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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

IMPORTANCE Clinical trials suggest that higher doses of task-oriented training are superior to

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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 onehour 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 25 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 betweengroup 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
occurred in 109 participants, resulting in 8 patients withdrawing from the study.
CONCLUSIONS AND RELEVANCE Among patients with motor stroke and primarily moderate
upper extremity impairment, use of a structured, task-oriented rehabilitation program did not
significantly improve motor function or recovery beyond either an equivalent or a lower dose of
UCC upper extremity rehabilitation. These findings do not support superiority of this program
among patients with motor stroke and primarily moderate upper extremity impairment.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00871715

JAMA. 2016;315(6):571-581. doi:10.1001/jama.2016.0276

Author Affiliations: University of


Southern California, Los Angeles
(Winstein, Lane, Nelsen, Lewthwaite,
Cen, Azen); Emory University,
Atlanta, Georgia (Wolf); MedStar
National Rehabilitation Hospital,
Washington, DC (Dromerick).
Group Information: The ICARE
Investigative Team members are
listed at the end of this article.
Corresponding Author: Carolee J.
Winstein, PhD, University of Southern
California, 1540 Alcazar St, CHP 155,
Los Angeles, CA 90033
(winstein@usc.edu).

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Research Original Investigation

Task-Oriented Rehabilitation and Recovery Following Motor Stroke

linicians providing care for patients with stroke lack evidence for determining the best type and amount of motor therapy during outpatient rehabilitation. Notwithstanding the considerable resources devoted to stroke
rehabilitation care, a recent Cochrane review of interventions for improving upper limb function after stroke concluded that high-quality evidence for the superiority of any current routinely practiced intervention is absent, including the
amount and content of motor training.1
Two large rehabilitation trials performed in the longterm phase of stroke, after initial rehabilitation had been
completed, suggested that intensive, high-repetition, taskoriented training was superior to usual care for improving
upper extremity motor
ASAP Accelerated Skill Acquisition
outcomes.2,3 With rehaProgram
bilitation training impleDEUCC 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 rehabilit at i o n i nt e r ve nt i o n s
WMFT Wolf Motor Function Test
differed in these studies
(constraint-induced movement therapy3 and robot-assisted
training2), both incorporated the same principles of high movement repetitions and structured task-oriented practice.
Despite this evidence and expert opinion that more practice
enhances recovery, these findings have not been incorporated 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 Rehabilitation 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 strategies (intensive, high-repetition, task-oriented training vs unstructured occupational therapy at 2 different doses: 30 hours
vs a lower-dose, observation-only control) among patients undergoing outpatient rehabilitation for moderate arm motor
impairment after stroke.

Methods
Study Oversight and Trial Design
A motor rehabilitation trial precludes double-blinding; participants were aware of their group assignment. The protocol
and design for this phase 3, parallel, 3-group, single-blind, randomized clinical trial are provided in Supplement 1 and were
detailed in the ICARE methods article.5 Following institutional review board approvals at each site, participants provided written informed consent. A data and safety monitoring board and medical monitor provided independent
oversight. Study biostatisticians with full access to deidentified data managed the statistical analyses with consultation
572

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 finger extension and who could participate in an intense but distributed rehabilitation program were recruited. To preclude severe cognitive and sensory impairments, the National Institutes
of Health Stroke Scale subscale scores for neglect and sensory impairment were used, thus allowing focus on upper extremity motor recovery. Per sponsor mandate, race and ethnicity 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 randomization 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 stratification midpoint. Full eligibility criteria are provided in eTable 1
in Supplement 2. An abbreviated list of inclusion criteria includes age older than 21 years; ischemic or hemorrhagic stroke
meeting World Health Organization criteria6; upper extremity hemiparesis; voluntary finger extension; no more than 6
outpatient occupational therapy sessions; and absence of traumatic or nonvascular brain injury and subarachnoid or primary intraventricular hemorrhage. Participants were randomized into 1 of 3 treatment groups. Intervention was completed
within 16 weeks of randomization. A stratified block randomization scheme within sites balanced assignment by motor severity and time from stroke onset. The biostatistician performed 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 assessment was completed, the study site requested randomization; 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 intervention, a structured, task-oriented upper extremity motor
training program, termed the Accelerated Skill Acquisition Program (ASAP), is a best-practice synthesis implementing neuroscientific 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 previously described and feasibility tested.5,8,9,11-14 The ASAP intervention included an initial evaluation and 30 one-hour treatment 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, collaborative problem solving to identify and address movement

