Stroke

ORIGINAL CONTRIBUTION

Additional, Mechanized Upper Limb Self-

Rehabilitation in Patients With Subacute Stroke
The REM-AVC Randomized Trial
Olivier Rémy-Néris , MD, PhD; Anaïs Le Jeannic , MSc; Angelina Dion, MSc; Béatrice Médée, MD;
Emmanuel Nowak, PhD; Élodie Poiroux, MD; Isabelle Durand-Zaleski , MD, PhD; on behalf of the REM Investigative Team*

BACKGROUND AND PURPOSE: Additional therapy may improve poststroke outcomes. Self-rehabilitation is a useful means to
increase rehabilitation time. Mechanized systems are usual means to extend time for motor training. The primary aim was
to compare the effects of self-rehabilitation using a mechanized device with control self-exercises on upper extremity
impairment in patients with stroke.

METHODS: Phase III, parallel, concealed allocation, randomized controlled, multicenter trial, with 12-month follow-up. Patients
aged 18 to 80 years, 3 weeks to 3 months poststroke with a Fugl-Meyer Assessment score of 10 to 40 points, were
randomized to the Exo or control groups. All undertook two 30-minute self-rehabilitation sessions/day, 5 days/wk for 4 weeks
in addition to usual rehabilitation. The Exo group performed games-based exercises using a gravity-supported mechanical
exoskeleton (Armeo Spring). The control group performed stretching plus basic active exercises. Primary outcome was
change in upper extremity Fugl-Meyer Assessment score at 4 weeks.

RESULTS: Two hundred fifteen participants were randomly allocated to the Exo group (107) or the control group (108).
Mean age (SD), 58.3 (13.6) years; mean time poststroke, 54.8 (22.1) days; and mean baseline Fugl-Meyer Assessment
score, 26.1 (9.5). There was no between-group difference in mean change in Fugl-Meyer Assessment score following the
intervention: 13.3 (9.0) in the Exo group and 11.8 (8.8) in the control group (P=0.22). There were no significant between-
group differences in changes for any of the other outcomes at any time point (except for perception of the self-rehabilitation).
There was no between-group difference in cost utility at 12 months.

CONCLUSIONS: In patients with moderate-to-severe impairment in the subacute phase of stroke, the purchase and use of
complex devices to provide additional upper limb training may not be necessary: simply educating patients to regularly move
and stretch their limbs appears sufficient.

REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01383512.

GRAPHIC ABSTRACT: An online graphic abstract is available for this article.

Key Words: exercise ◼ follow-up studies ◼ rehabilitation ◼ stroke ◼ upper extremity

E
vidence suggests that early active movement after
stroke stimulates brain reorganization and that inten-
sive rehabilitation accelerates functional upper limb
(UL) recovery, increasing overall recovery and improving
quality of life.1–3 Five to 10 hours of physiotherapy per
week provided in addition to the usual dose has been
shown to significantly improve motor function.4 How-
ever, increasing therapy time is often limited by a lack

 
Correspondence to: Olivier Rémy-Néris, MD, PhD, Physical and Rehabilitation Medicine Department, Brest University Hospital, Brest, France. Email olivier.remy-neris@
univ-brest.fr
*A list of the REM Investigative Team is given in the Appendix.
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.120.032545.
For Sources of Funding and Disclosures, see page XXX.
© 2021 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

