Motor Recovery Following the Comprehensive Intensive Rehabilitation Program After Stroke Implementing the International Classification of Functioning, Disability and Health Model: A Randomized Controlled Trial Protocol
Phase: NA
Conditions: Stroke, Rehabilitation, Physical Therapy Modalities
Sponsor: Charles University, Czech Republic

Study protocol for Randomised Double Blinded Controlled Trial with a longitudinal 
design monitoring effect of COMprehensive Intensive REhabilitation Program 
after STROKE (COMIRESTROKE) 
 
NCT05323916 
 
22.4.2022 
 
 
 
1. Introduction  
 
Ischemic stroke is one of the leading causes of neurological dysfunction, the most common 
being motor disability which negatively impacts quality of life and active participation (1, 2). 
There is evidence supporting the positive influence of rehabilitation in well-coordinated 
multidisciplinary stroke units (3) where physiotherapy (PT) plays an indisputable role in 
impairment reduction, activity independence, social participation and quality-of-life 
improvement (4). On the other hand, clear evidence concerning the effectiveness of different 
PT approaches as part of rehabilitation is still lacking. Several large intervention trials have 
reported that participants’ motor performance increased. Nevertheless, this was enhanced to a 
similar extent for both the intervention and control groups in most trials (5). Small beneficial 
differences between groups could be caused by a non-systematic/accidental indication of PT 
methods in rehabilitation processes. Research from other areas also suggests that between-
group differences in improvement may be found on an item level of multi-item measurements 
even in cases when they are not observed on the total scores, and thus, a more detailed item-
level analysis may provide an important insight (6, 7). 
 
Many PT techniques have been developed to facilitate the recovery of motor disability in 
patients after stroke (3, 8-10). All are related to neural plasticity via the development of new 
neuronal interconnections, acquiring new functions, and compensating for impairment (11), 
but they explain little in relation to the mechanisms underlying motor recovery heterogeneity. 
Physical activity training acts as an acute stress that enhances neurobiological processes such 
as activity-dependent plasticity, learning and memory. Motor/skill acquisitions and 
technology based PTs systematically train damaged function by the repetition of new and 
complex movements, which induces a substantial cortical network reorganization closely 
related topographically to the trained movement which leads to synaptogenesis (12). 
Neuroproprioceptive “facilitation, inhibition” (neurofacilitation) PT enhances the 
effectiveness of the synaptic connections among neurons forming functional networks, which 
leads to the evocation of movement by some otherwise weak and insufficient stimuli. A 
suitable combination of afferent stimuli modulates interneuronal systems, repeatedly activates 
motor programs at the subcortical level, and as such induces adaptive and plastic processes of 
the CNS (13). We are convinced that to prevent maladaptive plasticity, and maximize 
functional gain in patients with stroke, individualized therapeutic goals, should be considered. 
The ICF model proposes a comprehensive, biopsychosocial approach to patients, setting 
personalised goals based not only on diagnosis but also on the patients´ functional status and 
activities. It has been recommended by the World Health Organisation (WHO) (14), and was 
globally agreed-on as a conceptual framework and common language to document and code 
functional status information (15, 16). However, to date the basis of such a personalised 
approach to ischemic stroke (IS) therapy has not been clearly clarified, described and 
confirmed yet. This clinical trial will address this gap in IS rehabilitation as follows using a 

three-pronged approach to the COMprehensive Intensive REhabilitation Program after 
STROKE (COMIRESTROKE): COMIRESTROKE – ICF, the mostly individualized 
approach implementing the International Classification of Functioning, Disability and Health 
(ICF) model with aim to improve an individual's recovery (rather than impairment) through 
effective management of care (14); COMIRESTROKE – TECH, approach implementing 
technology-based PT” and COMIRESTROKE – NEFI, approach implementing 
neuroproprioceptive “facilitation and inhibition” PT.  
There is very limited evidence to guide judgements regarding the rehabilitation potential 
following stroke (17-20).  Research shows that some clinical features such as the level of 
consciousness, severity of hemiplegia, incontinence, dysphagia and dysphasia (21) or disease 
severity (22, 23) may be considered as indicators as to whether the rehabilitation process could 
be effective. However, confusion between predicting natural unassisted recovery and predicting 
responsiveness to targeted rehabilitation still remains (17). Moreover, prediction models of 
rehabilitation potential have never been fully and properly prospectively tested. The models 
considered by Prabhakaran et al., 2008 were only able to explain 47% of the variance in 
recovery after stroke with 53% of the variance remaining unaccounted (24). Nowadays focus 
shifted from the determination of rehabilitation potential to identifying clear indicators of 
effective rehabilitation including molecular biological readouts (25). This is reason why a wide 
range of patient characteristics will be collected. We consider, the patients´ subjective feelings 
about how they have improved to be the most important aspect. Therefore, the Goal Attainment 
scale (GAS) together with the Patient-reported Outcomes Measurement Information System 
(PROMIS) Global Health, and the World Health Organization Disability Assessment Schedule 
(WHODAS 2.0) were chosen as primary outcomes. As secondary outcomes, measurements 
will be taken of motor, cognitive, psychological, speech and swallowing functions as well as 
functional independence.  
Moreover, focus will be placed on the identification of novel biological molecules reflective of 
effective rehabilitation by molecular assessment. Long non-coding RNA (lncRNA) are 
defined as RNA transcripts >200 nucleotides with limited coding potential (26). They have 
been classified into anti-sense, intronic, large intergenic, promoter associated and UTR-
associated lncRNAs (27). They are involved in vital cellular regulation (28) including genomic 
imprinting (29), epigenetic chromatin modification (30), transcriptional interference (31) and 
nuclear export (32). Importantly, lncRNAs determine nervous system development (33). 
A majority of lncRNA display specific expression within neuroanatomical regions (34). Many 
of these lncRNAs display genomic localizations in close 
proximity to known 
neurodevelopmental regulators (35). This has led to the general hypothesis that the expanded 
diversity in lncRNAs is pivotal to the higher order cognitive ability of humans. Long non-
coding RNAs as promising therapeutics biomarkers in IS: LncRNAs regulate key factors 
involved in ischemic/reperfusion injury eg. calcium overload (Chen et al 2019). Excessive 
calcium accumulation results in the activation of calcium/calmodulin-dependent protein kinase 
II (CaMKII), a family of serine/threonine kinases involved in IS pathogenesis (36). CaMKII is 
controlled by lncRNA C2dat1. Elevated levels of lncRNA C2dat1 have been identified in both 
in vitro and in vivo models of IS (36). Studies showed that IS injury leads to increased glutamate 
release activating N-methyl-D-aspartate (NMDA) receptors which initiate cellular apoptosis 
(37). Overexpression of lncRNA GAS5 increased the apoptotic rate in neurons with its 
administration resulting in a greater area of cerebral infarction in animal models (38). It has 
been suggested that inhibition of the lncRNA GAS5 could potentially reduce apoptosis and 
infarct size in IS leading to improved neurological functioning. Evidence has pointed to 
lncRNA moderation of autophagy, angiogenesis and oxidative stress caused by IS. Exploring 
lncRNAs involved in such processes will assist in understanding the recovery networks induced 
by IS rehabilitation approaches. 

