Research

Original Investigation

Effect of a Task-Oriented Rehabilitation Program

on Upper Extremity Recovery Following Motor Stroke
The ICARE Randomized Clinical Trial
Carolee J. Winstein, PhD; Steven L. Wolf, PhD; Alexander W. Dromerick, MD; Christianne J. Lane, PhD; Monica A. Nelsen, DPT; Rebecca Lewthwaite, PhD;
Steven Yong Cen, PhD; Stanley P. Azen, PhD; for the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) Investigative Team

Supplemental content at
IMPORTANCE Clinical trials suggest that higher doses of task-oriented training are superior to jama.com
current clinical practice for patients with stroke with upper extremity motor deficits.

OBJECTIVE To compare the efficacy of a structured, task-oriented motor training program vs

usual and customary occupational therapy (UCC) during stroke rehabilitation.

DESIGN, SETTING, AND PARTICIPANTS Phase 3, pragmatic, single-blind randomized trial among
361 participants with moderate motor impairment recruited from 7 US hospitals over 44
months, treated in the outpatient setting from June 2009 to March 2014.

INTERVENTIONS Structured, task-oriented upper extremity training (Accelerated Skill

Acquisition Program [ASAP]; n = 119); dose-equivalent occupational therapy (DEUCC; n = 120); or
monitoring-only occupational therapy (UCC; n = 122). The DEUCC group was prescribed 30 one-
hour sessions over 10 weeks; the UCC group was only monitored, without specification of dose.

MAIN OUTCOMES AND MEASURES The primary outcome was 12-month change in
log-transformed Wolf Motor Function Test time score (WMFT, consisting of a mean of 15 timed
arm movements and hand dexterity tasks). Secondary outcomes were change in WMFT time
score (minimal clinically important difference [MCID] = 19 seconds) and proportion of patients
improving ⱖ25 points on the Stroke Impact Scale (SIS) hand function score (MCID = 17.8 points).

RESULTS Among the 361 randomized patients (mean age, 60.7 years; 56% men; 42% African
American; mean time since stroke onset, 46 days), 304 (84%) completed the 12-month primary
outcome assessment; in intention-to-treat analysis, mean group change scores (log WMFT,
baseline to 12 months) were, for the ASAP group, 2.2 to 1.4 (difference, 0.82); DEUCC group, 2.0
to 1.2 (difference, 0.84); and UCC group, 2.1 to 1.4 (difference, 0.75), with no significant between-
group differences (ASAP vs DEUCC: 0.14; 95% CI, −0.05 to 0.33; P = .16; ASAP vs UCC: −0.01;
95% CI, −0.22 to 0.21; P = .94; and DEUCC vs UCC: −0.14; 95% CI, −0.32 to 0.05; P = .15).
Secondary outcomes for the ASAP group were WMFT change score, −8.8 seconds, and improved
SIS, 73%; DEUCC group, WMFT, −8.1 seconds, and SIS, 72%; and UCC group, WMFT, −7.2 seconds,
and SIS, 69%, with no significant pairwise between-group differences (ASAP vs DEUCC: WMFT,
1.8 seconds; 95% CI, −0.8 to 4.5 seconds; P = .18; improved SIS, 1%; 95% CI, −12% to 13%; P = .54;
ASAP vs UCC: WMFT, −0.6 seconds, 95% CI, −3.8 to 2.6 seconds; P = .72; improved SIS, 4%; 95%
CI, −9% to 16%; P = .48; and DEUCC vs UCC: WMFT, −2.1 seconds; 95% CI, −4.5 to 0.3 seconds;
P = .08; improved SIS, 3%; 95% CI, −9% to 15%; P = .22). A total of 168 serious adverse events Author Affiliations: University of
Southern California, Los Angeles
occurred in 109 participants, resulting in 8 patients withdrawing from the study. (Winstein, Lane, Nelsen, Lewthwaite,
Cen, Azen); Emory University,
CONCLUSIONS AND RELEVANCE Among patients with motor stroke and primarily moderate Atlanta, Georgia (Wolf); MedStar
National Rehabilitation Hospital,
upper extremity impairment, use of a structured, task-oriented rehabilitation program did not
Washington, DC (Dromerick).
significantly improve motor function or recovery beyond either an equivalent or a lower dose of
Group Information: The ICARE
UCC upper extremity rehabilitation. These findings do not support superiority of this program Investigative Team members are
among patients with motor stroke and primarily moderate upper extremity impairment. listed at the end of this article.
Corresponding Author: Carolee J.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00871715 Winstein, PhD, University of Southern
California, 1540 Alcazar St, CHP 155,
Los Angeles, CA 90033
JAMA. 2016;315(6):571-581. doi:10.1001/jama.2016.0276 (winstein@usc.edu).