Stroke. 2021;52:00–00. DOI: 10.1161/STROKEAHA.120.032545 June 2021   1

 Rémy-Néris et al
Original Contribution
Nonstandard Abbreviations and Acronyms
Exo gravity-supporting exoskeleton with
integrated gaming system
FMA UE Fugl-Meyer Assessment Upper Extremity
QALY quality-adjusted life-year
REM Re-éducation Mécanisée après Accident
Vasculaire Cérébral–Mechanized Reha-
bilitation After Cerebrovascular Accident
UL upper limb
VIRTUES Virtual Reality Therapy Provided in Addi-
tion to Usual Therapy in Sub-Acute Stroke
of staff and resources; in addition, independent practice
can be difficult for patients with moderate-to-severe
motor impairment. Technology-supported UL training
with robotic or gravity-supporting devices can be used
to increase therapy time. Furthermore, such devices can
facilitate movement by supporting the arm while provid-
ing motivation using games-based interfaces. According
to recent systematic reviews and meta-analyses, such
devices have small, but beneficial, effects on impairment
and functional recovery when compared with therapy
delivered by a therapist.5–7
See related article, p XXX
The primary aim of this randomized controlled trial
was to test the hypothesis that two 30-minute daily ses-
sions of self-rehabilitation over 4 weeks using a gravity-
supporting, games-based device would improve upper
extremity impairment more than control self-rehabilitation
involving time-matched stretching and basic active exer-
cises in patients with moderate-to-severe impairment in
the subacute phase of stroke. The secondary aims were
(1) to compare the effects of the two self-rehabilitation
methods on impairment, function, independence, and
quality of life at day 30 (D30), month 3 (M3), month 6
(M6), and month 12 (M12) after randomization; (2) to
compare participants’ perceptions of the interventions;
and (3) to determine differences in cost utility between
the two interventions at D30 and M12.
METHODS
Study Design
REM-AVC (Re-éducation Mécanisée après Accident Vasculaire
Cérébral–Mechanized Rehabilitation After Cerebrovascular
Accident) was a parallel, randomized controlled, single-blind,
phase III trial with a 1:1 allocation ratio conducted in 21 rehabilita-
tion centers in France (Appendix) from June 2011 to December
2016. Informed consent was obtained from all participants, and
2   June 2021
Additional UL Self-Rehabilitation in Stroke
procedures were conducted according to the Declaration of
Helsinki. The study was approved by the Institutional Review
Board (Ouest VI CPP 653) and was registered on https://www.
clinicaltrials.gov (NCT01383512). The CONSORT (Consolidated
Standards of Reporting Trials) and TIDieR (Template for
Intervention Description and Replication) checklists were used to
report this study. Study data will not be made available.
Patients were enrolled by an allocated physician at each
site via a secure, web-based, centralized data entry system that
ensured all inclusion and exclusion criteria were respected.
Randomization was performed by the CS Randomization
Clinsight software module (Ennov, San Francisco, CA) and
was stratified by both site and Fugl-Meyer Assessment Upper
Extremity (FMA UE) score (more impaired, ≤20; less impaired,
>20). Randomly selected block sizes of 2, 4, or 6 were used,
and investigators were blinded to the size of each block.
Participants
All participants were inpatients for the duration of the trial (this
length of stay is normal in France). The inclusion criteria were
as follows: aged 18 to 81 years old, diagnosis of hemorrhagic
or ischemic middle cerebral artery stroke 3 weeks to 3 months
previously, and an FMA UE8 score between 10 and 40 points.
Exclusion criteria were as follows: pain in the affected shoul-
der >3/10 on a Visual Analogue Scale, a Boston Diagnostic
Aphasia Examination9 score ≤3 points, fatigue or visual impair-
ment that would prevent participation in an additional daily hour
of therapy, and an inability to sit independently (more details in
the Data Supplement).
Study Interventions
The study involved usual rehabilitation for all participants, fol-
lowed by an additional daily hour of self-rehabilitation (two
30-minute sessions) consisting of either gravity-supported,
games-based training using an exoskeleton (for the Exo group)
or basic stretching and active exercises (for the control group)
over a period of 4 weeks. This dose of self-rehabilitation was
chosen according to therapist’s opinions of the amount feasible
in the context of multidisciplinary rehabilitation and poststroke
fatigue. Participating therapists (physiotherapists and occupa-
tional therapists) received specific training in the use of the
device for the purposes of the study and in the control self-
rehabilitation during a 2-day training program. Performance of
self-rehabilitation was encouraged by the therapist in charge of
each patient who recorded attendance and session duration.
Usual Rehabilitation
All participants underwent the usual rehabilitation provided in each
center, 5 days per week. UL rehabilitation time was standardized
across centers to a maximum of 1.5 hours per day during the trial.
Exo Group
The ArmeoSpring exoskeleton device (Hocoma, Inc, Zurich,
Switzerland) was used for the gravity-supported, games-based
self-rehabilitation, following the response to a call to tender.
This is a mechanized, nonactuated exoskeleton that sup-
ports the weight of the arm by means of springs. It records
joint angles and the position of the end effector (handheld
by the user) in real time. It is designed to train shoulder and
elbow movements, pronation and supination, and grip-release
Stroke. 2021;52:00–00. DOI: 10.1161/STROKEAHA.120.032545
Rémy-Néris et al
through participation in games displayed on a screen. The
games are conceived to challenge movement distance or
speed or a combination of both. The workspace required for