 
 
2. Participants and methods 
 
2.1. Clinical trial design 
This will be a Four-Arm Parallel-Group Randomised Double Blinded Controlled Trial with a 
longitudinal design. Patients who fulfilled inclusion criteria will be randomly assigned to one 
of the four research groups (Group 1, 2, 3 or 4). Three groups will undergo an inpatient 
COMIRESTROKE (4 hours/day for 3 weeks). Group 1 (COMIRESTROKE – ICF) will 
undergo individualised rehabilitation therapy embodying the ICF system as a therapeutic tool, 
where current needs and wishes of the person after IS are integrated into an interdisciplinary 
team rehabilitation programme management. Group 2 and 3 will undergo a standard 
comprehensive intensive rehabilitation program three hours per day (39) plus one hour of 
specific PT (an individual neuroproprioceptive “facilitation inhibition” for Group 2, a 
technology-based training for Group 3). Group 4 will undergo standard care and will serve as 
comparative one to the intensified intervention groups.  
Participants will be examined four times (Figure 1). At the beginning and after three weeks of 
hospitalization (both primary, secondary outcomes and a blood draw will be obtained for total 
RNA extraction, cDNA synthesis and real-time QPCR assessment of lncRNA candidates 
previously identified as potential therapeutic influencers in ischemic stroke), and then three 
months and one year after the end of the program (primary outcomes only).  
Figure 1: Design of the study 
 
 
2.2. Eligibility criteria and subgroups 
Participants will be identified by specialists in neurology and rehabilitation from inpatients at 
the Department of Acute Care, Department of Neurology, Thomayer University Hospital or 
University Hospital Kralovske Vinohrady, Prague, Czech Republic.  
Inclusion criteria: Adults (18 – 85 years) after the first ischemic stroke in early sub-acute phase 
(40, 41), with a slight to moderately severe disability [2 – 4 on the Modified Rankin Scale (42)], 
• Demographic and 
anamnestic data
• primary outcomes
• secondary 
outcomes
• lncRNA
Examination 1
• primary 
outcomes
• secondary 
outcomes
• lncRNA
Examination 2
after 3 weeks of 
hospitalisation
• information 
about care
• primary 
outcomes
3 months 
follow-up
information 
about care
primary 
oucomes
12 months 
follow-up

with minimal or moderate motor deficit of upper or lower extremities (on NIHSS Item 5 or 6 
scores 1–3 points) who were able to perform activities of daily living prior to stroke event [0 – 
2 on the Pre-Stroke Modified Rankin Score (43)], with a potential to accept 4 hours of 
comprehensive rehabilitation per day and to profit from the physiotherapy. Czech is their native 
language or its knowledge is at the level of the mother tongue. 
 
Exclusion criteria: Low level of consciousness (vegetative state and/or minimally conscious 
state); severe cognitive decline that would interfere with administration of the tests, premorbid 
illiteracy, severe visual and/or auditory deficit that would prevent proper completion of the 
tests; behavioural disorders and/or lack of cooperation with therapist; and severe medical 
problems with a poor prognosis, (e.g., severe frailty, advanced and incurable cancer, fracture, 
cardiovascular disorders as chronic heart failure NYHA III, IV, symptomatic coronary artery 
disease Angina Severity Class III, IV, respiratory insufficiency as chronic obstructive 
pulmonary disease GOLD IV, and other severe disease) (44).  
 
Randomisation 
All patients meeting the above criteria will be invited to participate and asked to provide a 
written informed consent. They will be randomly assigned (1:1:1:1) as soon as possible, but 
always within 48 hours of admission, into one of the four interventions (represented by Group 
1, 2, 3 or 4) using offsite-independent randomization protocols (www.randomization.com). 
Concealed allocation will be performed using sequentially numbered opaque sealed envelopes 
only accessible by research personnel with no involvement in the trial. 
 