(Reprinted) 571

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 01/23/2020

 Research Original Investigation
C
linicians providing care for patients with stroke lack evi-
dence for determining the best type and amount of mo-
tor therapy during outpatient rehabilitation. Notwith-
standing the considerable resources devoted to stroke
rehabilitation care, a recent Cochrane review of interven-
tions for improving upper limb function after stroke con-
cluded that high-quality evidence for the superiority of any cur-
rent routinely practiced intervention is absent, including the
amount and content of motor training.1
Two large rehabilitation trials performed in the long-
term phase of stroke, after initial rehabilitation had been
completed, suggested that intensive, high-repetition, task-
oriented training was superior to usual care for improving
upper extremity motor
ASAP Accelerated Skill Acquisition outcomes.2,3 With reha-
Program
bilitation training imple-
DEUCC dose-equivalent usual and mented after spontaneous
customary care
recovery, improvements
SIS Stroke Impact Scale
can be attributed more
UCC usual and customary care directly to the training.
UEFM upper extremity Fugl-Meyer Even though the rehabili-
WMFT Wolf Motor Function Test t at i o n i nt e r ve nt i o n s
differed in these studies
(constraint-induced movement therapy3 and robot-assisted
training2), both incorporated the same principles of high move-
ment repetitions and structured task-oriented practice.
Despite this evidence and expert opinion that more practice
enhances recovery, these findings have not been incorpo-
rated into clinical practice when patients with stroke actually
receive rehabilitation therapy. Typical outpatient treatment
sessions last 36 minutes, during which patients engage in an
average of only 12 purposeful actions within an otherwise
unstructured treatment session.4
The goal of the Interdisciplinary Comprehensive Arm Re-
habilitation Evaluation (ICARE) was to test the efficacy of the
same task-oriented approaches during the outpatient phase of
rehabilitation, which typically begins within a month after
stroke occurrence. ICARE compared 2 different treatment strat-
egies (intensive, high-repetition, task-oriented training vs un-
structured occupational therapy at 2 different doses: 30 hours
vs a lower-dose, observation-only control) among patients un-
dergoing outpatient rehabilitation for moderate arm motor
impairment after stroke.
Methods
Study Oversight and Trial Design
A motor rehabilitation trial precludes double-blinding; par-
ticipants were aware of their group assignment. The protocol
and design for this phase 3, parallel, 3-group, single-blind, ran-
domized clinical trial are provided in Supplement 1 and were
detailed in the ICARE methods article.5 Following institu-
tional review board approvals at each site, participants pro-
vided written informed consent. A data and safety monitor-
ing board and medical monitor provided independent
oversight. Study biostatisticians with full access to deidenti-
fied data managed the statistical analyses with consultation
572 JAMA February 9, 2016 Volume 315, Number 6 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 01/23/2020
Task-Oriented Rehabilitation and Recovery Following Motor Stroke
from a blinded statistician. The statistical analysis plan
(Supplement 1) was developed and sample size estimations
were performed during proposal development and approved
by the data and safety monitoring board and the sponsor.
Study Population, Screening, and Randomization
Patients with moderate upper extremity motor impairment
who demonstrated at least minimal initiation of hand and fin-
ger extension and who could participate in an intense but dis-
tributed rehabilitation program were recruited. To preclude se-
vere cognitive and sensory impairments, the National Institutes
of Health Stroke Scale subscale scores for neglect and sen-
sory impairment were used, thus allowing focus on upper ex-
tremity motor recovery. Per sponsor mandate, race and eth-
nicity were self-selected from categories determined in 1997
by the US Office of Management and Budget.
Participants were recruited from 7 sites, predominantly
during inpatient rehabilitation. Early in recruitment, the ran-
domization window was amended from 30 to 90 days to 14 to
106 days after stroke, enabling randomization 16 days earlier
and necessitating a 16-day extension to retain the stratifica-
tion midpoint. Full eligibility criteria are provided in eTable 1
in Supplement 2. An abbreviated list of inclusion criteria in-
cludes age older than 21 years; ischemic or hemorrhagic stroke
meeting World Health Organization criteria6; upper extrem-
ity hemiparesis; voluntary finger extension; no more than 6
outpatient occupational therapy sessions; and absence of trau-
matic or nonvascular brain injury and subarachnoid or pri-
mary intraventricular hemorrhage. Participants were random-
ized into 1 of 3 treatment groups. Intervention was completed
within 16 weeks of randomization. A stratified block random-
ization scheme within sites balanced assignment by motor se-
verity and time from stroke onset. The biostatistician per-
formed randomization using hybrid block sizes of 3 or 6,
depending on anticipated sample size within each site. Once
a participant provided informed consent and the baseline as-
sessment was completed, the study site requested random-
ization; the data manager confirmed eligibility and the site team
leader was notified of the assignment.
Treatment Interventions
An overview of the interventions in each treatment group is
shown in eTable 2 in Supplement 2. The investigational inter-
vention, a structured, task-oriented upper extremity motor
training program, termed the Accelerated Skill Acquisition Pro-
gram (ASAP), is a best-practice synthesis implementing neu-
roscientific evidence regarding motor training approaches and
schedules. This program is principle based, impairment
focused,7 task specific,3 intense,4 engaging, collaborative,
self-directed,8,9 and patient centered10; it has been previ-
ously described and feasibility tested.5,8,9,11-14 The ASAP in-
tervention included an initial evaluation and 30 one-hour treat-
ment sessions (3 times per week for 10 weeks). A constraint
or mitt worn on the less affected hand was available but not
mandated. Purposeful and skilled movement execution was
emphasized. Support for patients’ control or autonomy was
provided by choices of specific tasks to be practiced, collab-
orative problem solving to identify and address movement
jama.com
 Task-Oriented Rehabilitation and Recovery Following Motor Stroke
needs, and encouragement of self-direction in extending prac-
tice to community contexts.5,8
The monitoring-only usual and customary care (UCC) and
dose-equivalent usual and customary care (DEUCC) therapy
groups received outpatient occupational therapy based on
usual and customary practice as determined by the therapist(s),
local practices, payer guidelines, and participant prefer-
ences. These groups differed only by the number of sessions
of outpatient therapy. For the DEUCC group, study-related
treatment prescribed 30 hours of outpatient therapy. Treat-
ment adherence for the dose-equivalent groups was set at 27
hours or more. The UCC group was only monitored, without
specification of dose.
To prevent contamination of treatment across groups, at
each site, the DEUCC and UCC therapies were delivered by dif-
ferent clinicians situated in separate locations from the inves-
tigational intervention. The ASAP Manual of Procedures was em-
bargoed during the trial5; it included a formal standardization
process. All ASAP therapists signed nondisclosure agreements.
Outcome Assessment
Participants were assessed at baseline (prerandomization), post-
intervention (end of therapy), 6 months, and 12 months (end
of study) after randomization by clinicians masked to treat-
ment assignment and standardized in administration of pri-
mary and secondary outcome assessments.5 A 12-month change
in the log-transformed Wolf Motor Function Test (WMFT) time
score was the primary outcome. The WMFT time score is a mean
of 15 hierarchically arranged timed arm movements and hand
dexterity tasks.15-18 If a task could not be completed in 2 min-
utes (ie, 120 seconds), a time score of 121 seconds was as-
signed. A log transformation is used to accommodate for the
nonnormality in the raw time score.
Secondary outcomes included the 12-month change in
WMFT time score (minimum clinically important difference, 19
seconds faster, 16% of the range on the dominant side and un-
known on the nondominant side19) and improvement in par-
ticipant-reported Stroke Impact Scale (SIS), version 3.0, hand
subscale score (percentage with improvement ≥25 points). Be-
cause the SIS hand function range is 0 to 100 points, partici-
pants with SIS hand function scores of 75 or higher at baseline
(n = 15) were excluded from this analysis. The minimal detect-
able change and minimal clinically important difference for the
SIS hand function subscale are 25.9 points and 17.8 points,
respectively.20 The primary end point was the end of study (12
months after randomization; mean, 13.5 months after stroke),
while end of therapy (16 weeks after randomization; mean, ap-
proximately 22 weeks after stroke) was a secondary end point.
Patients (or their designated representatives or care-
givers) were contacted by monthly telephone calls to review
health status, health care utilization, medications, and ad-
verse events. Adverse events were reported regarding 3 inde-
pendent characteristics: expectedness, relation to study, and
severity.5
Statistical Analysis
Baseline characteristics and outcomes, attrition, adherence,
and adverse events were compared across groups. Data dis-
jama.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 01/23/2020
Original Investigation Research
tribution assumptions were assessed and data transforma-
tions made as necessary. All analyses were performed using
the intention-to-treat principle, comparing outcomes by as-
signed group. Data were analyzed for patterns of missing data;
because no pattern was found, Markov chain Monte Carlo im-
putation was used to account for missing data from loss to
follow-up or missed evaluations at end of study. Complete case
analyses were also performed, although there were no differ-
ences in results, so we report the planned intention-to-treat
results with multiple imputation herein. Changes from base-
line in continuous outcomes were analyzed using analysis-of-
covariance models adjusting for baseline values and stratifi-
cation factors (site, severity, time since onset). For the primary
outcome, a 2-sided P < .05 was used to indicate a difference
between the ASAP intervention and DEUCC therapy. To ad-
just for multiple comparisons in secondary aims (DEUCC vs
UCC and ASAP vs UCC), a 2-sided P < .025 was used. Per the
protocol, the proportion of participants who improved 25
points or more on the SIS hand subscale, that which exceeds
a clinically important change20 and would represent at least a
full category of difficulty improvement (eg, from “very diffi-
cult” to “somewhat difficult”), was also examined. This
outcome was evaluated using logistic regression models.
Analyses were performed using SAS software, version 9.3
(SAS Institute Inc). In addition to data checks before analy-
ses, residuals for the total group and by group were examined
to ensure that model assumptions were met. Besides means
and confidence intervals, effect size (Cohen d) was computed
to determine the magnitude of effects. This effect size was cal-
culated as the between-group difference in outcome variable
mean divided by the common standard deviation of the out-
come variable21; confidence intervals for d were estimated as
described by computing the 95% confidence intervals for the
noncentrality distribution from the t test of group differences.22
Sample size calculations were performed during ICARE
proposal development to ensure sufficient power to detect a
difference in log-transformed WMFT at 12 months between the
ASAP and DEUCC groups at a significance level of .05 and 80%
power. Given the population being recruited and the rela-
tively short duration of time from stroke occurrence to enroll-
ment in ICARE, the primary outcome group differences were
expected to be between those found in EXCITE 3 and
VECTORS.23 EXCITE resulted in d = 0.50 for log-transformed
WMFT between the high-functioning and the delayed inter-
vention (control) groups and d = 0.63 between the low-
functioning and the delayed intervention groups. For EXCITE,
there was a 26% change in the control group (from baseline to
1 year) for the primary outcome. VECTORS resulted in a smaller
effect between the high-dose and control groups (d = 0.20) for
the Action Research Arm Test,24 although the variance of the
effect was higher for VECTORS (inpatient acute) than EXCITE
(outpatient subacute). For VECTORS, there was a 77% change
in the control group (from baseline to 90 days) for the Action
Research Arm Test.
For ICARE, the DEUCC group was estimated to demon-
strate a proportional recovery of approximately 50% on the
primary outcome (midway between the 26% in EXCITE and
the 77% in VECTORS); thus, the effect size for power was set
(Reprinted) JAMA February 9, 2016 Volume 315, Number 6 573
 Research Original Investigation Task-Oriented Rehabilitation and Recovery Following Motor Stroke