the games is personalized for each user (by the therapist) as
the maximum space in which they can actively reach the limits
of the virtual environment.
A therapist was present during the first 4 sessions; for
the remaining sessions, the therapist set the patient up in
the device, adjusted the device parameters, and programmed
the exercises, but the participant then trained independently.
The exercises were progressed using a systematic method
(Data Supplement).
Control Group
The control group performed their self-rehabilitation in the
rehabilitation room. A 2×2-m instruction poster with written and
photographic instructions of stretches and active exercises was
fixed to a wall (Data Supplement). Participants were instructed
to perform 10 minutes of stretching (5-second stretches of
the main muscles that shorten after stroke) and 20 minutes of
active exercises (10 repetitions of each exercise) that involved
simple movements of the UL joints through range and no func-
tional exercises. Exercises involving range of motion could
be progressed in terms of distance and height, but no formal
method of progression was determined.
A therapist was present throughout the first 4 sessions: for
the remaining sessions, they checked the participant’s atten-
dance, recommended exercises to be performed, provided
encouragement to continue if the patient stopped exercising,
but did not supervise the exercise program.
Outcome Measures
Evaluating therapists were trained in the performance of all out-
come measures in groups of 5 by a single investigator during
a 2-day program to ensure correct and standardized practices.
Evaluations were performed at 5 time points: baseline (D0, pre-
randomization ≤4 days before beginning the intervention), D30
(the end of the interventions) and at months 3, 6, and 12 after
randomization (M3, M6, and M12). Therapists were blinded to
group allocation. The National Institutes of Health Stroke Scale
was used to characterize participants.10
Primary Outcome
The primary outcome was change in FMA UE score8 between
D0 and D30.
The FMA UE evaluates movement, coordination, and reflex
action of the shoulder, forearm, wrist, and hand. The maximum
score is 66 points.
Secondary Outcomes
The secondary outcomes were as follows:
1. Change in sensorimotor impairment (FMA UE) at M3, M6,
and M12.
2. Change in severity of shoulder pain at rest and during
active and passive movements (Visual Analogue Scale,
from 0 to 10 points).
3. Change in spasticity of the wrist and elbow flexors
and extensors and finger flexors (modified Ashworth
Scale11—a 6-point scale for the rating of spasticity. 0, no
increase in muscle tone; 4, affected parts rigid in flexion
or extension).
Stroke. 2021;52:00–00. DOI: 10.1161/STROKEAHA.120.032545
Additional UL Self-Rehabilitation in Stroke
4. Change in functional status (Functional Independence
Original Contribution
Measure12—an 18-item tool that assesses function in
self-care, continence, mobility, transfers, communication,
and cognition. Each item is graded from 1 to 7 according
to the level of assistance required. 1, total assistance; 7,
complete independence).
5. Change in UL function (Action Research Arm Test13:
assesses the ability to perform simple and complex
grasp tasks and global arm movements. Each task is
graded from 0 to 3. 0, unable; 3, normal. The maximum
score is 57 points).
6. Change in quality of life using the EuroQol 5 Dimensions14
(evaluates generic quality of life in 5 dimensions: mobil-
ity, self-care, usual activities, pain/discomfort, and anxi-
ety/depression. Each item is graded from 1 to 3. 1, no
problems; 3, extreme problems) and the Stroke Impact
Scale15 (a self-report questionnaire that evaluates 8 items
relating to quality of life: hand function, strength, activities
of daily living, mobility, communication, emotion, memory
and thinking, and social participation. Each item is rated
from 1 to 5).
7. Between-group differences in cost utility (Data
Supplement).
8. Comparison of the participants’ perception of their group’s
exercise intervention using 5 custom-made questions
rated on a 5-point Likert scale from 1 (totally disagree)
to 5 (totally agree):
– It was easy to learn to use the robot/to learn the exer-
cises at the beginning
– Using the robot/doing the exercises was easy
– I felt independent using the robot/doing the exercises
– I got pain from using the robot/doing the exercises
–  (At M3 only) I am satisfied with the intervention I
received and would be willing to add it to my usual
treatment.
Safety
No data monitoring committee was set up since all investiga-
tors and evaluating therapists were blinded to group allocation.
However, the scientific committee met 5× during the study period.
All adverse events during the intervention period and up to
M12 were recorded in a specific file by the physician in charge
of the patient and monitored by a clinical research assistant.
A serious adverse event was defined as fatal, life-threatening,
requiring or prolonging hospitalization, or resulting in disability
or incapacity of a significant or lasting nature. All other adverse
events were considered as minor.
Cost Utility Analysis
Cost utility analysis provides an indication of the relative costs
to achieve a unit of utility.16 In this study, a cost utility analysis
was conducted prospectively over a 12-month period to deter-
mine the financial cost to the health care system in light of the
quality-adjusted life-year (QALY) gains experienced by patients
in the Exo group, compared with those in the control group.
Details are provided in the Data Supplement.
Statistical Analysis
Analyses were performed using an intention-to-treat approach;
change in FMA UE scores was compared between the two
June 2021   3
 Rémy-Néris et al Additional UL Self-Rehabilitation in Stroke