2.3. A detailed description of four groups 
Three groups in intervention cohorts will receive the same length of rehabilitation, i.e., 4 hours 
per day. Therapists in each group will be maximally helpful and will adopt a schedule for each 
patient to complete all the sessions. The treatment in each session will be led in person by well-
educated, experienced therapists specially trained in each method. The treatment will be 
modified according to the patient´s status and reaction to the therapy. Physical load during all 
therapies will be perceived maximally as a moderate level of intensity [12 - 14 on the Borg 
Scale (45)]. Information about the treatment will be recorded using codes of Public Health 
Insurance, Czech Republic (codes correspond to The Current Procedural Terminology code set 
system). 
 
Group 1: COMprehensive Intensive REhabilitation Program after STROKE 
implementing the ICF concept (COMIRESTROKE – ICF)  
This interventional arm suits the purposes of setting individual goals of the therapy which take 
account of the given situation of the rehabilitated person (46-48). The ICF system establishes a 
common health language to articulate human functioning across the lifespan and from 
individual to population health settings system (49, 50). On the individual level, functioning is 
considered as an interaction between a health condition and the contextual factors facilitating 
or acting as a barrier for functioning (51). Focusing on patient’s quality of life and participation 
domain of the ICF applies a paradigm shift in neurorehabilitation research design (52). 
Engagement in valued activities was found to be significantly associated with subsequent 
improvement in emotional well-being (53) . 
Patients randomized to the GROUP 1 will undergo a multidimensional assessment, a functional 
profile will be created and the individual goals and intervention proposed and defined 
throughout the ICF framework. Clinical application can be rather arduous (54) and sharing of 
the feasibility experience is highly valued. This study arm design follows recommendations and 

experience with implementation of the ICF model into clinical practice in rehabilitation in 
people after stroke (55). 
Limiting the burden of iterative processing the proposed battery of  clinical examinations, 
questionnaires surveys and filling out the ICF core set documentation which is then used to 
compile "ICF Categorical Profile”, this study proposes a direct linking of some clinical test 
results to the codes included in the Comprehensive ICF core set for stroke used (56). Linking 
of normal-range clinical examination results may ease the procedure. Linking will take place 
regarding specified items from the test battery: WHODAS 2.0 (57) NIHSS, mRS, MoCA (58), 
MAL (59), FIM, BBS (60), TUG, NHPT, ARAT, GSS, 3F test, MAST. Overlapping items will 
be further discussed.  
The clinical assessment involves the following three steps: 1) description of patient’s problems 
and resource; 2) setting of mutually agreed goals, based on the functional profile; 3) and 
determination of intervention targets. The interdisciplinary team together with the patient will 
use the functional profile to define in detail the overall goal and sub-goals, and to determine 
specific therapeutic interventions to achieve them (42). Participants in this group will undergo 
four hours of treatment per day (the same time as in the remaining two cohorts), but the time 
spent with each specialist will depend on the individually set goals. The “ICF Intervention 
Table” will be used to monitor and evaluate the work during individual targeted interventions 
and will also serves as a means of communication between the members of the interdisciplinary 
team. The team will meet weekly to provide feedback, evaluate the fulfilment of the set goals 
and to adjust therapeutic procedures so that the goals of the therapy are best met.  
After the end of the intensive complex inpatient program COMIRESTROKE – ICF, as the 
continuum of care, participants will be referred and to a short-term outpatient rehabilitation 
programme.  
Group 2 and 3 
Participants will undergo COMprehensive Intensive REhabilitation Program after STROKE 
routinely offered at the Department of Rheumatology and Rehabilitation, Third Faculty of 
Medicine, Charles University and Thomayer University Hospital (39) three hours per day. In 
the program, the multidisciplinary team of practitioners from different clinical fields 
(physiotherapy, occupational therapy, clinical speech therapy and psychology) will be led by a 
medical doctor, a specialist in rehabilitation and physical medicine. Efforts of the different team 
members are parallel and discipline oriented.  
In addition, participants in these two groups will undergo one hour of physiotherapy per day. 
Group 2: COMprehensive Intensive REhabilitation Program after STROKE implementing 
technology-based physical PT (COMIRESTROKE – TECH) Participants will receive a 
technology-based PT that follows the principles of sensorimotor learning, i.e. repeated specific 
and targeted functions in different environments / conditions in order to strengthen the memory 
footprint and initiate structural changes in the CNS. According to the indication, participants 
will be offered one of the robotic systems using an exoskeleton (Gloreha, Erigo and Meditutor) 
or a therapy using a virtual environment (61, 62). 
Group 3: COMprehensive Intensive REhabilitation Program after STROKE implementing 
neuroproprioceptive “facilitation and inhibition” physiotherapy (COMIRESTROKE – NEFI). 
Participants will receive an individual neuroproprioceptive “facilitation, inhibition” PT (Vojta 
reflex locomotion, Bobath concept), where appropriate stimuli in a suitable time sequence are 
combined with the aim to maintain optimal motor pathway function and ability control (63, 64). 
After finishing this intensive complex inpatient program COMIRESTROKE, participants will 
undergo standard/not directed treatment offered by the Czech Health Care system. Information 

as to the health and social care the rehabilitant received after hospitalisation will be collected 
by phone call.  
Group 4: A comparative group will undergo standardly provided care at department of 
neurology including face to face physiotherapy (bed mobility, transfers, gait, therapeutic 
exercises, positioning, education). 
 
2.4. Pre- and post-intervention assessments 
Once an informed consent is obtained prior to randomisation; participants will be referred to 
study examiners - a Physical Medicine and Rehabilitation physician, a neurologist, a physical 
therapist, an occupational therapist and a psychologist, who will not know the treatment group 
of the patient. They will administer baseline testing during the 2nd and 3rd day after admission 
to the department (Pre-assessment). The Post-assessment 1 will be done at the end of the three-
week inpatient intensive comprehensive rehabilitation (during the last two days of 
hospitalization). Follow-up assessments will take place 3 and 12 months after the admission, 
respectively, by a telephone interview and hospital visit for blood draw. The aim is to be 
assessed only by one examiner, in case of more examiners, inter-rater reliability will be assessed 
(Table 2). 
 