Figure 1. Participant Flow in the ICARE Trial

11 051 Individuals assessed for eligibility

119 Randomized to receive ASAP
94 Adherent to therapy
25 Not adherent to therapy
13 Did not complete study
6 Withdrew
6 Medical condition
1 Lost to follow-up
119 Included in intention-to-
treat analysis
10 690 Excluded
9219 Did not meet inclusion criteria
4863 Clinician judgment
954 Language barrier
2155 No stroke
88 Dementia ASAP indicates Accelerated
87 Upper extremity Fugl-Meyer Skill Acquisition Program;
motor score >58 DEUCC, dose-equivalent usual and
1072 Other reasons customary care; UCC,
645 Declined
monitoring-only usual and customary
826 Other reasons
care. Reasons for exclusion are not
exclusive. Adherence in the ASAP and
DEUCC was defined as 27 hours or
361 Randomized
more of prescribed treatment; there
was no adherence data collected for
the UCC group. The study was
120 Randomized to receive DEUCC 122 Randomized to receive UCC
89 Adherent to therapy designed with an estimated a priori
31 Not adherent to therapy attrition rate of 25%; actual attrition
rates by group were considerably
lower, ranging from 9% to 16% across
11 Did not complete study 22 Did not complete study groups. Attrition rate of withdrawal
10 Withdrew 15 Withdrew
across groups was not statistically
1 Lost to follow-up 2 Medical condition
5 Lost to follow-up significant (P = .24). Evaluable data at
12 months ranged from 79% to 88%;
for intention-to-treat analyses,
120 Included in intention-to- 122 Included in intention-to- multiple imputation models were
treat analysis treat analysis
used to estimate end-of-study data
for primary analyses.

at d = 0.42. With this effect, using a 2-sided t test with a
type I error of .05 and 80% power, at least 90 patients per
group would need to be evaluable. With an expected attri-
tion rate of 25%, 120 patients per group was the planned
sample size. The secondary outcome measure was the suc-
cess rate in the SIS hand subscale score, defined as the pro-
portion of patients with a change of 25 points or higher out
of 100 on the normalized SIS hand at end of study. Given
the estimates for SIS hand function subscale change from
acute (VECTORS, 46% [n = 13]), postacute (Kansas City
home-based exercise study,25 35% [n = 71]), and subacute
(EXCITE, 24% [n = 86]) control data, if the DEUCC group
success rate was greater than in EXCITE, less than in
VECTORS, and comparable with that of the Kansas City
study, then ICARE was powered sufficiently to detect a
minimum of 21% difference between groups.
Results
Study Participants and Baseline Characteristics
From June 2009 through February 2013, 11 051 patients
were screened. Given the need for participants to remain in
the trial, the most frequent reason for exclusion at chart
screening was the clinician’s best judgment about the likeli-
hood of the patient completing the study (44%), which
included consideration of social instability, inability to
travel for study-related procedures, and concomitant ill-
ness. The second most frequent reason for exclusion was no
diagnosis of stroke (19.5%). During clinical screening, other
exclusions included possible dementia (11.4%), upper
extremity Fugl-Meyer (UEFM) motor score too high (11.3%),
and clinician’s best judgment (10.9%). See Figure 1 for
participant flow through the study.
Table 1 summarizes baseline characteristics. Mean age
of the participants was 60.7 (SD, 12.5) years; 56% were men
and 42% were Afric an Americ an. The 2 largest sites
(Atlanta, Georgia, and Washington, DC) were urban Stroke
Belt hospitals. 26 At randomization, the mean number of
days since stroke was 45.8 (SD, 22.4). Eighty-three percent
experienced an ischemic stroke without hemorrhagic con-
version; 43% affected the left hemisphere; 48% affected the
right hemisphere; and 7% affected the brain stem. The
stroke affected the dominant upper extremity in 49% of the
sample. Sixty-eight percent of participants underwent inpa-
tient rehabilitation and 18% were referred directly from
acute care. Fifty-seven percent were in the less severe
(UEFM score ≥36), early-onset (<60 days) stratum, with 19%
in the next most common stratum of more severe (UEFM
score <36), early onset. A median National Institutes of
Health Stroke Scale score of 4 (interquartile range, 2-5) was
consistent with a study population with primarily motor
hemiparesis without substantial cognitive or sensory
impairment. The overall mean UEFM motor impairment
score of 41.6 (95% CI, 40.7-42.6) for the entire sample was
in the moderately severe range of 21 to 50; 78% were within
this range at baseline and 21% were classified with mild
impairment (>50). The baseline mean WMFT time score was
14.9 (95% CI, 12.9-16.8) seconds. Twenty-nine percent of
participants had received some outpatient occupational
therapy prior to randomization, though none received more
than 6 hours.

574 JAMA February 9, 2016 Volume 315, Number 6 (Reprinted) jama.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 01/23/2020

 Task-Oriented Rehabilitation and Recovery Following Motor Stroke Original Investigation Research

Table 1. Baseline Characteristics by Treatment Groupa

Total ASAP DEUCC UCC
Characteristics (N = 361) (n = 119) (n = 120) (n = 122)
Age, mean (SD), y 60.7 (12.5) 60.9 (13.7) 59.9 (10.5) 61.1 (13.1)
Sex, No. (%)
Male 203 (56.2) 64 (53.8) 67 (55.8) 72 (59.0)
Female 158 (43.8) 55 (46.2) 53 (44.2) 50 (41.0)
Race, No. (%)
American Indian, Aleutian, or Eskimo 5 (1.4) 4 (3.5) 1 (0.8) 0
Asian 19 (5.3) 9 (7.8) 7 (5.8) 3 (2.5)
Pacific Islander 7 (2.0) 3 (2.6) 1 (0.8) 3 (2.5)
African American 151 (42.4) 47 (40.9) 50 (41.7) 54 (44.6)
White 124 (34.8) 38 (33.0) 43 (35.8) 43 (35.5)
Other 50 (14.0) 14 (12.2) 18 (15.0) 18 (14.9)
Ethnicity, No. (%)b
Hispanic/Latino 36 (10.1) 9 (7.8) 14 (11.7) 13 (10.8)
Non-Hispanic/Latino 320 (89.9) 107 (92.2) 106 (88.3) 107 (89.2)
Education, No. (%)
Less than high school 8 (2.2) 4 (3.4) 2 (1.7) 2 (1.7)
Some high school 26 (7.2) 6 (5.0) 12 (10.0) 8 (6.6)
Completed high school 72 (20.0) 24 (20.2) 21 (17.5) 27 (22.3)
Some college 130 (36.1) 42 (35.3) 42 (35.0) 46 (38.0)
Completed bachelor’s degree 71 (19.7) 22 (18.5) 26 (21.7) 23 (19.0)
Completed master’s degree 33 (9.2) 15 (12.6) 11 (9.2) 7 (5.8)
Completed doctoral degree 20 (5.6) 6 (5.0) 6 (5.0) 8 (6.6)
Referral source, No. (%)
Inpatient rehabilitation 247 (68.4) 80 (67.2) 79 (65.8) 88 (72.1)
Outpatient 16 (4.4) 6 (5.0) 5 (4.2) 5 (4.1)
Acute care 66 (18.3) 21 (17.6) 26 (21.7) 19 (15.6)
Transitional day program 7 (1.9) 3 (2.5) 2 (1.7) 2 (1.6)
Open referral 24 (6.6) 9 (7.6) 7 (5.8) 8 (6.6)
Other 1 (0.3) 0 1 (0.8) 0
Language, No. (%)
English 357 (98.9) 117 (98.3) 119 (99.2) 121 (99.2)
Spanish 4 (1.1) 2 (1.7) 1 (0.8) 1 (0.8)
Time from stroke to randomization, 45.8 (22.4) 45.2 (20.3) 45.0 (22.8) 47.0 (23.9)
mean (SD), d
Stroke type, No. (%)
Ischemic without hemorrhagic conversion 299 (83.3) 100 (84.0) 98 (82.4) 101 (83.5)
Ischemic with hemorrhagic conversion 11 (3.1) 3 (2.5) 4 (3.4) 4 (3.3)
Intraparenchymal hemorrhagic 43 (12.0) 16 (13.4) 12 (10.1) 15 (12.4)
Other 6 (1.7) 0 5 (4.2) 1 (0.8)
Stroke location, No. (%)
Right hemisphere 173 (47.9) 57 (47.9) 56 (46.7) 60 (49.2)
Left hemisphere 154 (42.7) 49 (41.2) 55 (45.8) 50 (41.0)
Cerebellum 1 (0.3) 0 1 (0.8) 0
Brain stem 25 (6.9) 11 (9.2) 5 (4.2) 9 (7.4)
Other 8 (2.2) 2 (1.7) 3 (2.5) 3 (2.5)
Side of hemiparesis, No. (%)
Right 168 (46.5) 51 (42.9) 60 (50) 57 (46.7)
Left 193 (53.5) 68 (57.1) 60 (50) 65 (53.3)