groups using (1) a Student t test, (2) a multivariate linear model differences (95% CI) were calculated using nonparametric
Original Contribution

with adjustment for age and baseline values, and (3) using a
sensitivity analysis to evaluate the robustness of the results
by assigning a zero change to participants with missing data.
Secondary outcomes were analyzed using a Student t test,
except for the modified Ashworth Scale and the responses
to the questionnaire, which were compared between groups
using the Mood test. A multivariate linear model with adjust-
ment for age and baseline values was also applied to all out-
comes. All statistical tests were performed at the 0.05 level of
significance with 95% CIs.
The sample size calculation was based on unpublished
data from our group where the FMA UE score increased by
16 points (SD, 9 [90% CI, 7–13]) over a similar time span in
a similar sample of patients who underwent usual rehabilita-
tion. We, therefore, expected that the control group would also
show an improvement in FMA UE score of 16 points. We arbi-
trarily estimated that the Exo group would show an additional
improvement of 6 points, that is, total improvement in the FMA
UE score of 22 points, with an arbitrary maximum SD of 13
points. A sample of 198 patients was thus required to show a
difference of 6 points with a power of 90%. To accommodate
10% attrition, a total sample of 220 was, therefore, planned.
QALYs and costs were presented as numbers and means
(SD or 95% CI). The average total costs and the mean number
of QALYs were determined in both groups, and differences in
costs and QALYs were tested using a Mann-Whitney U test
and presented as means (95% CI). The incremental cost
bootstrapping with 1000 replications. The uncertainty on the
incremental cost-effectiveness ratio was described using 1000
bootstrap replications on the cost-effectiveness plane.
Analyses were performed using the SAS 9.3 (SAS Institute,
Inc, Cary, NC) software.
RESULTS
Characteristics of Participants, Sessions, and
Baseline Data
Two hundred and fifteen participants (mean age, 58.31
[SD, 13.63] years; mean number of days since stroke,
54.8 [SD, 22.11 (range, 18–116)]) were randomized
(Table 1 for baseline characteristics): 107 to the Exo
group and 108 to the control group. A total of 208
patients completed the D30 study visit (105 in the Exo
group and 103 in the control group), and a total of 172
patients completed the M12 study visit (86 in each
group; Figure 1).
Mean session duration was 33.43 (SD, 15.50) min-
utes in the control group and 33.22 (SD, 16.10) minutes
in the Exo group (P=0.86). Mean number of sessions
performed was 39.25 (SD, 3.50) in the control group and
38.81 (SD, 4.67) in the Exo group (P=0.45).

Table 1.  Baseline Participant Characteristics

Total Control group Exo group

Characteristics (n=215) (n=108) (n=107)
Age, y; mean±SD 58.31±13.63 58.53±13.27 58.08±14.05
Sex, n (%)
 Male 140 (65.1) 73 (67.59) 67 (62.62)
 Female 75 (34.9) 35 (32.41) 40 (37.38)
Laterality, n (%)
  Left handed 13 (6.1) 7 (6.54) 6 (5.71)
  Right handed 199 (93.9) 100 (93.46) 99 (94.29)
Time from stroke to randomization, d; mean±SD 54.8±22.11 53.93±22.68 55.67±21.6
Stroke type, n (%)
 Ischemic 152 (70.7) 75 (69.44) 77 (71.96)
 Hemorrhagic 63 (29.3) 33 (30.56) 30 (28.04)
Side of hemiparesis, n (%)
 Left 125 (58.7) 61 (57.01) 64 (60.38)
 Right 88 (41.3) 46 (42.99) 42 (39.62)
NIHSS, mean±SD 5.22±2.41 5.4±2.45 5.04±2.36
FMA UE, mean±SD 26.11±9.48 26.36±9.96 25.87±9.01
ARAT, mean±SD 11.76±12.86 12.2±13.24 11.33±12.53
FIM, mean±SD 99.15±17.17 99.95±16.7 98.35±17.67
SIS hand function, mean±SD 9.71±17.17 7.24±12.58 12.19±20.54
EQ-5D 51.78±20.01 50.13±19.82 53.43±20.17
Modified Ashworth, median (quartiles) 3.0 (2.0–6.0) 3.0 (2.0–6.0) 3.5 (2.0–5.0)

ARAT indicates Arm Research Arm Test; EQ-5D, EuroQol Five Dimensions Questionnaire; Exo, gravity-supporting exo-
skeleton with integrated gaming system; FIM, functional independence measure; FMA UE, Fugl-Meyer Assessment Upper
Extremity; NIHSS, National Institutes of Health Stroke Scale; and SIS, Stroke Impact Scale.