Table 2: Timing and distribution of examination in the team 
test 
abbreviation 
Inclusion 
and 
exclusion 
criteria 
 
Examination No 
 
 
 
1 
2 
3 
4 
 
 
 
baseli
ne 
+3 
weeks 
+3 
month
s 
+ 1 
year 
Neurologist 
 
 
 
 
 
 
Demographic and anamnestic data  
(age, after first ischemic stroke, days after the stroke) 
x 
 
 
 
 
Demographic and anamnestic data  
(weight and height, cardiovascular risk factors, Bamford classification, 
medication) 
x 
 
 
 
Modified Rankin Scale 
mRS 
x 
 
x 
 
 
Pre-Stroke Modified Rankin Score  
pre-stroke mRS 
x 
 
 
 
 
Historic Stroke Motor Severity Score  
HSSS 
x 
 
 
 
 
National Institute of Health Stroke 
Scale 
NIHSS 
x 
 
 
 
 
Psychologist* 
 
 
 
 
 
 
Montreal Cognitive Assessment 
MoCA 
 
x 
 
 
 
Amnesia Light and Brief Assessment  
ALBA 
 
x 
x 
 
 
NEO-Five Factor Inventory 
NEO - FFI 
 
x 
 
 
 
Patient-reported 
Outcomes 
Measurement 
Information 
System 
Global Health 
PROMIS 
 
x 
x 
x 
x 
the 
World 
Health 
Organization 
Disability Assessment Schedule  
WHODAS 
 
x 
x 
x 
x 

the Goal Attainment scale  
GAS 
 
 
 
 
 
Picture naming and immediate recall  
PICNIR 
 
x 
x 
 
 
Neuro - QOL depression  
 
 
x 
x 
 
 
physical therapist  
 
 
 
 
 
 
Hand Dynamometer  
 
 
x 
x 
 
 
postural tremor  
 
 
x 
x 
 
 
Action Research Arm Test* 
ARAT 
 
x 
x 
 
 
Motor Activity Log* 
MAL 
 
x 
x 
 
 
Timed Up and Go* 
TUG 
 
x 
x 
 
 
Berg Balance Scale* 
BBS 
 
x 
x 
 
 
The 10 Metre Walk Test* 
 
 
x 
x 
 
 
The 6 Minute Walk Test* 
 
 
x 
x 
 
 
Functional Independence Measure* 
FIM 
 
x 
x 
 
 
Laterality index 
LI 
 
x 
 
 
 
Nine Hole Peg Test 
 
 
x 
x 
 
 
speech therapist* 
 
 
 
 
 
 
The Gugging Swallowing Screen  
GSS 
 
x 
x 
 
 
The 3F Test – Dysarthric Profile  
3F test 
 
x 
x 
 
 
Dysan 
 
 
x 
x 
 
 
The Mississippi Aphasia Screening 
Test  
MAST 
 
x 
x 
 
 
Image Naming Test  
INT 
 
x 
x 
 
 
Blood – Total RNA extraction 
cDNA synthesis 
lncRNA assessment (C2dat1, GAS5, 
MALAT1, PARTICLE, H19, MEG3) 
 
 
x 
x 
 
 
 
*Tests recommended by General Health Insurance (GHI), Czech Republic. 
 
The qualitative data will be collected in semi-structured interviews with patients as well as 
clinical specialists with the aim of capturing an extended health evaluation. Specialists will 
have the possibility to look at the hospital information system, or search in the National Register 
of Paid Health Services. Data will be captured using an electronic Case Report Form (eCRF) 
(65). 
 
The following data will be collected: 
 
Demographic and anamnestic data including personal factors (sex, age, education, 
occupation, social relations, living situation), weight and height, laterality index (66), number 
of days after the stroke event, personality based on the NEO-Five Factor Inventory (NEO-FFI) 
(67), pre-stroke functional status based on modified Rankin Scale (68), cardiovascular risk 
factors (69), the degree of neurological impairment according to the National Institute of Health 
Stroke Scale  (70) and disability with the Modified Rankin Scale (42), Bamford classification 
of IS based on the initial presenting symptoms and clinical signs (71) as well as 
pharmacotherapy. 
 
2.5. Outcomes and measures 

 
2.5.1. 
Primary Outcomes 
 
 
 PROMIS Global Health is a 10-item scale which asks the patient to assess (self-report) 
their physical, mental and social health in the past 7 days (72, 73).  
 
 WHODAS 2.0 is a generic assessment instrument developed by WHO to provide a 
standardized method for measuring health and disability. It is grounded in the 
conceptual framework of the ICF and integrates an individual's level of functioning in 
major life domains and directly corresponds with ICF's "activity and participation" 
dimensions. The 36-item version will be used. Higher score means higher disability 
(74).  
 
 GAS is an individualized outcome measure involving goal selection and goal scaling 
that is standardized in order to calculate the extent to which patient's goals are met. Each 
goal is rated on 5-point scale (-2 much less than expected, 0 achieved the expected level, 
2 much more than expected (75, 76). 
Three types goals will be established: 
A. Overarching long-term goal (Global Goal, G) that reflects a desired improvement on 
the level of participation: usually restoration of previous life including remunerative 
employment, sport and leisure activities (interview by call at 3 and 12 months follow 
up). 
B. Mid-term goal (Program Goal, P) that reflects improvement mainly in the domain of 
activities and participations achievable by the rehabilitation program: restoration of self-
care, (almost) independence in daily living etc. (interview by call at 3 months follow 
up) 
C. Three Short-term goals (Cycle Goals C1, C2, C3) mainly in the domain of 
functioning and activities. Usually specific, most problematic components of the 
Program Goal (evaluated by the rehabilitation team together with the rehabilitant). 
 
