Wilks tests were done to assess
normality. Parametric measures were analyzed with ANOVA followed by post-hoc analysis with
bonferroni correction. Repeated measure ANOVA was used to find out between group and within
group variability. Non parametric measures were analyzed with Kruskal Wallis test followed by
post hoc analysis with Mann Whitney U test. Friedmans test and Kendalls W test was done to
find the changes in three groups over a period of one year. All analyses were done using SPSS
version 17.0 and p value of less than 0.05 was considered significant.