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Rémy-Néris et al Additional UL Self-Rehabilitation in Stroke

Original Contribution

Figure 1. Study flowchart.

A total of 238 individuals were enrolled in the study. This includes 20 healthy subjects enrolled for an ancillary study and 3 patients with stroke
who were wrongly included.

Primary Outcome Secondary Outcomes

There was no between-group difference in the mean There were no between-group differences in any of the sec-
change in FMA UE score (P=0.22) at D30 (Table 2). ondary outcomes at any time point except for the questions
Accounting for missing data had no effect on the regarding ease of learning and ease of practice of the exer-
results (Table 2). cises that received higher ratings in the Exo group (Table 2).

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 Rémy-Néris et al Additional UL Self-Rehabilitation in Stroke

Table 2.  Primary and Secondary Outcomes

Original Contribution

Control group Exo group

(n=108) (n=107) Difference (95% CI) P value
FMA UE (mean±SD)
  Change from baseline
  At D30 11.78±8.84 13.32±9.03 1.54 (−0.91 to 3.99) 0.22
Adj, 1.62 (−0.78 to 4.02) Adj, 0.18
  At M3 15.97±10.80 18.02±10.73 2.05 (−0.97 to 5.07) 0.18
Adj, 2.12 (−0.90 to 5.14) Adj, 0.17
  At M6 18.78±10.74 20.55±12.17 1.77 (−1.51 to 5.05) 0.29
Adj, 1.77 (−1.53 to 5.07) Adj, 0.29
  At M12 22.41±10.53 23.44±11.09 1.03 (−2.22 to 4.29) 0.53
Adj, 1.03 (−2.22 to 4.29) Adj, 0.54
ARAT (mean±SD)
  Change from baseline
  At D30 11.65±13.76 15.17±14.32 3.52 (−0.35 to 7.39) 0.074
Adj, 3.54 (−0.34 to 7.42) 0.073
  At M3 17.4±16.00 19.85±16.71 2.44 (−2.15 to 7.04) 0.30
Adj, 2.42 (−2.20 to 7.04) 0.30
  At M6 20.02±17.90 24.78±17.45 4.76 (−0.31 to 9.84) 0.066
Adj, 4.63 (−0.44 to 9.71) 0.073
  At M12 24.98±18.17 27.73±17.11 2.76 (−2.53 to 8.04) 0.30
Adj, 2.62 (−2.62 to 7.86) 0.33
Ashworth score; median (interquartile range)*
  Change from baseline
  At D30 0.0 (−1.0 to 1.0) 0.0 (−1.0 to 1.0) Adj, −0.19 (−0.88 to 0.48) 0.56
0.85
  At M3 0.0 (−1.0 to 2.0) 0.0 (−1.0 to 2.0) Adj, −0.08 (−0.83 to 0.66) 0.71
0.53
  At M6 0.0 (−2.0 to 2.0) 0.0 (−2.0 to 1.0) Adj, 0.016 (−0.82 to 0.85) 0.97
0.65
  At M12 0.0 (−2.0 to 2.0) 0.0 (−2.0 to 2.0) Adj, −0.10 (−1.01 to 0.81) 0.83
0.81
Pain VAS (mean±SD)
  Change at D30 from baseline
  At rest 0.70±1.64 0.43±1.28 −0.27 (−0.67 to 0.13) 0.19
Adj, −0.26 (−0.65 to 0.14) 0.20
   During passive mobilization 1.60±2.48 1.55±2.36 −0.05 (−0.71 to 0.61) 0.88
Adj, −0.15 (−0.74 to 0.45) 0.63
   During active movement 1.79±2.57 1.32±2.22 −0.47 (−1.13 to 0.18) 0.16
Adj, −0.45 (−1.06 to 0.16) 0.15
FIM (mean±SD)
  Change from baseline
  At D30 10.68±10.02 10.81±9.38 0.12 (−2.55 to 2.80) 0.93
Adj, −0.51 (−2.58 to 1.56) 0.63
  At M3 14.79±13.4 14.56±12.83 −0.24 (−3.95 to 3.48) 0.90
Adj, −1.19 (−3.71 to 1.32) 0.35
  At M6 16.54±14.58 16.57±13.38 0.03 (−4.01 to 4.07) 0.99
Adj, −0.07 (−2.40 to 2.26) 0.96
  At M12 18.65±14.75 18.51±13.3 −0.14 (−4.33 to 4.05) 0.95
Adj, −0.80 (−2.99 to 1.38) 0.47