 
2.5.2. 
The secondary outcomes 
The secondary outcomes include clinical tests and questionnaires of physical functions and 
functional independence (examined by an independent physical therapist), speech and 
swallowing (examined by an independent speech therapist), cognitive and psychological 
functions (examined by an independent clinical psychologist).  
 
2.5.2.1. Physical functions and functional independence 
Upper extremity functions 
 Jamar Hydraulic Hand Dynamometer will be used to measure isometric grip force from 
0-90 kg. Five handle positions from 35-87 mm will be tested. The measurement is in kg 
(the higher the value, the better the function) (77). 

 A postural tremor will be measured by the 3-axis accelerometer and 3-axis gyroscope 
chip (Motion Tracking sensor MPU-6050) which can measure acceleration up to 16 g 
and rotation up to 2000 degrees per second. The sensor will be fixed to the patient using 
a ring on a finger during stretching the whole arm forward, separately passed for the left 
and right hand and with opened and closed eyes (one-minute measurement for each 
position). Data from the chip will be acquired by an own measuring device with 
microcontroller Atmel Mega 328 and stored on an SD card. 
For the signal analysis, the magnitude of acceleration – the root of sum of each 
component squares – will be computed from separate axes. The sampling frequency will 
be 100 Hz. Thus, four signals with 6000 samples will be recorded for each patient – 
records of postural tremor for right/left hand with opened/closed eyes. 
For each record, the signal of acceleration will be filtered by a filter of isoline (typically 
by high-pass 2nd order Butterworth filter with cut-off frequency of 0.5 Hz). 
Consequently, the power spectral density (PSD) will be estimated. 
The spectral characteristic will be parameterized by selected parameters, for example 
fMAX (a frequency for which the smoothed PSD is maximal - lower value, lower tremor) 
or Pf1-f2 (a power of the signal in band from f1 to f2 - lower value, lower tremor) (78).  
 Nine Hole Peg Test is used to measure finger dexterity. A client takes the pegs from a 
container, one by one, and places them into the holes on the board, as quickly as 
possible. Shorter times reflect better function (79). 
 
 Action Research Arm Test (ARAT) is a 19 item observational measure to assess upper 
extremity performance (coordination, dexterity and functioning). Items are categorized 
into four subscales (grasp, grip, pinch and gross movement). A higher score means 
better function (80). 
 
 Motor Activity Log is a scripted, structured interview to measure real-world upper 
extremity function consisted of 14 activities of daily living such as using a towel, 
brushing teeth, and picking up a glass. A higher score means better function (81). 
Mobility and walking 
 Timed Up and Go is a simple performance-based measure of dynamic balance. The 
subject stands up from a chair, walks 3m, turns back, and sits down again as quickly 
and safely as possible while being timed. Shorter times reflect better mobility (82). 
 Berg Balance Scale is a 14-task scale that requires subjects to maintain their balance in 
positions and tasks of increasing difficulty. A lower score means worse balance (83). 
 The 10 Metre Walk Test is a performance measure used to assess walking speed in 
meters per second over 10 meters. Shorter time reflects better mobility (84). 
 The 6 Minute Walk Test is a long walking capacity test recording the maximal distance 
a subject can walk at the fastest speed possible in 6 minutes. The more distance covered, 
the better the walking performance is (84). 
Functional Independence 
Functional Independence Measure is an 18-item measurement tool which explores an 
individual's physical, psychological and social function. It uses the level of assistance an 

individual needs to grade functional status from total independence to total assistance. The 
higher the score, the better (higher independence) (85). 
2.5.2.2. Speech and swallowing 
The Gugging Swallowing Screen is a simple stepwise bedside screen that allows a graded rating 
with separate evaluations for nonfluid and fluid nutrition starting with nonfluid textures. It 
assesses the severity of aspiration risk. A higher score means better function (85).  
The 3F Test – Dysarthric Profile consists of three subtests (Faciokinesis, Phonorespiration, 
Phonetics). The overall Index of Dysarthria (ID) is a sum of 45 items with the maximum score 
of 90 (the best function) (86).  
Following the previously published guideline (87), the dysarthria assessment is based on the 
automatic evaluation of utterances, including sustained phonation, speech diadochokinetic task, 
and connected speech. Utterances will be recorded during the sessions with speech language 
pathologist. The recording will take place in a quiet room with low ambient noise using a head-
mounted condenser microphone (Shure Beta 53, Niles, Illinois, U.S.), placed approximately 
5cm from the mouth corner at an angle of 70°. The recordings will be sampled at 48kHz with 
16bit resolution. The automatic analysis will be performed using the beta version of the freely 
available Dysarthria Analyzer (Czech Technical University in Prague, available at 
http://dysan.cz/). 
 
The Mississippi Aphasia Screening Test (MAST) was developed as a brief, repeatable 
screening measure for individuals with severely impaired communication/language skills. It 
has nine subtests that range from 1 to 10 items per subscale. The Index scores sum to 50 points 
each and are added for the MAST Total Score (0 -100 points). The higher the score, the better 
function (88).  
 