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Task-Oriented Rehabilitation and Recovery Following Motor Stroke

needs, and encouragement of self-direction in extending practice 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 preferences. 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. Treatment 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 different clinicians situated in separate locations from the investigational intervention. The ASAP Manual of Procedures was embargoed during the trial5; it included a formal standardization
process. All ASAP therapists signed nondisclosure agreements.

Outcome Assessment
Participants were assessed at baseline (prerandomization), postintervention (end of therapy), 6 months, and 12 months (end
of study) after randomization by clinicians masked to treatment assignment and standardized in administration of primary 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 minutes (ie, 120 seconds), a time score of 121 seconds was assigned. 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 unknown on the nondominant side19) and improvement in participant-reported Stroke Impact Scale (SIS), version 3.0, hand
subscale score (percentage with improvement 25 points). Because the SIS hand function range is 0 to 100 points, participants with SIS hand function scores of 75 or higher at baseline
(n = 15) were excluded from this analysis. The minimal detectable 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, approximately 22 weeks after stroke) was a secondary end point.
Patients (or their designated representatives or caregivers) were contacted by monthly telephone calls to review
health status, health care utilization, medications, and adverse events. Adverse events were reported regarding 3 independent 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-

Original Investigation Research

tribution assumptions were assessed and data transformations made as necessary. All analyses were performed using
the intention-to-treat principle, comparing outcomes by assigned group. Data were analyzed for patterns of missing data;
because no pattern was found, Markov chain Monte Carlo imputation 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 differences in results, so we report the planned intention-to-treat
results with multiple imputation herein. Changes from baseline in continuous outcomes were analyzed using analysis-ofcovariance models adjusting for baseline values and stratification 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 adjust 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 difficult 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 analyses, 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 calculated as the between-group difference in outcome variable
mean divided by the common standard deviation of the outcome 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 relatively short duration of time from stroke occurrence to enrollment 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 intervention (control) groups and d = 0.63 between the lowfunctioning 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 demonstrate 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

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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
10 690 Excluded
9219 Did not meet inclusion criteria
4863 Clinician judgment
954 Language barrier
2155 No stroke
88 Dementia
87 Upper extremity Fugl-Meyer
motor score >58
1072 Other reasons
645 Declined
826 Other reasons

361 Randomized

119 Randomized to receive ASAP


94 Adherent to therapy
25 Not adherent to therapy

120 Randomized to receive DEUCC


89 Adherent to therapy
31 Not adherent to therapy

122 Randomized to receive UCC

13 Did not complete study


6 Withdrew
6 Medical condition
1 Lost to follow-up

11 Did not complete study


10 Withdrew
1 Lost to follow-up

22 Did not complete study


15 Withdrew
2 Medical condition
5 Lost to follow-up

119 Included in intention-totreat analysis

120 Included in intention-totreat analysis

122 Included in intention-totreat analysis

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 attrition rate of 25%, 120 patients per group was the planned
sample size. The secondary outcome measure was the success rate in the SIS hand subscale score, defined as the proportion 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 clinicians best judgment about the likelihood of the patient completing the study (44%), which
included consideration of social instability, inability to
travel for study-related procedures, and concomitant illness. 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
574

ASAP indicates Accelerated


Skill Acquisition Program;
DEUCC, dose-equivalent usual and
customary care; UCC,
monitoring-only usual and customary
care. Reasons for exclusion are not
exclusive. Adherence in the ASAP and
DEUCC was defined as 27 hours or
more of prescribed treatment; there
was no adherence data collected for
the UCC group. The study was
designed with an estimated a priori
attrition rate of 25%; actual attrition
rates by group were considerably
lower, ranging from 9% to 16% across
groups. Attrition rate of withdrawal
across groups was not statistically
significant (P = .24). Evaluable data at
12 months ranged from 79% to 88%;
for intention-to-treat analyses,
multiple imputation models were
used to estimate end-of-study data
for primary analyses.

extremity Fugl-Meyer (UEFM) motor score too high (11.3%),


and clinicians 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 conversion; 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 inpatient 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.