(continued)

jama.com (Reprinted) JAMA February 9, 2016 Volume 315, Number 6 575

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 01/23/2020

 Research Original Investigation Task-Oriented Rehabilitation and Recovery Following Motor Stroke

Table 1. Baseline Characteristics by Treatment Groupa (continued)

Total ASAP DEUCC UCC Abbreviations: ASAP, Accelerated
Characteristics (N = 361) (n = 119) (n = 120) (n = 122)
Skill Acquisition Program;
Stroke severity, mean (SD) DEUCC, dose-equivalent usual
Baseline upper extremity Fugl-Meyer 41.6 (9.4) 41.7 (9.5) 41.5 (9.2) 41.6 (9.5) and customary care;
motor scorec UCC, monitoring-only usual and
customary care.
National Institutes of Health Stroke 3.6 (1.8) 3.6 (2.0) 3.4 (1.7) 3.7 (1.7)
a
Scale score Percentages may not add to 100%
Strata, No. (%) d due to rounding.
b
Ethnicity was determined by
Low severity, early onset 205 (56.8) 68 (57.1) 70 (58.3) 67 (54.9)
self-report; decline to report was
Low severity, late onset 50 (13.9) 16 (13.5) 16 (13.3) 18 (14.8) removed from the comparison of
High severity, early onset 70 (19.4) 23 (19.3) 22 (18.3) 25 (20.5) ethnicity.
c
Upper extremity Fugl-Meyer motor
High severity, late onset 36 (10.0) 12 (10.1) 12 (10.0) 12 (9.8)
score range, 19-58 (low severity,
Concordance, No. (%)e ⱖ36; high severity, <36).
d
Concordant 176 (48.8) 55 (46.2) 64 (53.3) 57 (46.7) Stroke onset range, 14 to 106 days
(early onset, <60 days; late onset,
Discordant 185 (51.2) 64 (53.8) 56 (46.7) 65 (53.3)
>59 days).
Prerandomization occupational therapy, 105 (29.1) 34 (28.6) 29 (24.2) 42 (34.4) e
Concordant: the paretic limb is the
No. (%)
dominant limb; discordant: the
Amount of prerandomization occupational 3.8 (3.0) 4.4 (3.1) 3.3 (2.3) 3.7 (3.4) paretic limb is the nondominant
therapy, mean (SD), h limb.

Attrition Rate and Treatment Adherence
A total of 304 patients (84%) completed the 12-month evalu-
ation (87% in the ASAP, 88% in the DEUCC, and 79% in the UCC
groups; P = .09 for difference in primary end-point attrition).
Treatment adherence for the dose-equivalent groups, de-
fined as completion of at least 27 treatment hours, was com-
parable across the groups at 79% for the ASAP intervention and
74% for DEUCC participants. The mean number of treatment
visits per week in the ASAP group was 2.4 (95% CI, 2.3-2.5) vs
2.1 (95% CI, 2.0-2.2) in the DEUCC group. The mean number
of hours of treatment received was 28.3 (95% CI, 27.1-29.5) and
26.7 (95% CI, 25.3-28.1) for the ASAP and DEUCC groups, re-
spectively. In the UCC group, 81% (99/122) reported receiving
some upper extremity therapy; the mean treatment time per
week was 1.7 hours (95% CI, 1.5-1.9 hours). The UCC group com-
pleted a mean of 11.2 (95% CI, 9.5-12.9) total hours of treat-
ment that varied widely (range, 0-46 hours; see the eFigure
in Supplement 2 for details). Monitoring of health and ad-
verse events via monthly telephone calls was comparable
across groups. There was an overall 54% improvement in mean
motor performance as measured by the WMFT time score, and
71% (215/302) of participants met or exceeded a meaningful
change in the SIS hand subscale score (≥25 points at the pri-
mary end point). In 7 (0.8%) of the 898 follow-up evaluation
sessions, the assessor was unblinded to group assignment.
Primary Outcome
At the end of the study, the mean times for lnWMFT were as
follows: for ASAP, 1.4; DEUCC, 1.2; and UCC, 1.3 (Table 2 and
Figure 2). The differences in lnWMFT change between groups
at the end of the study (12 months) were small (eTable 3 in
Supplement 2): for ASAP vs DEUCC, the mean difference was
0.14 (95% CI, −0.05 to 0.33; P = .16); for ASAP vs UCC,−0.01
(95% CI, −0.22 to 0.21; P = .94); and for DEUCC vs UCC, −0.14
(95% CI, −0.32 to 0.05; P = .15); in raw seconds, these differ-
ences ranged from 0.5 to 2 seconds. Associated effect sizes of
group pair differences were small. The Cohen d was 0.15 (95%
CI, −0.30 to 0.21) for the primary pairwise comparison of ASAP
vs DEUCC; for the secondary pairwise comparisons, d = −0.01
(95% CI, −0.26 to 0.24) for DEUCC vs UCC and d = −0.10 (95%
CI, −0.15 to 0.36) for ASAP vs UCC (see eTable 3 in Supplement
2 for end-of-therapy and end-of study pairwise group com-
parison effect sizes).
Secondary Outcomes
For all participants, the baseline mean WMFT time score was
14.9 (95% CI, 12.9-16.8) seconds. At the end of the study, the
mean time score had improved to 6.8 (95% CI, 5.3-8.3) sec-
onds but was still slower than the age-matched normative mean
time of 1.3 seconds,18 indicating persistent motor impair-
ment. All groups showed comparable improvements in WMFT
times of 7 to 8 seconds, adjusted for baseline and covariates;
by group, WMFT mean times improved; ie, for ASAP, 8.8 sec-
onds, for DEUCC, 8.1 seconds, and for UCC, 7.2 seconds. Be-
tween-group changes were not significantly different: for ASAP
vs DEUCC, the mean difference was 1.81 (95% CI, −0.83 to 4.45)
seconds (P = .18); for ASAP vs UCC, −0.59 (95% CI, −3.77 to 2.60)
seconds (P = .72); and for DEUCC vs UCC, −2.12 (95% CI, −4.52
to 0.27) seconds (P = .08).
Hand function improvement of more than 25 points on the
SIS subscale at the end of the study was 73% (72/99) in the ASAP
group, 72% (75/104) in the DEUCC group, and 69% (68/99) in
the UCC group; none of the group pairwise comparisons were
significant (P>.21) (Table 2). Differences in mean changes were
0.6 (95% CI, −6.4 to 6.5; P = .99) for ASAP vs DEUCC, 2.6 (−3.8
to 9.0; P = .42) for ASAP vs UCC, and 2.1 (95% CI, −4.0 to 8.3;
P = .49) for DEUCC vs UCC. Thirty-six percent of participants
had less than complete recovery (<100 points), despite im-
provement beyond a clinically meaningful amount (mean, 36
points; 95% CI, 34-40 points) by the end of the study.
Safety
There were no significant differences across groups in num-
ber of serious adverse events whether on or off site, ex-