Image Naming Test (Test pojmenování obrázků, TPO) is a test of confrontational naming of 
nouns and verbs. Words are selected based on success, frequency of occurrence, age of 
adoption, length, and visual complexity. The maximum sum is 60 points (30 verbs and 30 
nouns), the results can be assessed qualitatively according to the type of unexplained words 
(89). 
2.5.2.3. Cognitive and psychological functions 
 
The Montreal Cognitive Assessment (MoCA) is an assesment for detecting cognitive 
impairment ranged between 0 and 30 points. The more the better. The Czech version was 
validated and cut-offs and norms were established (90, 91).  
 
The Amnesia Light and Brief Assessment (ALBA) is an original Czech and innovative test to 
assess more cognitive functions (therefore Assessment in the name) including memory 
(therefore Amnesia) easily (therefore Light) and quickly in three minutes (therefore Brief). The 
ALBA consists of four tasks: (1) repetition and encoding of a six-word sentence "Indian 
Summer Brings First Morning Frost", (2) sequential demonstration of six gestures and (3) their 
immediate recall, and (4) final recall of the original sentence. The first task of a sentence 
repetition reflects (1) language (impaired in aphasia) or (2) encoding and working memory 
(impaired in memory and attention deficits). The second task of gesturing can be impaired as a 
result of sensory aphasia or apraxia. Short-term and episodic memory is measured in two 
different ways, (1) in the third part of the ALBA, i.e., incidental memory of the gestures, and 

(2) in the fourth part, i.e., intentional verbal memory of the sentence. Overall memory can be 
expressed as the ALBA score, which is a sum of correctly recalled sentence words and gestures. 
The higher scores of each ALBA part the better function. Scores of individual parts range from 
0 (the worst) to 6 points (the best) for each of four tasks: (1) the number of correctly repeated 
words of the sentence (Word 1 score: 0–6 points), (2) the number of correctly recalled words 
of the sentence after the distraction using the TEGEST (W2 score: 0–6), (3) the number of 
correctly performed gestures of the TEGEST (Gesture 1 score: 0–6), and (4) the number of 
correctly recalled gestures of the TEGEST (G2 score: 0–6). The sum, called ALBA score, is 
derived from correctly recalled words of the sentence and correctly recalled gestures together 
(W2 + G2: 0–12 (6 + 6)). Example scores of the ALBA test can be the following: 5/1 + 5/3 
(W1/2 + G1/2) that gives a total ALBA score: 4 (1 + 3) points (92, 93).  
Picture naming and immediate recall (PICNIR) is an original Czech and brief test which is a 
method certified by Ministry of Health of the Czech Republic in 2017. The purpose of the 
PICNIR is to evaluate written speech, long-term sematic and short-term visual memory 
simultaneously and quickly in five minutes. The test consists of two parts. The task of an 
examinee is to write down names of 20 black and white pictures in one word and remember 
them at the same time. Then they are asked to rewrite as many picture names as they can recall 
during one minute. The results of the PICNIR include a number of wrongly named or unnamed 
pictures in the first naming part and a number of correctly recalled picture names in the second 
recall part. The less naming errors and more recalled picture names the better (94).  
Neuro - QOL depression is a self-report of health-related quality of life in domain concerning 
depression (95). (72) 
2.5.3. Other Pre-specified Outcome Measures - molecular biological readouts of 
rehabilitation  
Blood will be taken for total RNA extraction, cDNA synthesis and real-time QPCR assessment 
of lncRNA candidates previously identified as potential therapeutic influencers in ischemic 
stroke. Whole blood will be collected from fasting patients for RNA analysis. A RiboPure™-
Blood Kit (cat# AM1928, ThermoFisher Scientific) will be used for isolating high-quality RNA 
directly from whole blood. This kit contains an RNAlater® Solution (cat.# AM7020, 
ThermoFisher Scientific) that protects RNA and is designed to eliminate the need to process 
samples as soon as they are harvested.  RNAlater® Solution also "freezes" the gene expression 
profile of the cells. Treated samples can be safely stored at ambient temperature for extended 
periods of time (up to three days or more). Blood samples stored in RNAlater® Solution yield 
RNA of comparable quality to blood samples processed directly according to the commercial 
website. Expected average yields of total RNA will be between 2–4 µg/0.5 mL of whole blood. 
Total RNA will be reverse transcribed into cDNA. Human lncRNA and internal endogenous 
gene (eg. GAPDH) expression will be quantified using RNA extracted from blinded samples 
(ie. concealment of group allocation) to eliminate bias. 
 
2.6. Estimated size 
It is estimated that approximately 110 people will be recruited to the clinical trial each year. 
This number is based on the fulfilment of performance and quality indicators report of 
cerebrovascular care at the Centre for Highly Specialized Patient Care for Stroke Patients at 
Thomayer Hospital 2019. A total of 210 people is expected to be enrolled in the clinical trial 
over a period of two years (Figure 2), corresponding to a required sample number of 70 patients 
per group. This value is necessary in order to detect a significant difference in improvement 

between two groups when achieving a mean difference effect (Cohen's d = 0.5), a significance 
level of α = .05 and a strength of 1-β = .80. The sample size was determined based on the 
minimal clinically significant change on a Berg balance scale (96). 
 
Figure 2: Planned recruitment and randomisation process 
 
 
 
 
2.7. Descriptive statistics 
On the baseline, the distribution of all primary and secondary outcomes will be visualized using 
histograms and QQ plots. We expect normal distributions in most of the variables defined as 
raw scores from appropriate tests, or in their log transformations (e. g. tests measuring time 
needed to walk certain distance or to perform a task). The groups will be compared in their 
characteristics, primary, and secondary outcomes using the one-way analysis of variance 
(ANOVA), and its nonparametric version (Kruskal – Wallis test), where needed. The 
Benjamini-Hochberg correction (97) will be used to account for multiple comparisons. We 
expect no differences between groups on the baseline. If differences are observed, these will be 
accounted for in the longitudinal models. 
 