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Task-Oriented Rehabilitation and Recovery Following Motor Stroke

Original Investigation Research

Table 1. Baseline Characteristics by Treatment Groupa


Total
(N = 361)

Characteristics
Age, mean (SD), y

60.7 (12.5)

ASAP
(n = 119)

DEUCC
(n = 120)

UCC
(n = 122)

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
Asian
Pacific Islander

5 (1.4)

4 (3.5)

1 (0.8)

19 (5.3)

9 (7.8)

7 (5.8)

3 (2.5)

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)

36 (10.1)

9 (7.8)

14 (11.7)

13 (10.8)

320 (89.9)

107 (92.2)

106 (88.3)

107 (89.2)

2 (1.7)

Ethnicity, No. (%)b


Hispanic/Latino
Non-Hispanic/Latino
Education, No. (%)
Less than high school

8 (2.2)

4 (3.4)

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 bachelors degree

71 (19.7)

22 (18.5)

26 (21.7)

23 (19.0)

Completed masters 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)

88 (72.1)

Referral source, No. (%)


Inpatient rehabilitation

247 (68.4)

80 (67.2)

79 (65.8)

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)

7 (1.9)

3 (2.5)

2 (1.7)

2 (1.6)

Transitional day program


Open referral

24 (6.6)

Other

1 (0.3)

9 (7.6)

7 (5.8)

8 (6.6)

1 (0.8)

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,


mean (SD), d

45.8 (22.4)

45.2 (20.3)

45.0 (22.8)

47.0 (23.9)

Stroke type, No. (%)


Ischemic without hemorrhagic conversion

299 (83.3)

100 (84.0)

98 (82.4)

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)

5 (4.2)

1 (0.8)

Other

6 (1.7)

101 (83.5)

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)

1 (0.8)

Brain stem

25 (6.9)

11 (9.2)

5 (4.2)

9 (7.4)

8 (2.2)

2 (1.7)

3 (2.5)

3 (2.5)

Other

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)

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Research Original Investigation

Task-Oriented Rehabilitation and Recovery Following Motor Stroke

Table 1. Baseline Characteristics by Treatment Groupa (continued)


Total
(N = 361)

Characteristics

ASAP
(n = 119)

DEUCC
(n = 120)

UCC
(n = 122)

41.6 (9.4)

41.7 (9.5)

41.5 (9.2)

41.6 (9.5)

3.6 (1.8)

3.6 (2.0)

3.4 (1.7)

3.7 (1.7)

Stroke severity, mean (SD)


Baseline upper extremity Fugl-Meyer
motor scorec
National Institutes of Health Stroke
Scale score

Abbreviations: ASAP, Accelerated


Skill Acquisition Program;
DEUCC, dose-equivalent usual
and customary care;
UCC, monitoring-only usual and
customary care.
a

Percentages may not add to 100%


due to rounding.

Ethnicity was determined by


self-report; decline to report was
removed from the comparison of
ethnicity.

Upper extremity Fugl-Meyer motor


score range, 19-58 (low severity,
36; high severity, <36).

Stroke onset range, 14 to 106 days


(early onset, <60 days; late onset,
>59 days).

Concordant: the paretic limb is the


dominant limb; discordant: the
paretic limb is the nondominant
limb.

Strata, No. (%)

Low severity, early onset

205 (56.8)

68 (57.1)

70 (58.3)

67 (54.9)

Low severity, late onset

50 (13.9)

16 (13.5)

16 (13.3)

18 (14.8)

High severity, early onset

70 (19.4)

23 (19.3)

22 (18.3)

25 (20.5)

High severity, late onset

36 (10.0)

12 (10.1)

12 (10.0)

12 (9.8)

Concordant

176 (48.8)

55 (46.2)

64 (53.3)

57 (46.7)

Discordant

185 (51.2)

64 (53.8)

56 (46.7)

65 (53.3)

105 (29.1)

34 (28.6)

29 (24.2)

42 (34.4)

3.8 (3.0)

4.4 (3.1)

3.3 (2.3)

3.7 (3.4)

Concordance, No. (%)e

Prerandomization occupational therapy,


No. (%)
Amount of prerandomization occupational
therapy, mean (SD), h

Attrition Rate and Treatment Adherence


A total of 304 patients (84%) completed the 12-month evaluation (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, defined as completion of at least 27 treatment hours, was comparable 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, respectively. 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 completed a mean of 11.2 (95% CI, 9.5-12.9) total hours of treatment that varied widely (range, 0-46 hours; see the eFigure
in Supplement 2 for details). Monitoring of health and adverse 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 primary 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 differences ranged from 0.5 to 2 seconds. Associated effect sizes of
group pair differences were small. The Cohen d was 0.15 (95%
576

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 comparison 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) seconds but was still slower than the age-matched normative mean
time of 1.3 seconds,18 indicating persistent motor impairment. 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 seconds, for DEUCC, 8.1 seconds, and for UCC, 7.2 seconds. Between-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 improvement 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 number of serious adverse events whether on or off site, ex-

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104

104

End of study

Change from baseline

104

104

End of study

Change from baseline

104

104

End of study

Change from baseline

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99d

1
(12 to 13)

0.6
(6.4 to 6.5)

.54

.99

4
(9 to 16)

2.6
(3.8 to 9.0)

0.59
(3.77 to 2.60)

0.01
(0.22 to 0.21)

.48

.42

.72

.94

3
(9 to 15)

2.1
(4.0 to 8.3)

2.12
(4.52 to 0.27)

0.14
(0.32 to 0.05)

.22

.49

.08

.15

P Value

For the primary outcome (ASAP vs DEUCC), = .05; for the secondary outcomes (ASAP vs UCC and DEUCC vs
UCC), = .025. The end of the study was the primary end point and occurred 12 months after randomization.
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.

Because of skew in the Wolf Motor Function Test at baseline and end-of-study, both means and medians are
reported; median Wolf Motor Function Test scores are presented for descriptive purposes only.

68 (68.7)

37.1
(32.2 to 42.1)

.18

.16

DEUCC vs UCC
Mean (95% CI)

Participants whose baseline Stroke Impact Scale score was >75 (n = 15) were excluded from these analyses.

75 (72.1)

101

66.4
(61.0 to 71.7)

1.81
(0.83 to 4.45)

0.14
(0.05 to 0.33)

P Value

Denominators for outcome data.

104d

35.7
(30.4 to 40.9)

101

28.2
(24.2 to 32.3)

2.4
(9.4 to 0.6)

2.6
(1.9 to 4.5)

7.3
(3.1 to 16.5)

7.5
(10.5 to 4.6)

7.7
(4.7 to 10.7)

15.1
(11.8 to 18.4)

0.8
(1.0 to 0.6)

1.3
(1.1 to 1.5)

2.1
(1.9 to 2.3)

ASAP vs UCC
Mean (95% CI)

72 (72.7)

107

68.7
(63.9 to 73.6)

122

96

96

122

96

96

122

96

96

122

P Value

99d

Improved 25 points,
No. (%) with outcome

37.6
(31.7 to 43.5)

107

32.8
(28.7 to 36.9)

2.2
(11.2 to 1.04)

2.7
(2.0 to 4.0)

5.2
(3.5 to 13.7)

8.7
(11.6 to 5.8)

5.0
(3.2 to 6.7)

12.9
(9.6 to 16.3)

0.9
(1.0 to 0.7)

1.2
(1.0 to 1.3)

2.0
(1.8 to 2.2)

Mean (95% CI)

105

Change from baseline

68.2
(62.7 to 73.7)

120

104

104

120

104

104

120

104

104

120

Outcome

Between-Group Comparisons
ASAP vs DEUCC

105

End of study

31.1
(26.6 to 35.7)

3.1
(12.8 to 0.9)

2.8
(2.0 to 4.7)

6.9
(3.4 to 22.2)

8.1
(11.7 to 4.5)

7.8
(4.9 to 10.7)

16.6
(13.2 to 20.0)

0.8
(1.0 to 0.6)

1.4
(1.2 to 1.6)

2.2
(2.0 to 2.4)

No. of
Participants

UCC (n=122)

Abbreviations: ASAP, Accelerated Skill Acquisition Program; DEUCC, dose-equivalent usual and customary care;
UCC, monitoring-only usual and customary care.

119

Baseline

Stroke Impact Scale hand


function subscale score,
mean (95% CI)c

119

Baseline

Median (interquartile range)

119

Baseline

Mean (95% CI)

Wolf Motor Function Test


time, sb

119

Baseline

Log Wolf Motor Function Test


time, mean (95% CI), s

Outcome

No. of
Participants

No. of
Participants
Outcome

DEUCC (n=120)

ASAP (n=119)

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

Task-Oriented Rehabilitation and Recovery Following Motor Stroke


Original Investigation Research

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577

Research Original Investigation

Task-Oriented Rehabilitation and Recovery Following Motor Stroke

Figure 2. Longitudinal Changes in Unadjusted Imputed Mean Scores Across Months for the Primary and Secondary Outcomes
WMFT Time Score

1.5
1.0
0.5

Mean SIS Hand Function Score

ASAP
DEUCC
UCC

2.0

20
15
10
5
0

10

12

Months

10

80

60

40

20

12

Months

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

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.

pected, or study related, when either treating each event as


separate or accounting for repeated observations within individuals (all P>.40). There were 168 serious adverse events involving 109 participants; the most common were hospitalization (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.

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 misrepresent the actual differences between groups. This variability 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 between 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 welldesigned 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 psychological 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 intensive 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 hypothesis 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 consider the natural recovery transpiring during the early

Discussion
Among participants with primarily moderate upper extremity motor impairment after stroke, there were no group differences 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 outpatient occupational therapy for the same number of hours, showing no benefit for an evidence-based, intensive, restorative
therapy program. In addition, there was no advantage to providing 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 restoration. With payer pressures on reducing inpatient rehabilitation, 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 during the typical outpatient rehabilitation time window by licensed 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, commu578

SIS Hand Function Score

25

Mean WMFT Time Score, s

Mean Log WMFT Time Score, s

Log WMFT Time Score


2.5

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Task-Oriented Rehabilitation and Recovery Following Motor Stroke

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 setting. Future neurorehabilitation trials should include physiological and psychosocial domains and use designs that directly test hypothesized mechanisms of action. 34 This
consideration may include choosing primary outcomes that are
sensitive to participation and quality of life and are consistent with patient-centered aspects of health care reform.35
ICARE has several limitations related to the disadvantages 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 spontaneous recovery of impairments and activities, explaining 16%
to 42% of the observed improvements.33 Previous upper extremity stroke rehabilitation trials (ie, EXCITE and VA
Robotics)2,3 were performed later after stroke occurrence, after 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 considerably more than what was reported previously4 and consistent with reports of modified schedules of constraintinduced movement therapy that were shown to be effective.36-38
A different treatment schedule (for example, the same num-

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

Original Investigation Research

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 limited 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 testing a nonpharmacological intervention. Usual outpatient
upper extremity therapy may have evolved over time to resemble the investigational intervention, by following evidencebased 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 upper extremity impairment, the use of a structured, taskoriented rehabilitation program, compared with an equivalent dose of customary occupational therapy or with usual and
customary occupational therapy, did not significantly improve motor function or recovery after 12 months. These findings do not support superiority of this task-oriented rehabilitation program for patients with motor stroke and moderate
upper extremity impairment.

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,

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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, coprincipal 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,
coprincipal investigator, physician investigator;
Matthew A. Edwardson, neuroanatomical and
imaging analyst (NINDS-StrokeNet fellow);
Kathaleen Brady, site team leader (August 20122015), ASAP therapist; Rahsaan Holley, site team
leader (August 2009August 2012), ASAP
therapist; Lori Monroe, site team leader (August
2008August 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

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Research Original Investigation

Task-Oriented Rehabilitation and Recovery Following Motor Stroke

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;
Joaqun 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

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.
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