(Continued )

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Rémy-Néris et al Additional UL Self-Rehabilitation in Stroke

Table 2. Continued

Original Contribution
Control group Exo group
(n=108) (n=107) Difference (95% CI) P value
SIS: hand function (mean±SD)
  Change from baseline
  At D30 14.99±21.43 14.79±24.41 −0.20 (−6.64 to 6.24) 0.95
Adj, 0.84 (−5.60 to 7.28) 0.80
  At M6 28.43±28.38 35.30±29.00 6.87 (−1.45 to 15.19) 0.11
Adj, 8.16 (−0.14 to 16.45) 0.054
  At M12 35.27±32.24 37.83±31.22 2.56 (−6.96 to 12.09) 0.60
Adj, 3.73 (−5.77 to 13.24) 0.44
EQ-5D (mean±SD)
  Change from baseline
  At M12 19.08±22.80 14.41±19.86 −4.67 (−11.25 to 1.91) 0.16
Adj, −2.35 (−7.22 to 2.52) 0.34
Perception of intervention; median (interquartile range)
 Ease of learning the exercises/use of 4.0 (3.0 to 5.0) 4.0 (4.0 to 5.0) Adj, 0.34 (0.06 to 0.62) 0.017
the robot during the training
0.12
  Ease of performing self-rehabilitation 4.0 (3.0 to 4.0) 4.0 (4.0 to 5.0) Adj, 0.31 (0.02 to 0.61) 0.038
0.13
  Sense of independence 4.0 (4.0 to 5.0) 4.0 (4.0 to 5.0) Adj, 0.00 (−0.28 to 0.28) 0.99
0.38
  Pain caused by self-rehabilitation 2.67±1.41 2.43±1.40 −0.23 (−0.64 to 0.18) 0.27
3.0 (1.0 to 4.0) 2.0 (1.0 to 4.0) Adj, −0.23 (−0.64 to 0.18) 0.35
 Satisfaction and willingness to add 4.0 (4.0 to 5.0) 5.0 (4.0 to 5.0) Adj, 0.16 (−0.10 to 0.41) 0.22
the intervention to usual treatment
0.18

Adj indicates adjusted value for age and baseline values; ARAT, Arm Research Arm Test; D30, day 30; EQ-5D, EuroQol Five Dimensions
Questionnaire; Exo, gravity-supporting exoskeleton with integrated gaming system; FIM, functional independence measure; FMA UE, Fugl-
Meyer Assessment Upper Extremity; M3, month 3; M6, month 6; M12, month 12; SIS, Stroke Impact Scale; and VAS, Visual Analogic Scale.
*The value presented is the median value of the sum of the modified Ashworth scale scores for the elbow, wrist and finger flexors
and extensors.

Safety 46 904–54 794]; P=0.99). QALYs calculated at M12 did

A total of 403 adverse events occurred with no differ-
ence in frequency between the two groups (51% in the
Exo group and 49% in the control group). Nine serious
events occurred, 4 in the exo group and 5 in the control
group; none were considered to be related to the inter-
ventions. The remaining 394 adverse events were minor,
a total of 104 of which were musculoskeletal, connective
tissue, or nervous system disorders relating to the UL
(45 in the exo group and 59 in the control group: see
Table I in the Data Supplement for details).
Cost Utility Analysis
The cost utility analysis was based on 215 patients
(Table I in the Data Supplement). At D30, the mean cost
per patient was €1270 (1505 USD [95% CI, −4430 to
6037]; P=0.087) and was higher in the Exo group. At
M12, the mean per-patient cost (therapy plus all medical
events related to the stroke) was €50 959 (60 376 USD
for the control group [95% CI, 46 812.9–54 904.5]) and
€50 849 (60 246 USD) for the Exo group ([95% CI,
not differ significantly between the groups (Table I in the
Data Supplement). There was no between-group differ-
ence in cost utility at M12 (Figure 2).
DISCUSSION
The results of this phase III, randomized controlled trial
did not support the hypothesis that additional self-reha-
bilitation performed with a gravity-supporting, games-
based device would improve impairment (FMA UE score)
more than basic stretching and active exercises in the
subacute phase of stroke in patients with moderate-
severe impairment of UL function.
The lack of difference between the effects of the
two types of additional self-rehabilitation was surpris-
ing. We believe that this was not due to a lack of con-
trast between the techniques.17 The ARMEO Spring
device used in the present study provided games for
motivation, performance feedback,18,19 continuous
challenging exercises, and allowed 3-dimensional UL
movement while the exercises performed by the control