576 JAMA February 9, 2016 Volume 315, Number 6 (Reprinted) jama.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 01/23/2020

 Table 2. Outcomes at Baseline and End-of-Study by Groupa

ASAP (n=119) DEUCC (n=120) UCC (n=122) Between-Group Comparisons

jama.com
ASAP vs DEUCC ASAP vs UCC DEUCC vs UCC
No. of No. of No. of
Participants Outcome Participants Outcome Participants Outcome Mean (95% CI) P Value Mean (95% CI) P Value Mean (95% CI) P Value
Log Wolf Motor Function Test
time, mean (95% CI), s
Baseline 119 2.2 120 2.0 122 2.1
(2.0 to 2.4) (1.8 to 2.2) (1.9 to 2.3)
End of study 104 1.4 104 1.2 96 1.3
(1.2 to 1.6) (1.0 to 1.3) (1.1 to 1.5)
Change from baseline 104 −0.8 104 −0.9 96 −0.8 0.14 .16 −0.01 .94 −0.14 .15
(−1.0 to −0.6) (−1.0 to −0.7) (−1.0 to −0.6) (−0.05 to 0.33) (−0.22 to 0.21) (−0.32 to 0.05)
Wolf Motor Function Test

Downloaded From: https://jamanetwork.com/ on 01/23/2020

time, sb
Mean (95% CI)
Baseline 119 16.6 120 12.9 122 15.1
(13.2 to 20.0) (9.6 to 16.3) (11.8 to 18.4)
End of study 104 7.8 104 5.0 96 7.7
Task-Oriented Rehabilitation and Recovery Following Motor Stroke

(4.9 to 10.7) (3.2 to 6.7) (4.7 to 10.7)

Change from baseline 104 −8.1 104 −8.7 96 −7.5 1.81 .18 −0.59 .72 −2.12 .08
(−11.7 to −4.5) (−11.6 to −5.8) (−10.5 to −4.6) (−0.83 to 4.45) (−3.77 to 2.60) (−4.52 to 0.27)
Median (interquartile range)
Baseline 119 6.9 120 5.2 122 7.3
(3.4 to 22.2) (3.5 to 13.7) (3.1 to 16.5)
End of study 104 2.8 104 2.7 96 2.6
(2.0 to 4.7) (2.0 to 4.0) (1.9 to 4.5)
Change from baseline 104 −3.1 104 −2.2 96 −2.4
(−12.8 to −0.9) (−11.2 to −1.04) (−9.4 to −0.6)
Stroke Impact Scale hand
function subscale score,
mean (95% CI)c
Baseline 119 31.1 120 32.8 122 28.2
(26.6 to 35.7) (28.7 to 36.9) (24.2 to 32.3)
End of study 105 68.2 107 68.7 101 66.4

Copyright 2016 American Medical Association. All rights reserved.

(62.7 to 73.7) (63.9 to 73.6) (61.0 to 71.7)
Change from baseline 105 37.6 107 35.7 101 37.1 0.6 .99 2.6 .42 2.1 .49
(31.7 to 43.5) (30.4 to 40.9) (32.2 to 42.1) (−6.4 to 6.5) (−3.8 to 9.0) (−4.0 to 8.3)
Improved ≥25 points, 99d 72 (72.7) 104d 75 (72.1) 99d 68 (68.7) 1 .54 4 .48 3 .22
No. (%) with outcome (−12 to 13) (−9 to 16) (−9 to 15)
b
Abbreviations: ASAP, Accelerated Skill Acquisition Program; DEUCC, dose-equivalent usual and customary care; Because of skew in the Wolf Motor Function Test at baseline and end-of-study, both means and medians are
UCC, monitoring-only usual and customary care. reported; median Wolf Motor Function Test scores are presented for descriptive purposes only.
a c
For the primary outcome (ASAP vs DEUCC), α = .05; for the secondary outcomes (ASAP vs UCC and DEUCC vs Participants whose baseline Stroke Impact Scale score was >75 (n = 15) were excluded from these analyses.
UCC), α = .025. The end of the study was the primary end point and occurred 12 months after randomization. d
Denominators for outcome data.
P values for group comparisons of change from baseline to end of study were derived from the imputed
intention-to-treat model; imputed data are in eTable 3 in Supplement 2.