2.8. Hypotheses 
 
 
This clinical trial will test the following scientific hypotheses: 
 
I.  
COMIRESTROKE under all three settings has a positive influence on all outcomes and 
higher effect than control group.  
II.  
COMIRESTROKE - ICF will have the highest impact on primary outcomes (GAS, 
PROMIS, WHODAS 2.0) and on such secondary outcomes that were identified as treatment 
goals. Furthermore, we expect the highest impact on the primary outcomes in the follow-up 
(three and twelve months after finishing the rehabilitation). 
III.  
COMIRESTROKE – NEFI will have the highest effect on the secondary outcomes, 
mainly on motor functions. Moreover, it will most significantly lead to the initiation of plastic 
and adaptive processes, assessed by the level of lncRNAs in the peripheral blood. 
Agreement with Participation and Randomisation
280
Eligible
300 
COMIRESTROKE – ICF
70
COMIRESTROKE – TECH 
70
COMIRESTROKE – NEFI 
70
control group
70 

IV. The most important predictor of effective rehabilitation will be the level of disability at 
admission time; however, the content of the rehabilitation will have an impact on perceived, 
clinical, and physiological changes of the rehabilitant. 
 
The exploratory goals of this clinical trial are as follows: 
Goal I - Improvement patterns: Considering the high number of measured outcomes, for a 
deeper understanding of therapy efficacy with respect to patient and treatment characteristics, 
this clinical trial will aim to identify groups of patients with similar improvement patterns post 
therapy. 
Goal II - Item-level analysis: To provide a deeper understanding of the differences in 
effectiveness between the three therapeutic approaches, this clinical trial will plan to explore 
item-level between-group differences in improvement. 
 
 
 
2.9. Measuring the effectiveness of rehabilitation  
To test hypothesis I., i.e., a positive influence on all outcomes, the effect of therapy for each 
therapeutic group will be assessed separately by paired t-tests performed on pre-test and post-
test scores. The Wilcoxon rank test will be used on data where normal distribution cannot be 
expected. 
 
To test hypotheses II. and III, a comparison between therapeutic groups will be performed using 
two sample Student t-tests on differences between measurement time points (or Wilcoxon tests 
respectively for data, where normal distribution of the differences cannot be expected). For 
hypothesis II, the COMIRESTROKE - ICF group will be compared against the rest of the 
participants. For hypothesis III, the COMIRESTROKE - NEFI group will be compared against 
the rest of the participants. A one-sided alternative will be tested according to our hypotheses. 
We will also implement the one-way ANOVA test to jointly compare all three groups for pre-
post differences. In addition, a Tukey post-hoc comparison will be made to detect any further 
group differences beyond our hypotheses.  
 
To assess the overall impact of rehabilitation and to compare effectiveness of different 
therapeutic approaches for Hypotheses I – III in more complex way, and to test for effect of 
other covariates in Hypothesis IV, a linear mixed effect model will be used with random patient 
effect fitted to longitudinal patient data. Measurement effect, group effect and their interaction, 
as well as effects of other covariates such as the level of disability in admission time will be 
tested by F test.  
 
To address Goal I, correlations between changes in different examination scores will be 
evaluated using Pearson correlation coefficient and its nonparametric analogies. A cluster 
analysis will be performed to identify different phenotypes. This will allow the identification 
of different groups of patients in relation to the efficacy of the neuro-rehabilitation programs.  
 
To address Goal II, for selected multi-item instruments, item-response theory (IRT) and 
generalized linear regression models will be used to study differential item functioning with 
respect to rehabilitation groups. Account will be taken for other respondent characteristics. Use 
will be made of differential item functioning in change (DIF-C) analysis (7) in order to detect 
between-group differences. 
 
2.10. 
Statistical software 

Analysis will be performed using the free statistical environment R (98) and its libraries. The 
lme (99) and nlme (100) library will be used for implementing mixed effect models. Library 
difNLR (101) will be used for the detection of DIF. Modules of the interactive 
ShinyItemAnalysis application will enable lme (99), nlme (100) and difNLR (101) library 
sample analyses to be interactively displayed (102). 
 
3. Discussion 
Undoubtedly, early intensive and complex rehabilitation is necessary for people after ischemic 
stroke (103). To address all functions and activities of the patient, the ICF model (3) provides 
systematic categorization potentially increasing the effectiveness of therapy (104). This clinical 
trial will implement a biopsychosocial approach in which individual goals set by an 
interdisciplinary team and rehabilitator will take into account the functioning, activity and 
participation level of the patient. To date, no study implementing the ICF model, has evaluated 
the effectiveness of rehabilitation in comparison with other interventions. (14, 105).  
Ischemic stroke causes an extensive range of clinical dysfunctions. To narrow the program, 
motor disability was chosen as one of the inclusion criteria, as it is the most common and widely 
recognised problem (8). Motor recovery provides a direct means of addressing the effectiveness 
of therapy. Nineteen intervention types relevant to motor recovery after stroke have been 
identified (8). The most commonly applied include those involving Motor/Skill acquisition and 
Technology-based individualized interventions where the patient is increasingly active in the 
motor re-training process and the principles of sensory-motor learning are applied. 
Neurophysiological approaches including Bobath which stimulate neuroproprioceptive 
“facilitation, inhibition” (106, 107), are rarely utilised.  In the Czech Republic, Vojta reflex 
locomotion, is routinely used in clinical practice. To date, only one very recent study has 
documented its effectiveness in stroke patients (108). This clinical trial should confirm this 
promising finding, and moreover enable the comparison of its effectiveness with alternative 
rehabilitation approaches implementing technology-based physiotherapy as well as those 
applying the ICF model. Importantly, this clinical trial will enable the systematic collection of 
demographics, biometric and molecular marker information allowing an opportunity for 
association analysis that may provide further evidence identifying indicators of effective 
rehabilitation. It is expected that the treatment will be much more effective in patients who start 
the rehabilitation soon after the ischemic stroke event. Patients will be scored for disability, 
personality traits, cardiovascular function and cognitive ability as outlined above.   
 