Stroke. 2021;52:00–00. DOI: 10.1161/STROKEAHA.120.032545 June 2021   7

 Rémy-Néris et al
Original Contribution
group were laborious and more difficult to perform; no
specific feedback was provided, and the progression of
the exercises was limited. Despite this, participants in
both groups were equally satisfied with their respective
interventions and willing to add them to usual treat-
ment. This lack of difference in outcomes between
groups thus questions the need for technological sys-
tems involving gravity support and games to imple-
ment motor learning principles in the subacute phase
of stroke. Although smaller studies have found some
additional benefits of robotic therapy compared with
conventional therapy,20–22 the recent, large, randomized
controlled RATULS trial (Robot Assisted Training for the
Upper Limb After Stroke) found no difference between
additional robotic therapy and enhanced UL therapy
in patients in the subacute to early chronic phase
of stroke on arm function (measured by the Action
Research Arm Test).23 Furthermore, a recent meta-
analysis of 17 articles found no effect of UL robotic
therapy on impairment (FMA) or activities of daily living
during the subacute phase of stroke.5 With regard to
the virtual-environment (gaming) aspect of the inter-
vention, other studies have also reported few benefits:
the VIRTUES trial (Virtual Reality Therapy Provided in
Addition to Usual Therapy in Sub-Acute Stroke) found
no additional benefits on functional outcomes.24
The mean improvement in FMA UE score at D30 of
13.32 (±9.03) in the Exo group and 11.78 (8.84) in the
control group can be attributed to the rehabilitation since
the participants were, on average, 8 weeks poststroke
at inclusion and spontaneous recovery is almost com-
plete after 6 to 10 weeks poststroke.25 Furthermore,
the amount of change exceeded the minimum clinically
important difference of 4 points for the FMA UE score.26
8   June 2021
Additional UL Self-Rehabilitation in Stroke
Figure 2. Cost utility analysis of
self-rehabilitation using a gravity-
supporting games-based device
compared with basic exercises.
The scatterplot represents the uncertainty
associated with the difference in costs
(vertical axis) and the difference in
effectiveness (horizontal axis). The central
position of the scatterplot indicated that
there was no difference in either the
12-mo costs or 12-mo quality-adjusted
life-years (QALY) between the 2 groups.
Nevertheless, the anticipated improvements of 16 FMA
UE points in the control group and 22 FMA UE points
in the Exo group were not achieved. This may also have
been due to the fact that 8 weeks poststroke is rela-
tively late in terms of the recovery window.27 The amount
of improvement found in rehabilitation studies involving
patients in the subacute phase of stroke is highly vari-
able. This can, at least, in part, be attributed to differ-
ences in inclusion criteria.28,29 Among the recent large
clinical trials, RATULS inclusion criteria were an initial
Action Research Arm Test score between 0 and 39
points and stroke that occurred between 1 week and
5 years previously23; VIRTUES inclusion criteria were
a minimum of 20° of active shoulder flexion/abduction
and stroke that occurred <3 months previously24; and
ICARE (Interdisciplinary Comprehensive Arm Rehabilita-
tion Evaluation) inclusion criteria were voluntary finger
extension and stroke that occurred 14 to 106 days previ-
ously.30 The present study was aimed at a homogenous
group of patients who had some recovery (FMA, >10)
but not those with fast, spontaneous recovery as defined
by Winters et al.28
The neutral outcome of this study could also be
attributed to a lack of prior knowledge of how much
additional self-rehabilitation is required to impact out-
comes,29,31 which might have been determined by a
phase II study.31 Such studies are, however, difficult to
perform in the rehabilitation setting. Increasing reha-
bilitation time has been shown in both animal32 and
human1 studies to improve outcomes. The present trial
was based on these data, and the dose of self-rehabil-
itation was set according to the amount deemed to be
feasible by therapists in the context of multidisciplinary
rehabilitation and poststroke fatigue.
Stroke. 2021;52:00–00. DOI: 10.1161/STROKEAHA.120.032545
Rémy-Néris et al
A systematic review of studies evaluating the cost
of robotic rehabilitation in 213 stroke patients reported
that robot therapy was more cost-effective than conven-
tional therapy, particularly for patients with severe impair-
ments.16 The present study did not find a difference in
costs between the two types of self-rehabilitation. This
discrepancy is likely due to the smoothing out of any
differences by the costs of usual rehabilitation, which
is relatively intensive in France. An important difference
between the present study and previous studies of costs
are that we evaluated cost utility, whereas previous stud-
ies did not relate costs to health benefits.16
This study has several limitations. First, the sample size
was calculated from unpublished data; however, the sen-
sitivity analysis confirmed the robustness of the primary
outcome results. Second, measurement reliability was
not evaluated, as in the ICARE study,30 for example; how-
ever, all therapists, including any who joined during the
study period, received formal training from study inves-
tigators. Third, recruitment was relatively long (5 years)
due to the involvement of university hospitals in which
other trials were being performed, limiting the number
of potential participants, as well as the strictness of the
inclusion criteria (Data Supplement). Regarding the cost
of rehabilitation, there seemed to be an overestimation
of transport cost in both groups compared with average
French transport costs. This may have masked between-
group differences in cost utility. The results of the cost
evaluation are specific to the French system and may not
be applicable to other countries.
CONCLUSIONS
The results of this large study showed that two 30-minute
daily sessions of additional self-rehabilitation performed
over 4 weeks using a gravity-assisted, games-based
therapy system did not reduce impairment any more than
the same duration of additional basic active and stretch-
ing exercises. These findings suggest that, in patients
with severe-moderate impairment (ie, an FMA UE score
between 10 and 40 points) in the subacute phase of
stroke (ie, 3 weeks to 3 months poststroke), additional
therapy can be performed using simple means.
ARTICLE INFORMATION
Received September 22, 2020; final revision received November 26, 2020;
accepted January 21, 2021.
Presented in part at the International Society of Physical and Rehabilitation
Medicine-French Society of Physical and Rehabilitation Medicine Congress, Par-
is, France, July 8–12, 2018.
Affiliations
Physical and Rehabilitation Medicine Department (O.R.-N., B.M., É.P.) and IN-
SERM, CIC 1412 (A.D., E.N.), Brest University Hospital, France. University of
Brest, France (O.R.-N.). Laboratory of Medical Information Processing, INSERM
UMR 1101, Brest, France (O.R.-N., B.M.). Health Economics Clinical Research
Unit (URC Eco), APHP, Paris, France (A.L.J., I.D.-Z.).
Stroke. 2021;52:00–00. DOI: 10.1161/STROKEAHA.120.032545
Additional UL Self-Rehabilitation in Stroke
Acknowledgments
Original Contribution
We are grateful to all the patients and health care professionals for their partici-
pation. Many thanks to the data management team, especially Valentine Guiton,
to Nicolas Sweighofer for constructive criticism, and to Johanna Robertson and
Jennifer Dandrea-Palethorpe for writing assistance.
Sources of Funding
This study was supported by the French Ministry of Health: EMREM_AVC CHU
BREST 20 220.
Disclosures
None.
Supplemental Materials
Detailed Inclusion and Exclusion Criteria
Cost Analysis
Online Tables I and II
Progression of Exo Group Exercises
Exercise Posters for the Control Self-Rehabilitation Group
APPENDIX
REM Investigative Team: Jean-Marie Beis, Physical Medicine and Rehabilitation
Department [PM&R], CHU de Nancy, France; Djamel Bensmaïl, PM&R, Hôpi-
tal Poincaré, Garches, France; Charles Benaim, PM&R, CHU de Dijon, France;
Jacques Luaute, PM&R, CHU de Lyon, France; Isabelle Bonan, PM&R, CHU
de Rennes, France; François Boyer, PM&R, CHU de Reims, France; Emmanuel
Coudeyre, PM&R, CHU de Clermont Ferrand, France; Jean-Christophe Daviet,
PM&R, CHU de Limoges, France; Patrick Dehail, PM&R, CHU de Bordeaux,
France; Anne-Laure Ferrapie, PM&R, C3RF Les Capucins, Angers, France; Jean-
Luc Isambert, PM&R, CRF Le Normandie, Granville, France; Jacques Kerdraon,
PM&R, CRF Kerpape, Ploemeur, France; Philippe Marque, PM&R, CHU de Tou-
louse, France; Jerome Froger, PM&R, CHU de Nîmes, France; Etienne Allart,
PM&R, CHR de Lille, France; Raphaël Gross, PM&R, CHU de Nantes, France;
Alain Yelnik, PM&R, Hôpital Lariboisière APHP, Paris, France; Laurent Bensous-
san, PM&R, CHU de Marseille, France; Sophie Tasseel-Ponche, PM&R, CHU
d’Amiens, France.
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