(Reprinted) JAMA February 9, 2016 Volume 315, Number 6

Original Investigation Research

577
 Research Original Investigation
Figure 2. Longitudinal Changes in Unadjusted Imputed Mean Scores Across Months for the Primary and Secondary Outcomes
Log WMFT Time Score
2.5
Mean Log WMFT Time Score, s
Mean WMFT Time Score, s
ASAP
2.0 DEUCC
UCC
1.5
1.0
0.5
0 2 4 6 8 10 12
Months
Primary outcome, log-transformed Wolf Motor Function Test (WMFT) time
score (left) and secondary outcomes, WMFT time score (center) and
patient-reported Stroke Impact Scale (SIS) hand function subscale score (right).
N=119 in the Accelerated Skill Acquisition Program (ASAP) group; n = 120 in the
dose-equivalent usual and customary care (DEUCC) group; and n = 122 in the
pected, or study related, when either treating each event as
separate or accounting for repeated observations within indi-
viduals (all P>.40). There were 168 serious adverse events in-
volving 109 participants; the most common were hospitaliza-
tion (n = 143; 85% of adverse events; 25% of randomized
participants) and recurrent stroke (n = 42; 25% of adverse
events; 9% of randomized participants). Two of the serious
events were deemed related to the intervention, one from
hypertension and the other from a wrist fracture.
Discussion
Among participants with primarily moderate upper extrem-
ity motor impairment after stroke, there were no group dif-
ferences in upper extremity motor performance at 12 months
after randomization with a structured, task-oriented motor
training program compared with UCC occupational therapy
during outpatient rehabilitation. Specifically, the structured,
task-oriented motor therapy was not superior to usual outpa-
tient occupational therapy for the same number of hours, show-
ing no benefit for an evidence-based, intensive, restorative
therapy program. In addition, there was no advantage to pro-
viding more than twice the mean dose (mean, 27 hours) of
therapy compared with the average 11 hours received by the
observation-only group, showing that substantially more
therapy time was not associated with additional motor resto-
ration. With payer pressures on reducing inpatient rehabilita-
tion, outpatient rehabilitation may be of greater importance
for patients with stroke. The findings from this study provide
important new guidance to clinicians who must choose the best
treatment for patients with stroke. The results suggest that
usual and customary community-based therapy, provided dur-
ing the typical outpatient rehabilitation time window by li-
censed therapists, improves upper extremity motor function
and that more than doubling the dose of therapy does not lead
to meaningful differences in motor outcomes.
However, these results cannot be assumed to generalize
to other outcomes (eg, health-related quality of life, commu-
578 JAMA February 9, 2016 Volume 315, Number 6 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 01/23/2020
Task-Oriented Rehabilitation and Recovery Following Motor Stroke
WMFT Time Score SIS Hand Function Score
25 80
Mean SIS Hand Function Score
20
60
15
10
40
5
0 20
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Months Months
monitoring-only usual and customary care (UCC) group. Timing of each
assessment after randomization was as follows: 0 months = baseline;
4 months = end of therapy; 6 months = follow-up; and 12 months = end of
study. Statistical analyses were performed on the imputed intention-to-treat
data set. Error bars represent 95% CIs.
nity participation), other stroke-related impairments such as
walking,27 other stroke populations, or rehabilitation time
points earlier or later following stroke than those studied here.
Moreover, the lack of difference between dose groups may be
a measurement artifact. Although the mean dose of therapy
for the DEUCC group was more than twice that of the UCC
group, the latter group had considerable variation in actual dose
(ie, a range of 0-46 hours). Thus, mean differences may mis-
represent the actual differences between groups. This vari-
ability in the observation-only group was not unexpected and
was suggested by pretrial survey data (Supplement 1). Post hoc
exploratory analysis found no systematic relationship be-
tween dose of usual therapy and magnitude of change in WMFT
time scores, similar to results from secondary outcomes of the
EXCITE trial, 28 even though variability in dose across
patients was much lower in EXCITE than in ICARE.
The ICARE results support the necessity of well-
designed dose-response studies of motor training at key
clinical time points after stroke, including the periods of
inpatient and outpatient care and the long-term period
beyond a year after stroke. Different physiological and psy-
chological responses to rehabilitation training might occur
at different times after stroke onset,29 raising the possibility
that dosing and timing are not independent factors in stroke
rehabilitation intervention trials. This observation could
explain why trials conducted early after stroke (eg, AVERT30
and VECTORS23) found undesirable effects of more inten-
sive interventions, whereas the EXCITE trial,3 conducted
later after stroke, found a positive effect. ICARE, timed in
between, found no dose effect. This time window hypoth-
esis provides a plausible explanation for why the results
from ICARE are consistent with previous studies of therapy
dosing that did not find large dose effects31,32 but also are
inconsistent with other findings in which a high dose of
task-oriented training, as in EXCITE, was shown to be more
effective compared with the control group when the dose of
outpatient therapy varied considerably. Future trials in
rehabilitation should use designs and methods that con-
sider the natural recovery transpiring during the early
jama.com
 Task-Oriented Rehabilitation and Recovery Following Motor Stroke Original Investigation Research

period after stroke33 as well as the degree of neurological
severity and disability.
The data pertaining to dose of rehabilitation therapy may
be important to policy makers and may be useful to estimate
the cost and expected effect of aftercare in the outpatient set-
ting. Future neurorehabilitation trials should include physi-
ological and psychosocial domains and use designs that di-
rectly test hypothesized mechanisms of action. 34 This
consideration may include choosing primary outcomes that are
sensitive to participation and quality of life and are consis-
tent with patient-centered aspects of health care reform.35
ICARE has several limitations related to the disadvan-
tages that are typical of pragmatic trials of patient-centered
treatment decisions. Several consequences resulted from
choosing an experimental treatment in the context of current
practice.
First, spontaneous recovery may have been greater than
any treatment effect. Within 6 to 10 weeks after stroke, time
from stroke occurrence is independently associated with spon-
taneous recovery of impairments and activities, explaining 16%
to 42% of the observed improvements.33 Previous upper ex-
tremity stroke rehabilitation trials (ie, EXCITE and VA
Robotics)2,3 were performed later after stroke occurrence, af-
ter the early recovery had plateaued and when rehabilitation
is typically no longer prescribed.
Second, differences in the dose of rehabilitation therapy in
the ICARE trial may have been insufficient despite being con-
siderably more than what was reported previously4 and con-
sistent with reports of modified schedules of constraint-
induced movement therapy that were shown to be effective.36-38
A different treatment schedule (for example, the same num-
ber of hours delivered over a shorter period) might have been
more effective. Time on task was not measured in this study,
and information about the content of usual therapy was lim-
ited and dependent on site-specific clinical documentation and
procedural billing codes (eg, Current Procedural Terminology
codes); these choices were necessary for study completion.
Third, the use of standard care as a control group in this
pragmatic trial imposes limitations, particularly when test-
ing a nonpharmacological intervention. Usual outpatient
upper extremity therapy may have evolved over time to re-
semble the investigational intervention, by following evidence-
based guidelines. Continuing education, increased attention
to practice guidelines,39,40 awareness of the ongoing ICARE
trial, 41 and site (partner or affiliate of nearby academic
medical center) may have influenced usual care practices. This
limitation is inherent to pragmatic trial designs; for ICARE, both
usual therapy groups represented a relatively high standard
of outpatient practice.
Conclusions
Among patients with motor stroke and primarily moderate up-
per extremity impairment, the use of a structured, task-
oriented rehabilitation program, compared with an equiva-
lent dose of customary occupational therapy or with usual and
customary occupational therapy, did not significantly im-
prove motor function or recovery after 12 months. These find-
ings do not support superiority of this task-oriented rehabili-
tation program for patients with motor stroke and moderate
upper extremity impairment.

ARTICLE INFORMATION
Author Contributions: Dr Winstein had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Winstein, Wolf,
Dromerick, Nelsen, Lewthwaite.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Winstein, Wolf,
Dromerick, Lane, Nelsen, Lewthwaite, Cen.
Critical revision of the manuscript for important
intellectual content: Winstein, Wolf, Dromerick,
Lane, Nelsen, Lewthwaite, Azen.
Statistical analysis: Lane, Cen, Azen.
Obtained funding: Winstein, Wolf, Dromerick, Azen.
Administrative, technical, or material support:
Winstein, Wolf, Dromerick, Lane, Nelsen,
Lewthwaite, Cen.
Study supervision: Winstein, Wolf, Dromerick,
Nelsen.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
Funding/Support: The ICARE trial was funded
jointly by the National Institutes of Health, the
National Institute of Neurological Disorders and
Stroke (primary), and the National Center for
Medical Rehabilitation Research of the Eunice
Kennedy Shriver National Institute of Child Health
and Human Development (grant U01NS056256).
Each author received support from this grant
during the conduct of the study.
Role of the Funder/Sponsor: The funders provided
input and oversight related to the design and
conduct of the study, as well as collection,
management, analysis, and interpretation of the
data. Preparation, review, and approval of the
manuscript and decision to submit the manuscript
for publication were solely the responsibility of the
authors.
Disclaimer: This article does not necessarily
represent the official views of the National
Institutes of Health.
Members of the ICARE Investigative Team:
University of Southern California, Administrative
Coordinating Center, Los Angeles, California:
Carolee J. Winstein, principal investigator; Monica
A. Nelsen, program director, SIS standardization
assessor; Jennifer Bandich, financial manager;
Shannon Massimo, project assistant; Michelle
Haines, project assistant; Patricia Hatchett, project
manager, ASAP therapist (pilot and proposal
phases); Veronica T. Rowe, WMFT standardization
assessor, WMFT FAS rater; Claire McLean, blinded
evaluator; Arlene Yang, blinded evaluator, WMFT
FAS rater; Rachel Tabak, blinded evaluator; Kristin
McNealus, Blinded Evaluator; Veronica Strickland,
Blinded Evaluator; Julie Y. Kasayama, WMFT FAS
Rater; Rebecca Lewthwaite, Co-Investigator, ASAP
standardization assessor; Burl Wagenheim,
coinvestigator, study psychologist; Brent Liu,
neuroanatomical and imaging database director;
Ximing Wang, neuroanatomical and imaging data
manager; Kevin Ma, neuroanatomical and imaging
data manager; David Russak, WMFT quality
assurance; Nhi Dang, WMFT quality assurance;
Katie Wongthipkongka, WMFT quality assurance;
Yanshu Hou, WMFT quality assurance; Sue Duff,
T32 fellow; Richard Nelson, webmaster (public
site). Emory University, Atlanta, Georgia: Steven L.
Wolf, co–principal investigator; Sarah Blanton, site
team leader, ASAP therapist; David Burke, Physician
investigator; Susan Murphy, research assistant;
Aimee Reiss, blinded evaluator; Marsha Bidgood,
blinded evaluator; Lois Wolf, ASAP therapist; Gina
Holecek, usual care therapist; Megan Hite, usual
care therapist; Melissa Tober, usual care therapist;
Sara Zeforino, usual care therapist. National
Rehabilitation Hospital and Georgetown University,
Washington, DC: Alexander W. Dromerick,
co–principal investigator, physician investigator;
Matthew A. Edwardson, neuroanatomical and
imaging analyst (NINDS-StrokeNet fellow);
Kathaleen Brady, site team leader (August 2012-
2015), ASAP therapist; Rahsaan Holley, site team
leader (August 2009–August 2012), ASAP
therapist; Lori Monroe, site team leader (August
2008–August 2009); Matthew Elrod, ASAP
therapist (pilot and proposal phases); Kate
Burdekin, research assistant; Siena Quitania,
research assistant; Sara Loftin, research assistant;
Margot Gianetti, research assistant; Rebecca

jama.com (Reprinted) JAMA February 9, 2016 Volume 315, Number 6 579

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 01/23/2020

 Research Original Investigation
Feldman, research assistant; Deirdra Tiffany,
research assistant; Annie Simons, research
assistant; Lauro Halstead, physician investigator;
Kanan Desai, blinded evaluator; Hansen Chan,
blinded evaluator; Jessica Barth, blinded evaluator;
Sambit Mohapatra, blinded evaluator; Carrie Pappe,
blinded evaluator; Nora E. Barrett, blinded
evaluator; Ericka Breceda Tinoco, blinded
evaluator; Diane Nichols, ASAP therapist; Alison
Lichy, ASAP therapist; Melissa Cross, ASAP
therapist; Mara Levy, usual care therapist; Connie
Guercin, usual care therapist; Teresa Tracy, usual
care therapist; Jutta Brettschneider, usual care
therapist; Molly Fieldsend, usual care therapist;
Janice Underwood, usual care therapist. University
of Southern California Data Management and
Analysis Center, Los Angeles: Christianne J. Lane,
DMAC director (years 2-7); Stanley P. Azen, blinded
statistician; Steven Yong Cen, database director;
James Gardner, database programmer; Li Ding,
statistician; Christopher Hahn, statistician; Jiaxiu
He, statistician; Caron Park, statistician; Ge Wen,
statistician; Miwa Takayanagi, statistician; Anny
Xiang, DMAC director (year 1). Long Beach Memorial
Medical Center, Long Beach, California: Candice
Burtman-Regalado, site team leader, ASAP
therapist; Charro Scott, site team leader, ASAP
therapist; Richard Adams, physician investigator;
Diehma Hoang, physician investigator; Audrey
Huang, physician investigator; Shannon Massimo,
research assistant; Shuywe Jenq, usual care
therapist. Casa Colina Hospital and Centers for
Rehabiliation, Pomona, California: Stephanie
Kaplan, site team leader, ASAP therapist, ASAP
standardization assessor; David Patterson,
physician investigator; Cathelyn Timple, ASAP
therapist; Shelia Mendon, usual care therapist;
Jacob Hazen, usual care therapist; Deborah
Ouellette, usual care therapist. Rancho Los Amigos
National Rehabilitation Center, Downey, California:
Oscar Gallardo, site team leader, ASAP therapist
(Spanish bilingual); Covey Lazouras, site team
leader, ASAP therapist; Xiao-Ling Zhang, physician
investigator; Babak Bina, physician investigator;
Joaquín Torres, research assistant; Rosemary
Tamayo, research assistant; Byanca Rodriguez,
research assistant; Chester Lin, research assistant;
Alex Villegas, blinded evaluator (Spanish bilingual);
Claire Smith, ASAP therapist; Mark Wolfson, usual
care therapist; Kelly Love, usual care therapist.
Cedars Sinai Medical Center, Los Angeles, California:
Richard Riggs, physician investigator; Michelle
Demond, site team leader; Pamela Roberts, site
team leader; Nuvia Solis, research assistant; Sara
Benham, ASAP therapist; Karina Fakheri, ASAP
therapist; Aimee Davis, ASAP therapist; B. A.
MacCormack, usual care therapist. Huntington
Rehabilitation Medical Associates, Pasadena,
California: Sunil Hegde, physician investigator;
Cynthia Kushi, site team leader, ASAP therapist; Ilin
Ohanessians, clinical site coordinator, site team
leader; Michael Parkinson, ASAP therapist; Miriam
Burch, usual care therapist. Rehabilitation Institute
of Chicago, Chicago, Illinois: Richard L. Harvey,
medical safety monitor. The following individuals
provided oversight during the conduct and analysis
of the study: Data Safety and Monitoring Board:
Bruce Coull (chair), University of Arizona, Tucson;
Stephen Nadeau, University of Florida, Gainesville;
Michael Parides, Icahn School of Medicine at Mount
Sinai, New York, NY; Sue Ann Sisto, Stony Brook
University, Stony Brook, NY. National Institutes of
Health, Bethesda, Maryland: Scott Janis, scientific
580 JAMA February 9, 2016 Volume 315, Number 6 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 01/23/2020
Task-Oriented Rehabilitation and Recovery Following Motor Stroke
program officer (NINDS); Janice Cordell, program
official (NINDS); Louise Ritz, DSMB liaison (NINDS);
Mary Ellen Michel, program official (NCMRR).
Ancillary Study (ICAREGEN; NIH grant R01
NS058755): Steven C. Cramer, principal
investigator; Jill See, project coordinator, University
of California, Irvine.
REFERENCES
1. Pollock A, Farmer SE, Brady MC, et al.
Interventions for improving upper limb function
after stroke. Cochrane Database Syst Rev. 2014;11
(11):CD010820.
2. Lo AC, Guarino PD, Richards LG, et al.
Robot-assisted therapy for long-term upper-limb
impairment after stroke. N Engl J Med. 2010;362
(19):1772-1783.
3. Wolf SL, Winstein CJ, Miller JP, et al; EXCITE
Investigators. Effect of constraint-induced
movement therapy on upper extremity function 3
to 9 months after stroke: the EXCITE randomized
clinical trial. JAMA. 2006;296(17):2095-2104.
4. Lang CE, MacDonald JR, Gnip C. Counting
repetitions: an observational study of outpatient
therapy for people with hemiparesis post-stroke.
J Neurol Phys Ther. 2007;31(1):3-10.
5. Winstein CJ, Wolf SL, Dromerick AW, et al; ICARE
Investigative Team. Interdisciplinary
Comprehensive Arm Rehabilitation Evaluation
(ICARE): a randomized controlled trial protocol.
BMC Neurol. 2013;13(5):5.
6. Aho K, Harmsen P, Hatano S, Marquardsen J,
Smirnov VE, Strasser T. Cerebrovascular disease in
the community: results of a WHO collaborative
study. Bull World Health Organ. 1980;58(1):113-130.
7. Platz T. Impairment-oriented training
(IOT)—scientific concept and evidence-based
treatment strategies. Restor Neurol Neurosci. 2004;
22(3-5):301-315.
8. Winstein C, Lewthwaite R, Blanton SR, Wolf LB,
Wishart L. Infusing motor learning research into
neurorehabilitation practice: a historical
perspective with case exemplar from the
accelerated skill acquisition program. J Neurol Phys
Ther. 2014;38(3):190-200.
9. Winstein CJ, Wolf SL, Schweighofer N.
Task-oriented training to promote upper extremity
recovery. In: Stein J, Harvey RL, Winstein CJ,
Zorowitz RD, Wittenberg GF, eds. Stroke Recovery
and Rehabilitation. 2nd ed. New York, NY: Demos
Medical; 2015:320-343.
10. Institute of Medicine. Crossing the Quality
Chasm: A New Health Care System for the 21st
Century. Washington, DC: National Academy Press;
2001.
11. Tretriluxana J, Runnarong N, Tretriluxana S,
Prayoonwiwat N, Vachalathiti R, Winstein C.
Feasibility investigation of the Accelerated Skill
Acquisition Program (ASAP): insights into
reach-to-grasp coordination of individuals with
postacute stroke. Top Stroke Rehabil. 2013;20(2):
151-160.
12. James GA, Lu ZL, VanMeter JW, Sathian K, Hu
XP, Butler AJ. Changes in resting state effective
connectivity in the motor network following
rehabilitation of upper extremity poststroke
paresis. Top Stroke Rehabil. 2009;16(4):270-281.
13. Lum PS, Mulroy S, Amdur RL, Requejo P,
Prilutsky BI, Dromerick AW. Gains in upper
extremity function after stroke via recovery or
compensation: potential differential effects on
amount of real-world limb use. Top Stroke Rehabil.
2009;16(4):237-253.
14. Winstein CJ, Kay DB. Translating the science
into practice: shaping rehabilitation practice to
enhance recovery after brain damage. In: Dancause
N, Rossignol S, eds. Sensorimotor Rehabilitation: At
the Crossroads of Basic and Clinical Sciences. Vol 218.
Amsterdam, the Netherlands: Elsevier BV; 2015:331-
360.
15. Wolf SL, Catlin PA, Ellis M, Archer AL, Morgan B,
Piacentino A. Assessing Wolf Motor Function Test
as outcome measure for research in patients after
stroke. Stroke. 2001;32(7):1635-1639.
16. Morris DM, Uswatte G, Crago JE, Cook EW III,
Taub E. The reliability of the Wolf Motor Function
Test for assessing upper extremity function after
stroke. Arch Phys Med Rehabil. 2001;82(6):750-755.
17. Ang JHY, Man DWK. The discriminative power
of the Wolf Motor Function Test in assessing upper
extremity functions in persons with stroke. Int J
Rehabil Res. 2006;29(4):357-361.
18. Wolf SL, McJunkin JP, Swanson ML, Weiss PS.
Pilot normative database for the Wolf Motor
Function Test. Arch Phys Med Rehabil. 2006;87(3):
443-445.
19. Lang CE, Edwards DF, Birkenmeier RL,
Dromerick AW. Estimating minimal clinically
important differences of upper-extremity measures
early after stroke. Arch Phys Med Rehabil. 2008;89
(9):1693-1700.
20. Lin KC, Fu T, Wu CY, et al. Minimal detectable
change and clinically important difference of the
Stroke Impact Scale in stroke patients. Neurorehabil
Neural Repair. 2010;24(5):486-492.
21. Cohen J. Statistical Power Analysis for the
Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence
Erlbaum Associates; 1988.
22. Cumming G, Finch S. A primer on the
understanding, use, and calculation of confidence
intervals that are based on central and noncentral
distributions. Educ Psychol Meas. 2001;61(4):532-574.
doi:10.1177/0013164401614002.
23. Dromerick AW, Lang CE, Birkenmeier RL, et al.
Very Early Constraint-Induced Movement during
Stroke Rehabilitation (VECTORS): a single-center
RCT. Neurology. 2009;73(3):195-201.
24. Yozbatiran N, Der-Yeghiaian L, Cramer SC.
A standardized approach to performing the action
research arm test. Neurorehabil Neural Repair.
2008;22(1):78-90.
25. Duncan P, Studenski S, Richards L, et al.
Randomized clinical trial of therapeutic exercise in
subacute stroke. Stroke. 2003;34(9):2173-2180.
26. Mozaffarian D, Benjamin EJ, Go AS, et al;
American Heart Association Statistics Committee
and Stroke Statistics Subcommittee. Heart disease
and stroke statistics—2015 update: a report from
the American Heart Association. Circulation. 2015;
131(4):e29-e322.
27. Duncan PW, Sullivan KJ, Behrman AL, et al;
LEAPS Investigative Team. Body-weight-supported
treadmill rehabilitation after stroke. N Engl J Med.
2011;364(21):2026-2036.
28. Wolf SL, Newton H, Maddy D, et al. The EXCITE
trial: relationship of intensity of constraint induced
movement therapy to improvement in the Wolf
jama.com
 Task-Oriented Rehabilitation and Recovery Following Motor Stroke
Motor Function Test. Restor Neurol Neurosci. 2007;
25(5-6):549-562.
29. Murphy TH, Corbett D. Plasticity during stroke
recovery: from synapse to behaviour. Nat Rev
Neurosci. 2009;10(12):861-872.
30. AVERT Trial Collaboration Group. Efficacy and
safety of very early mobilisation within 24 h of
stroke onset (AVERT): a randomised controlled trial.
Lancet. 2015;386(9988):46-55.
31. Minelli C, Gondim FAA, Barreira AA, Dromerick
AW. Rehabilitation of the upper extremity and basic
activities of daily living in the first month after
ischemic stroke: an international cohort
comparison study. Neurol Int. 2009;1(1):e4.
32. Kwakkel G, van Peppen R, Wagenaar RC, et al.
Effects of augmented exercise therapy time after
stroke: a meta-analysis. Stroke. 2004;35(11):2529-
2539.
jama.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 01/23/2020
33. Kwakkel G, Kollen B, Twisk J. Impact of time on
improvement of outcome after stroke. Stroke.
2006;37(9):2348-2353.
34. Hart T, Tsaousides T, Zanca JM, et al. Toward a
theory-driven classification of rehabilitation
treatments. Arch Phys Med Rehabil. 2014;95(1)
(suppl):S33-44.e2.
35. Rosenbaum L. The whole ball
game—overcoming the blind spots in health care
reform. N Engl J Med. 2013;368(10):959-962.
36. Page SJ, Sisto S, Levine P, McGrath RE. Efficacy
of modified constraint-induced movement therapy
in chronic stroke: a single-blinded randomized
controlled trial. Arch Phys Med Rehabil. 2004;85(1):
14-18.
37. Page SJ, Sisto S, Johnston MV, Levine P.
Modified constraint-induced therapy after subacute
stroke: a preliminary study. Neurorehabil Neural
Repair. 2002;16(3):290-295.
(Reprinted) JAMA February 9, 2016 Volume 315, Number 6
Original Investigation Research
38. Sterr A, Elbert T, Berthold I, Kölbel S, Rockstroh
B, Taub E. Longer vs shorter daily
constraint-induced movement therapy of chronic
hemiparesis: an exploratory study. Arch Phys Med
Rehabil. 2002;83(10):1374-1377.
39. Hubbard IJ, Parsons MW, Neilson C, Carey LM.
Task-specific training: evidence for and translation
to clinical practice. Occup Ther Int. 2009;16(3-4):
175-189.
40. Bravi L, Stoykov ME. New directions in
occupational therapy: implementation of the
task-oriented approach in conjunction with cortical
stimulation after stroke. Top Stroke Rehabil. 2007;
14(6):68-73.
41. Kaplan RM, Irvin VL. Likelihood of null effects of
large NHLBI clinical trials has increased over time.
PLoS One. 2015;10(8):e0132382.
581