Information gathered regarding whether a person will benefit from rehabilitation at a particular 
time point will improve the management of care in post-stroke people (17). Significant regard 
will be given to a participants’ subjective feelings about how they feel they have improved, 
with tests chosen that provide a psychometric basis of assessment  (109-111). If a correlation 
is confirmed between such tests and specific treatment, it will increase the likelihood of 
implementation into clinical stroke practice as quality indicators (72). Secondary outcomes 
have been chosen mainly in accordance with the Cranio-program (112). While financially 
demanding, the general health insurance system of the Czech Republic, requires fulfilment of 
a number of the above-standard conditions (for example, comprehensive testing - see table 2; 
and minimally 4 hours of rehabilitation per day). Recommended tests have been supplemented 
by objective examinations which may provide more extensive information e.g., Nine Hole Peg 
Test or the Hand Dynamometer. Moreover, specialized technological methods for assessing 
tremor (78) and dysarthria (87) have been supplemented with the aim of comprehensively 
describing algorithms of tremor and speech in people after stroke. To avoid overburdening 
patients, the examination will be effectively organized over two days. Additionally, 
examination by a clinical psychologist and speech therapist will be done in such a way as to 

bring a therapeutic effect. One of the most important outputs of this clinical trial will be the 
recommendation concerning which clinical tests and scales are the most useful in post-stroke 
rehabilitation based on the framework of the ICF model. As in clinical practice, outcome 
measurements are used to guide rehabilitation programs, we consider that an item-level analysis 
may provide a deeper insight into the effectiveness of different interventions. 
 
The benefits of previous rehabilitation have already been confirmed in individuals in the late 
phase after stroke (4, 113). In the context of the ICF model, it is important to assess the impact 
of rehabilitation from a long-term perspective (114). This clinical trial will document the 
enduring effect of rehabilitation after the subacute phase. This is the most important phase for 
recovery involving spontaneous improvement as well as benefits arising from previous 
therapeutic intervention (10).  
 
In future, rehabilitation strategies should consider molecular biomarkers as indicators of 
improvements in neurobiological principles that support repair or compensatory strategies that 
stimulate adaptive responses in people after stroke (115). The role of lncRNA e.g., MALAT1, 
SNHG12, MEG3 and H19, in ameliorating IS brain injury has now been recognised (25). They 
are pivotal factors in neuronal repair processes and enhance neurogenesis. Nevertheless, there 
is a lack of human studies and clinical trials involving lncRNAs in IS treatment. The medical 
community has stressed the urgency of implementing studies that may clarify the clinical 
impact of lncRNAs in the specific context of IS given their promising involvement in nervous 
system recovery.  
 
In conclusion, the proposed clinical trial will determine the effectiveness of various 
rehabilitation approaches via analysis of physical, emotional and biological readouts.  
Therefore, this clinical trial will offer an innovative approach and will provide new direct and 
biological evidence of the effect of implementing the ICF model into the rehabilitation 
therapeutic arena. 
 
 
 
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Informed consent form 
Patient name: 
Birthdate: 
The patient was included in the study under the number: 
Name of the authorized expert for this study: 
 
1. I, the undersigned, agree to my participation in the study. I am over 18 years old. 
2. I have been informed in detail about the objectives of the study, its procedures, and 
what is expected of me. The doctor in charge of the study explained to me the expected 
benefits and possible health risks that might arise during my participation in the study 
and explained how it would proceed if it occurred in an adverse event. I acknowledge 
that the study being conducted is a research activity. If the study is randomized, the 
probability of randomization to different treatment groups is taken into account. 
3. I have informed the doctor in charge of all the medicines I have taken in the last 28 
days, including those I am currently taking. If a medicine is prescribed to me by another 
doctor, I will inform him of my participation in the clinical study and I will not take it 
without the consent of the doctor in charge of that study. 

4. I will work with my doctor during my treatment and will inform him immediately if any 
unusual or unexpected symptoms occur. 
5. I will not be a blood donor for the duration of the study and for another 4 weeks after 
its completion. 
6. I understand that I may suspend or withdraw from my participation at any time 
without affecting the course of my further treatment. My participation in the study is 
voluntary. 
7. When enrolled in the study, my personal data will be kept with full protection of 
confidentiality according to the valid laws of the Czech Republic. Based on my consent, 
they will be able to inspect my original medical records in order to verify the data 
obtained by representatives of independent ethics committees and foreign or local 
competent authorities. For these cases, the confidentiality of my personal data is 
guaranteed. In the actual conduct of the study, personal data may be provided to 
entities other than those mentioned above only without identification data, ie 
anonymous data under a numerical code. Also for research and scientific purposes, 
my personal data can only be provided without identification data (anonymous data) 
or with my express consent. 
8. There is no reward for my participation in the study. 
9. I understand that my name will never appear in papers on this study. I agree with 
the use of the results from this study. 
10. I have received a signed copy of this informed consent. 
 
Patient's signature:  
Signature of the specialist in charge of this study: 
 
Date: