Speech Entrainment for Aphasia Recovery
Phase: PHASE2
Conditions: Aphasia, Aphasia Non Fluent, Stroke
Sponsor: Medical University of South Carolina

v.14 
02MAY2024 
 
1
         
 
 
 
 
 
 
 
 
 
 
 
Speech Entrainment for Aphasia Recovery 
 
SpARc 
 
Leonardo Bonilha, M.D., Ph.D. and Julius Fridriksson, Ph.D. 
 
Version 14.0 
 
02MAY2024 
 
 
 

v.14 
02MAY2024 
 
2
Table of Contents 
1.0 
Protocol Summary .............................................................................................................................. 4 
1.1 ....................................................................................................................................... Synopsis
 ................................................................................................................................................................................... 4 
1.2 ........................................................................................................................................ Schema
 ................................................................................................................................................................................... 5 
1.3 Schedule of Activities ........................................................................................................................................... 6 
2.0 
Introduction ..................................................................................................................................... 15 
2.1 Study Rationale.................................................................................................................................................. 15 
2.2 Background ........................................................................................................................................................ 16 
2.3 Risk/Benefit Assessment .................................................................................................................................... 21 
3.0 
Objectives and Endpoints .................................................................................................................. 22 
4.0 
Study Design ..................................................................................................................................... 23 
4.1 Overall Design.................................................................................................................................................... 23 
4.2 Scientific Rationale for Study Design ................................................................................................................. 24 
4.3 Justification for Dose ......................................................................................................................................... 25 
4.4 End of Study Definition ...................................................................................................................................... 26 
5.0 
Study Population .............................................................................................................................. 26 
5.1 Inclusion Criteria ................................................................................................................................................ 26 
5.2 Exclusion Criteria ............................................................................................................................................... 26 
5.3 Screen Failures ................................................................................................................................................... 27 
5.4 Strategies for Recruitment and Retention ......................................................................................................... 27 
6.0 
Study Intervention ............................................................................................................................ 28 
6.1 Study Intervention Administration .................................................................................................................... 28 
6.2 Measures to Minimize Bias: Randomization and Blinding Instructions ............................................................ 29 
6.3 Study Intervention Compliance ......................................................................................................................... 30 
7.0 
Study Intervention Discontinuation and Participant Discontinuation or Withdrawal ............................ 30 
7.1 Discontinuation of Study Intervention ............................................................................................................... 30 
7.2 Participant Discontinuation/Withdrawal from Study: Instructions .................................................................. 31 
7.3 Lost to Follow-up ............................................................................................................................................... 31 
8.0 
Study Assessments and Procedures ................................................................................................... 31 
8.1 Efficacy Assessments ......................................................................................................................................... 31 
8.2 Safety and Other Assessments .......................................................................................................................... 30 

v.14 
02MAY2024 
 
3
8.3 Adverse Events and Serious Adverse Events ...................................................................................................... 32 
9.0 
Statistical Considerations .................................................................................................................. 33 
9.1 Statistical Hypotheses ....................................................................................................................................... 33 
9.2 Sample Size Determination ............................................................................................................................... 34 
9.3 Populations for Analyses ................................................................................................................................... 34 
9.4 Statistical Analyses ............................................................................................................................................ 34 
10.0 
Regulatory, Ethical, and Study Operational Considerations ................................................................. 37 
10.1 Informed Consent Process ............................................................................................................................... 37 
10.2 Consent Procedures and Documentation ........................................................................................................ 37 
10.3 Study Discontinuation and Closure.................................................................................................................. 37 
10.4 Confidentiality and Privacy .............................................................................................................................. 38 
10.5 Future Use of Stored Data ............................................................................................................................... 38 
10.6 Key Roles and Study Governance .................................................................................................................... 38 
10.7 Safety Oversight .............................................................................................................................................. 38 
10.8 Clinical Monitoring .......................................................................................................................................... 38 
10.9 Data Collection and Management Responsibilities ........................................................................................ 39 
11.0 
References........................................................................................................................................ 40 
 
 
 

v.14 
02MAY2024 
 
4
1.0 
Protocol Summary 
1.1 Synopsis  
Title: 
Speech Entrainment for Aphasia Recovery 
Study Description: 
Speech entrainment therapy (SET) targets speech production in 
persons with non-fluent aphasia and has yielded promising results in 
phase I trials. SET involves online mimicking of an audiovisual speech 
model, which allows many non-fluent individuals to practice 
producing fluent speech. This trial aims to determine the best dose 
of SET for the treatment of chronic non-fluent aphasia.  
Objectives: 
 
 
Primary Objective:  To determine the dose of SET with the highest 
effect size on speech fluency Verbs Per Minute (VPM). 
 
Endpoints: 
Primary Endpoint: VPM at 3 months post conclusion of SET or post 
no SET period. 
Secondary Endpoints: Stroke and Aphasia Quality of Life Scale 
(SAQOL-39g) at 3 months post conclusion of SET or post no SET 
period.  
Study Population: 
80 adults (ages 21-81) with chronic (>6 months) aphasia due to left 
hemispheric stroke. 
Phase: 
2 
Description of 
Sites/Facilities 
Enrolling Participants: 
There are 3 participating sites: Medical University of South Carolina 
(MUSC), University of South Carolina (UofSC), and University of Utah 
(UoU). All sites will be conducting this trial via telehealth. 
Description of Study 
Intervention: 
A - SET for 3 weeks (15 days, 1 hour daily, 5 x week)   
B - SET for 4.5 weeks (22 days, 1 hour daily, 5 x week)  
C - SET for 6 weeks (30 days, 1 hour daily, 5 x week) 
D - No-SET for 6 weeks (control condition) 
Study Duration: 
5 years 
Participant Duration: 
28-31 weeks dependent on participant group randomization 
 
 
 
 
 
 
 
 
 
 
 
 

v.14 
02MAY2024 
 
5
1.2 Schema 
 
                   SpARc Flow Diagram 
 
Screening 
Days -5 to 0 
 
 
 
Entry 
Randomization 
Day 0 
 
 
 
 
 
 
 
Visit 1  
Days 1-5 (+/-4 days) 
(Refer to section  
1.3.2 for more details on baseline assessments)  
 
 
Visits 2-30a 
For 3, 4.5, or 6 weeks 
 
 
 
 
Follow up Visit 1 
1 week post  
intervention or no SET 
 
Follow up Visit 2 
3 months post  
intervention or no SET 
 
 
Follow up Visit 3 
6 months post  
intervention or no SET 
 
 
Screening & Randomization   
Informed consent, review eligibility, WAB-R24 , Apraxia of Speech Rating Scale 3.0 
(ASRS 3.0)57, review of clinical images. 
*Assessments taken during screening will also be utilized as baseline data 
 
Baseline Assessments 
Refer to Table 1, Schedule of Activities 
Follow-up assessments  
Refer to Table 1, Schedule of Activities 
Follow-up assessments  
Refer to Table 1, Schedule of Activities 
N=80 
Arm D 
NO SET 6 weeks 
N:20
Arm A 
SET 3 weeks 
N:20
Intervention is administered 
aRandomization arm determines number of intervention visits (or 6 
weeks no SET) 
Refer to Table 1, Schedule of Activities 
Randomize 
Arm B 
SET 4.5 weeks 
N:20
Arm C 
SET 6 weeks 
N:20
Follow-up assessments 
Refer to Table 1, Schedule of Activities 

v.14 
02MAY2024 
 
6
1.3 Schedule of Activities 
1.3.1 Screening and Randomization (Visit 0) 
Once consented, either in person or eConsent (see section 10.2 for more details about 
the consent process), participants will be contacted via telephone or email to schedule a 
screening and randomization telehealth visit. Once scheduled, research staff will email the 
participant a link to access the secure visit at the set appointment time. All visits will be 
conducted through a secure, HIPAA-compliant, telehealth platform. The online platform allows 
researchers to connect to participants in their own homes via video-conferencing.     
Research staff will go through the inclusion and exclusion criteria (see section 5.1 and 
5.2). Participants will be asked to provide medical records to confirm presence of left 
hemisphere stroke. This can be done through electronic medical records if available. Presence 
of right hemisphere, cerebellar, or brainsterm stroke or other structural neurological conditions 
(such as brain tumors or arteriovenous malformations) with persistent deficits will exclude 
them from participation in this study. The NIH Stroke Scale (NIHSS) is administered by a trained 
clinician (speech-language pathologist [SLP] or neurologist) to assess for post-stroke 
neurological deficits. If the MRI verifies presence of left hemisphere stroke, participants will 
then be given the Western Aphasia Battery-Revised (WAB-R), a common clinical aphasia 
assessment to determine the presence of non-fluent aphasia. The Apraxia of Speech Rating 
Scale 3.0 (ASRS 3.0) will be given to determine presence and severity of dysarthria. The 
modified Rankin Scale (mRS) will also be administered to determine eligibility (see section 5.1). 
The Revised Hearing Handicap Inventory-Screening (RHHI-S) will be given to the participant to 
screen for significant hearing loss. The SLP will consult the RHHI-S score and use clinical 
judgment to determine if hearing is adequate for the purposes of this trial. The participant must 
wear any individual corrective hearing devices if applicable. 
Videorecordings of assessments will be saved to the researcher’s local password 
protected and encrypted computer. Videos will be immediatley uploaded to a HIPAA-compliant 
Box account. Once vidoes are confirmed to have been successfully uploaded to the Box 
account, research staff will immediately delete the video stored on the  computer’s harddrive. 
Participants will be asked to have a friend or family member (assistant) present to help with 
technology. 
Once all assessments are complete, and the participant is found to have non-fluent 
aphasia as well as meets all eligibility criteria (section 5.1 and 5.2), the participant will be 
randomly assigned to one of four arms (Figure 1): 

v.14 
02MAY2024 
 
7
The baseline assessment visit will consist of the tests outlined below. All assessments 
are adapted to be administered online. A brief training session will take place before the 
administration of assessments to make sure that the participant and his/her assistant can 
demonstrate how to use controls in the telehealth platform to point to pictures on a shared 
screen. The assistant will also be instructed on how to alter the webcam to allow the clinician to 
view the participant completing different tasks.  
Figure 1. Overall study design. This diagram depicts the 3 different doses of SET (treatment 
arms) and the control arm. For clarity of visualization, the behavioral assessments are not 
depicted in this diagram, but are explained in Table 1 (Study Schedule) below. In brief, all 
participants will receive behavioral assessments one week before the initiation of therapy, 
then 1 week, 3 months, and 6 months after the conclusion of SET or no SET. 
 
        After randomization, a telehealth technology kit will be sent to the participant’s home. 
Each kit will include: 
1. A computer pre-loaded with the treatment applications, internet capeabilities for the 
telehealth platform, and Team Viewer, which will allow the SLP to see the 
participant’s computer to help with initial set-up and troubleshooting. 
2. A high-quality headset and microphone to maximize communication with research 
staff online. 
3. A mouse for optional use. 
4. A mobile WiFi hotspot if a participant does not have an adequate WiFi connection at 
home. 
Participants will be asked to review and sign the SpARc Telehealth Technology Contract upon 
receipt of equipment. The Technology Contract will also be created in RedCap so the patient 
can sign virtually. 
 
1.3.2 Baseline Assessments (Visit 1)  

v.14 
02MAY2024 
 
8
Baseline testing (demographic and baseline characteristics can be seen in Table 3 and 
the remaining assessments in Table 1) will be done in all groups. Per the discretion of the SLP, 
baseline assessments can be completed over the course of 2-5 days, depending on the 
participant’s ability and stamina. Descriptions of baseline assessments can be found in section 
1.4, Study Assessments. Instructions for administering assessments can be found in specific 
assessment manuals. The order of baseline assessment administration after screening is as 
follows:  
1. Verbs per Minute (VPM) – discourse assessments 
2. Modified Philadelphia Naming Test (PNT)68 
3. Stroke and Aphasia Quality of Life (SAQOL-39g)54 
4. Modified Charlson Comorbidity Index60 
5. Communicative Effectiveness Index (CETI)56 
6. Lexical Orthography Familiarity Test (LOFT)61 
7. Modified Epworth Sleepiness Scale (ESS)70 
8. Pyramids and Palm Trees Test (PPTT)58 
9. Matrix Reasoning - Wechsler Adult Intelligence Scale III (WAIS-III)59 
10. Vertical Numerical Rating Scale-Face Rating Scale for post-stroke fatigue (NRS-
FRS) 
11. Modified Philadelphia Repetition Test (PRT)69 
12. Community Stroke Aphasic Depression Questionnaire (SADQ-10)62 
 
We will keep the order of test administration constant but will leave it to the clinical 
judgment of the SLP to determine appointment duration and number of days required for each 
individual participant to complete testing. Factors that the clinician will consider include 
severity of aphasia, overall endurance, and tolerance of testing. From experience with prior 
aphasia trials, these factors can vary between participants.  
Schedule for screening, baseline assessments, intervention, and outcome measures can be seen 
below in Table 1: 

v.14 
02MAY2024 
 
9
 
Footnote: aNumber of visits depend on randomized arm. bFollow-up assessments can be 
completed over 1-5 days. cDefinitions for the follow-up visit target date and window provided in 
Table 2. dRepeat WAB-R/ASRS 3.0 measures prior to intervention if initiation of intervention 
period occurs >15 days post randomization. eUse of WAB-R scores obtained for other purposes, 
administered within 120-days before randomization, is allowed. 
Note: In the event of technological difficulties, readministration of baseline or follow-up testing 
will be conducted within study timeline constraints to maintain the integrity of data collection. 
 
Table 1. Schedule of Activities 
*Refer to Table 4 for assessment recording and scoring procedures 
Assessment 
 
Screening & 
Randomization 
Visit 0 
Days -5 to 0 
 
Baseline 
Assessments  
Visit 1 
Days 1-5 (+/-4 
days) 
Intervention 
Period 
Visits 2-30a 
For 3, 4.5, or 6 
weeks  
(+/- 3 days) 
 
Follow-Up  
Visit 1 
1-week post 
interventionb 
(+/- 3 days)c 
 
Follow-Up  
Visit 2 
3-month post 
interventionb 
(+/- 1 week)c 
 
Follow-Up  
Visit 3 
6-month post 
interventionb 
(+/- 1 week)c 
Informed consent 
X 
 
 
 
 
 
Review of eligibility criteria 
and randomization 
X 
 
 
 
 
 
Concomitant Aphasia 
Treatment 
 
 
X 
X 
Assess New Adverse Events 
 
 
X 
X 
 
 
Verbs per Minute (VPM) 
 
X 
 
X 
X 
X 
Gathering of individual 
demographic and baseline 
characteristics (Table 3) 
 
X 
 
 
 
 
NIH Stroke Scale (NIHSS) 
X 
 
 
 
 
 
Western Aphasia Battery-
Revised (WAB-R)  
Xd, e 
 
 
X 
X 
X 
Quality of life assessment - 
Stroke and Aphasia Quality 
of Life (SAQOL-39g)  
 
X 
 
X 
X 
X 
Charlson Comorbidity Index 
 
X 
 
 
 
 
Communicative 
Effectiveness Index (CETI) 
 
X 
 
X 
X 
 
Lexical Orthography 
Familiarity Test (LOFT) 
 
X 
 
 
 
 
Modified Epworth 
Sleepiness Scale (ESS) 
 
 
 
 
 
 
Apraxia of Speech Rating 
Scale 3.0 (ASRS 3.0) 
Xd 
 
 
X 
X 
 
Pyramids and Palm Trees 
Test (PPTT)  
 
X 
 
 
 
 
Matrix Reasoning - Wechsler 
Adult Intelligence Scale, 
Third Edition (WAIS-III) 
 
X 
 
 
 
 
Vertical Numerical Rating 
Scale-Face Rating Scale for 
post-stroke fatigue (NRS-
FRS) 
 
X 
 
 
 
 
Modified Philadelphia 
Repetition Test (PRT) 
 
X 
 
X 
X 
 
Modified Philadelphia 
Naming Test (PNT) 
 
X 
 
X 
X 
 
Stroke Aphasic Depression 
Questionnaire (SADQ-10) 
 
X 
 
 
 
 
MRI 
 
 
 
 
(optional) 

v.14 
02MAY2024 
 
10
 
Table 2. Follow-Up Visit Target and Visit Windows in Days 
 
Randomization 
Assignment 
Follow-Up  
Visit 1 
Follow-Up  
Visit 2 
Follow Up  
Visit 3 
 
SET (any dose) 
7 days after the last 
completed SET session 
+/-3 days 
 
90 days after the last 
completed SET session 
+/-7 days 
180 days after the last 
completed SET session +/-
7 days 
No SETa 
54 days post-
randomization +/-7 days 
 
137 days post-
randomization +/-11 days 
227 days post-
randomization +/-11 days 
 
Footnote: aThe No SET target date for follow-up visits accounts for time to complete baseline 
assessments (5 days), and the window for the follow-up visits is widened to account for the 
window for baseline assessment visits (additional +/-4 days). 
 
 
Table 3. Individual Demographic and Baseline Characteristics 
1- Age at the time of the stroke. 
2- Cardiovascular risk factors (each comorbidity will be collected and the cumulative score 
will be calculated using the Charlson Index60) 
3- Pre-morbid functioning (Lexical Orthographic Familiarity Test61, LOFT, a pre-morbid 
functional tool validated in subjects with aphasia). 
4- Post-stroke depression (assessed using the Stroke Aphasia Depression Questionnaire 
SADQ-1062). 
5- Post-stroke fatigue – (assessed using the Epworth Sleepiness Scaled70 modified for those 
with aphasia71 and the Visual Analogue Fatigue Scale72).  
For participant description in publications and secondary analyses, we will also collect 
information about prior treatment for aphasia (duration of treatment after stroke, type of 
treatment) as well as socio-demographic information including age, sex, race/ethnicity, 
handedness, pre-stroke household income, education level, insurance status, and marital 
status. 
 
 
Table 4. Scoring and Recording of Assessments 
Assessment 
Record and 
score 
Record and 
save to Box, 
but not 
scored 
Scorer 
No video 
recording 
Local site 
Centralized 
(UofSC) 
WAB-R baseline 
X 
 
X  
(for eligibility) 
X 
 
WAB-R follow-
up visits #1, 2, 3 
X 
 
 
X 
 

v.14 
02MAY2024 
 
11
ASRS 3.0 
baseline 
X 
 
X  
(qualitatively 
interpreted for 
eligibility) 
Xa 
 
ASRS 3.0 follow-
up visits #1, 2 
X 
 
 
Xa 
 
VPM follow-up 
visits #1, 2, 3 
X 
 
 
X 
 
Demographic 
and baseline 
characteristics 
(Table 3) 
 
 
X 
 
X 
SAQOL-39g 
baseline 
 
 
X 
 
X 
SAQOL-39g 
follow-up visits 
#1, 2, 3 
 
 
X 
 
X 
CETI 
 
 
X 
 
X 
CETI follow-up 
visits #1, 2 
 
 
X 
 
X 
PPTT 
 
 
X 
 
X 
WAIS-III (Matrix 
Reasoning) 
 
 
X 
 
X 
PRT baseline 
X 
 
 
X 
 
PRT follow-up 
visits #1, 2 
 
X 
 
 
 
PNT baseline 
X 
 
 
X 
 
PNT follow-up 
visits #1, 2 
 
X 
 
 
 
 
Footnote: aASRS 3.0 scored by an expert, blinded assessor at UoU. 
 
1.3.3 Intervention (Visits 2-30) 
 
Participants randomized into one of the three SET treatment arms (A, B, C) will begin 
intervention Monday-Friday for one hour a day. The no SET arm will not have interventional 
visits for 6 weeks. For specific details regarding intervention, please refer to section 6.  
1.3.3.1 Assessment of Adverse Events  
 
We will ask the participant to report adverse events (AEs) as they occur and will 
routinely ask the participant at the end of each week of intervention. We will also call each 
participant in the no SET group weekly to assess AEs. See section 8.2 for more information 
regarding the definition and classification of AE and guidelines for reporting events. 
1.3.3.2 Missed Intervention Appointments 
 
For missed intervention appointments, the participant has the option to make up 
sessions on weekends or in the days prior to testing. 

v.14 
02MAY2024 
 
12
1.3.4 Follow Up Testing (Follow Up Visits 1-3) 
 
All participants will receive follow-up testing according to the timeline shown in Table 1 
above (1 week, 3 months, and 6 months post intervention or no SET). Outcome measures 
obtained at each follow-up visit are also listed in Table 1. Assessment descriptions can be found 
in section 1.4, Study Assessments. Follow-up testing will be completed in 3-5 days, dependent 
on participant ability.  
1.3.5 Concomitant Aphasia Treatment  
 
Since we are not restricting behavioral speech and language therapy outside of the SET 
protocol, we will document concomitant speech therapy each participant is engaged in. We will 
collect this information at the follow-up visits listed in Table 1. Concomitant aphasia treatment 
will be obtained from participant and/or caregiver report and categorized by treatment type 
and frequency. The research team will record this information using Table 5 below. 
 
Table 5. Concomitant Aphasia Treatment 
Therapy type 
# Days of therapy from start of 
intervention until 3-month 
follow-up 
# Days of therapy between 3-
month follow-up and 6-month 
follow-up 
Face-to-face with an 
SLP 
 
 
Online or app based 
program 
 
 
Structured support 
group 
 
 
 
 
 
 
1.4 Study Assessments 
Verbs per Minute (VPM) 
VPM will be obtained at baseline and follow-up appointments through scoring of one procedural story 
telling task and one narrative story telling task. VPM from discourse samples provides us with the 
participant’s ability to produce verbs during discourse, which is a meaningful clinical representation of 
the participant’s overall fluency in discourse. VPM is obtained from the off-line transcription of the 
discourse assessments and subsequent scoring via the automated coding analysis (Computerized 
Language Analysis [CLAN]) systems available through AphasiaBank4. 
 

v.14 
02MAY2024 
 
13
Western Aphasia Battery-Revised (WAB-R)24 
The WAB-R will characterize the participant’s overall language impairment through the evaluation of the 
main clinical aspects of language functioning, including speech content, speech fluency, auditory 
comprehension, repetition, naming, and reading. It allows for the differentiation of these specific 
language abilities, as well as the classification of aphasia type (see Table 6 below). The WAB-R also yields 
a composite score, the Aphasia Quotient (AQ), which provides an overall measure of severity, in which 
lower scores denote more severe aphasia24 (see Table 7 below). For diagnostic purposes, non-fluent 
aphasia is defined by WAB-R Auditory Comprehension score >4 and WAB-R Fluency score <6, falling 
under the categories of global, Broca’s, transcortical motor, or transcortical mixed aphasia.  
 
Table 6. Aphasia Classification Criteria24 
Aphasia Type 
Fluency* 
Auditory Verbal 
Comprehension 
Repetition 
Naming and 
Word Finding 
Global 
<5 
0-3.9 
0.49 
<7 
Broca’s 
<5 
4-10 
0-7.9 
<9 
Isolation 
<5 
0-3.9 
5-10 
<7 
Transcortical 
Motor 
<5 
4-10 
8-10 
<9 
Wernicke’s  
>4 
0-6.9 
0-7.9 
<10 
Transcortical 
Sensory 
>4 
0-6.9 
8-10 
<10 
Conduction 
>4 
7-10 
0-6.9 
<10 
Anomic 
>4 
7-10 
7-10 
<10 
*In this study we will use a Fluency score of <6 for inclusion of participants with mild or improving non-
fluent aphasia as defined by the description of Fluency score 5 in the WAB-R administration and scoring 
manual.24 
Table 7. Aphasia Quotient (AQ) and Severity24 
AQ 
Severity 
0 < AQ ≤ 25 
Very severe 
25 < AQ ≤ 50 
Severe 
50 < AQ ≤ 75 
Moderate 
75 < AQ ≤ 93.7 
Mild 
93.7 < AQ ≤ 100 
No aphasia 
NIH Stroke Scale (NIHSS) 
The NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral 
infarction on the levels of conscioiusness, language, neglect, visual-field loss, extraocular movement, 
motor strength, ataxia, dysarthria, and sensory loss. Ratings for each item are scored from 0-3 , with 0 as 
normal. 
Stroke and Aphasia Quality of Life (SAQOL-39g)54 
The SAQOL-39g is a quality of life assessment specific to the stroke population with aphasia. It contains 
39 items relevant to quality of life that the participant rates from a scale of 1-5 (1=definitely yes, 

v.14 
02MAY2024 
 
14
2=mostly yes, 3=not sure, 4=mostly no, 5=definitely no). When scored, it provides a mean score and also 
breaks down items into different domains: physical score, communication score, and psychosocial score. 
 
Communicative Effectiveness Index (CETI)56 
The CETI is a self-rated scale of overall communicative effectiveness containing 16 items. It uses a 10cm 
visual-analogue scale ranging from “not able at all” to “as able as before.” The participant points on the 
scale to self-rate level of severity for each item. 
Revised Hearing Handicap Inventory-Screening (RHHI-S)78 
The RHHI-S is a short screen for hearing handicap that consists of 10 hearing-related handicaps. 
Participants must utilize personal hearing devices (if any) during the screen. The participant will select a 
response of “yes,” “sometimes,” or “no” for each item. The total score is collected based on participant 
responses: 
Yes= 4 
Sometimes= 2 
No= 0 
Apraxia of Speech Rating Scale 3.0 (ASRS 3.0)57 
The ASRS 3.0 will be utilized to rate the presence and severity of apraxia of speech (AOS) and to screen 
for severe dysarthria. It quantifies the frequency and severity of the characteristics associated with AOS. 
It contains 13 items with distinguishing features of AOS and is scored across three separate tasks:  
• Spontaneous Speech Tasks (alternating and sequential motion rates, maximum vowel 
prolongation, word repetition, sentence repetition) 
• Spontaneous Speech Subtest of the WAB-R 
• Discourse samples (same samples used at baseline for VPM) 
 
Pyramids and Palm Trees Test (PPTT)58 
The PPTT is a test of semantic processing. This test assesses the degree to which a patient can access 
meaning from pictures and words. Information from the test will help determine whether a participant’s 
difficulty in naming or pointing to a named pictured is due to a difficulty in retrieving semantic 
information from pictures, retrieving semantic information from words, or, in the case of a naming 
failure, retrieving the appropriate spoken form of the word.58 
 
Matrix Reasoning - Wechsler Adult Intelligence Scale, Third Edition (WAIS-III)59  
The Matrix Reasoning subtest of the WAIS-III is composed of four types of nonverbal reasoning tasks: 
pattern completion, classification, analogy, and serial reasoning. The participant looks at a matrix from 
which a section is missing and either identifies by number or points to one of five response options that 
complete the matrix. This test will allow for analysis of the cognitive status of the patients.59 
 
Neuroimaging 
We will obtain a release of medical records from the participants to review their peri-stroke brain 
imaging. Brain MRIs or head CT scans will be reviewed to confirm that the aphasia was caused by a left 
hemisphere stroke. As explained in the inclusion and exclusion criteria, we will exclude individuals with 
previous strokes outside the left hemisphere. An optional brain MRI will be offered to participants at 

v.14 
02MAY2024 
 
15
Note: All assessments are modified for online use via telehealth. 
 
2.0 
Introduction 
2.1 Study Rationale 
 
Aphasia is the neurological impairment defined by the compromised ability to 
comprehend or produce language1. It affects at least 20% of stroke survivors, and many 
individuals with aphasia persist with chronic language problems (>6 months after the stroke)2. 
follow-up visit #2 (3-months post-intervention) or #3 (6-months post-intervention). This MRI scan will 
include high-resolution structural brain imaging to evaluate the stroke lesion anatomy in more detail.  
 
Philadelphia Naming Test (PNT)68 
The PNT is a picture naming task consisting of 175 high- and low- frequency nouns that vary in length 
from 1-4 syllables that assess lexical access ability in aphasic participants. 
 
Philadelphia Repetition Test (PRT)69 
The PRT is a test of speech repetition ability. It uses the same items as the PNT, but instead of showing 
the pictures to the participants, the names of the items are spoken to them (once only), and participants 
must repeat the names back to the experimenter. 
 
Charlson Comorbidity Index60 
The Charlson Comorbidity Index is an index that collects specific comorbid conditions, including 
cardiovascular risk factors. Each comorbidity will be collected, and the cumulative score will be 
calculated. 
 
Lexical Orthographic Familiarity Test (LOFT)61 
The LOFT is a forced-choice recognition task based on lexical familiarity judgments. The participant is 
shown two words and instructed to choose which word looks more familiar.  
 
Stroke Aphasic Depression Questionnaire (SADQ-10)62 
The SADQ-10 is a questionnaire used to assess depression in individuals with aphasia. The participant 
and/or caregiver selects the frequency of each depression-related behavior the participant may exhibit.  
 
Modified Epworth Sleepiness Scale (ESS)70 
This is a scale in which the participant rates their level of sleepiness for daily activities from 0 (would 
never doze) to 3 (high chance of dozing). 
 
Vertical Numerical Rating Scale-Face Rating Scale (NRS-FRS) 
This is a visual analogue scale that the participant will use to self-rate their level of fatigue ranging from 
zero (no fatigue) to 10 (worst possible fatigue). 
 
Modified Rankin Scale (mRS) 
This measures severity of disability for the participant both before and after stroke. 
 

v.14 
02MAY2024 
 
16
Individuals with aphasia who experience difficulties in producing fluent speech are categorized 
as having non-fluent aphasia3. Broca’s aphasia, transcortical motor aphasia, and global aphasia 
are the classical examples of non-fluent aphasia. Unfortunately, non-fluent aphasia is common4, 
strongly associated with lower quality of life3, and notoriously difficult to treat. The majority of 
subjects with non-fluent aphasia do not achieve satisfactory gains in spontaneous speech with 
standard of care aphasia therapy5, 6 and this treatment gap constitutes and important and 
unmet clinical need, underscoring the importance of new and innovative forms of treatment. 
In a pilot study (Fridriksson et al., Brain 2012)7, we described a new approach to treat non-
fluent aphasia, termed speech entrainment therapy (SET). SET is a form of speech therapy that 
uses an audio-visual system to guide (entrain) the speech of the person with aphasia. In our 
original study, we observed that many subjects with non-fluent aphasia overcame the barrier 
towards fluency and achieved improvements in fluent speech with SET, with normal prosody 
and without many errors7. Since then, we expanded our pilot data and we observed that 
individuals with non-fluent aphasia treated with SET achieved greater than 20% improvement 
in verbs per minute (VPM) during spontaneous speech at three months after therapy. 
 
These are very encouraging results because they represent sustained post-treatment 
gains in producing verbs during discourse, which is a valid ecological measure that is a better 
predictor of language abilities compared with producing nouns, or object naming8. Based on 
these promising data, we hypothesize that SET may be a meaningful clinical tool for the 
treatment of non-fluent aphasia. Nonetheless, our preliminary results are based on an 
uncontrolled study with a limited number of individuals. A controlled study to better 
understand the full effect sizes of SET could define its best dose and justify future studies of SET 
versus other forms of therapy. For these reasons, we propose a phase II clinical trial to 
determine the optimal dose of SET.  
 
2.2 Background 
Post-stroke aphasia is a prevalent neurological disability with a negative impact on 
quality of life. Aphasia is a neurological deficit defined by the impaired ability to process 
language as a result of brain damage1. It is one of the most common forms of neurological 
disabilities after a stroke2, typically resulting from injury affecting the language-dominant brain 
hemisphere9. At least 20% of all stroke survivors remain with some degree of long-lasting 
aphasia2, 10-12. Since language is one of the most essential components of human interaction, 
aphasia has a profound and negative impact on quality of life13-15. Post-stroke aphasia often 
leads to social isolation13, 16, 17, worse rehabilitation outcomes18, and depression15, 17, 19.  
2.2.1 Non-fluent aphasia 
Individuals with aphasia can exhibit different types of language impairments, and 
aphasia is classified in accordance with the patterns of linguistic difficulties exhibited by each 
person20, 21. Non-fluent aphasia is defined by significantly reduced speech production, ranging 
from total mutism to utterances composed of only 3-5 words22, 23. Non-fluent aphasia is not 
only a very common type of aphasia, affecting approximately 40% of all chronic aphasia cases4, 
but also one of the most debilitating types. Non-fluent aphasia is frequently associated with 
profound frustration and depression3.  

v.14 
02MAY2024 
 
17
Slow speech, effortful speech, frequent pauses, short phrase length, single words, and 
poor articulation are commonly observed in subjects with non-fluent aphasia3. There is not a 
perfect diagnostic tool for non-fluent aphasia, given the complexity of the symptoms that may 
lead to fluency problems3. Nonetheless, one of the most robust tools for this purpose is the 
Western Aphasia Battery, revised edition (WAB-R)24, which, in spite of being relatively general, 
permits a reproducible agreement across clinicians and researchers. The WAB-R is one of the 
most commonly used tools in daily practice and basing this current research on the WAB-R will 
permit a clinical translation in the future[see section 1.4].  
This research will focus on the recovery of spontaneous speech and will include all forms of 
non-fluent aphasia, except for global aphasia. Global aphasia is a very severe form of aphasia, 
with suboptimal recovery potential and, unfortunately, is rarely associated with improvement 
in fluency.  
2.2.2 Speech Entrainment Therapy (SET) 
The basic premise behind most rehabilitation approaches, regardless of the targeted 
function or modality, is that repeated practice of a specific behavior within the therapy session 
leads to an increased likelihood that this behavior improves and can be executed outside the 
rehabilitation setting. This concept is related to the principle of Hebbian learning, which is 
based on the notion that synaptic strength and functional neuronal connections can be 
reinforced due to repeated stimulation36 and new experiences lead to molecular and cellular 
events that alter synaptic efficacy, leading to reorganization of neuronal circuits37. This principle 
should be considered in the context of aphasia therapy since conventional therapies typically 
induce numerous speech errors5, 6. In fact, treatment-induced errors can often exceed correct 
responses31. Based on the Hebbian learning principles of neuroplasticity, it is possible that 
repeated errors could, in fact, lead to maladaptive changes and contribute to the persistence of 
post-therapy errors and non-fluent speech. In contrast with conventional speech therapies, SET 
enables subjects with aphasia to practice fluent speech with few errors, which is, otherwise, 
unachievable. This innovative and unique feature of SET differentiates it from other forms of 
speech therapy. We know of no other method, besides SET, that enables non-fluent aphasic 
subjects to produce fluent, prosodically accurate, speech for a prolonged period of time.  
2.2.3 Overcoming learned nonuse 
 SET also directly addresses the issue of ‘learned nonuse,’ which implies that stroke 
survivors tend to avoid using affected functions because doing so is inefficient, relying instead 
on the spared functions38. In the context of motor impairments, learned non-use is manifested 
by the preferential use of the spared limb, with little or no use of the paretic limb39. Although 
learned nonuse has not been frequently addressed in the aphasia literature, it is clear that non-
fluent subjects tend to withdraw from communication situations. SET provides non-fluent 
stroke subjects with the opportunity to practice fluent speech and reverse some of the effects 
of learned nonuse in speech.   
2.2.4 Theoretical framework and mechanism of action of SET 
 There is abundant evidence from the current neuroscience literature to suggest that 
the adult brain is capable of reorganization after injury40, 41. Cortical representation, maps, and 
networks can be modified by new experiences and learning42, 43. Nonetheless, reorganization is 
less likely to occur in brains with larger injuries or in older age44-46.   

v.14 
02MAY2024 
 
18
The mechanism of action of SET is the sensorimotor transformation of speech, enabling 
the reproduction of the speech that is heard and seen. It entails the online transformation of 
auditory and visual signals into articulation and phonological output. As such, SET overcomes 
(or compensates for) speech production deficits but requires that auditory comprehension to 
be at least partly intact.  
Overall, SET-mediated improvements are likely related to the involvement of brain areas 
responsible for sensorimotor transformation of speech. Our preliminary data indicate that 
subjects who benefit the most from SET are those with preserved sensorimotor speech brain 
areas located in the temporal-parietal junction7, which is a hub for sensorimotor 
transformations for vision, movement, and language47. Within the left temporal-parietal region, 
area Spt (left posterior Sylvian region at the parietal-temporal boundary) is specialized in 
language sensorimotor integrations48-51. It plays a similar role in speech compared with other 
well-known areas responsible for sensorimotor integration of other modalities, such as the 
lateral intraparietal cortex (area LIP) for eye movement in primates52, and the anterior intra-
parietal cortex (area AIP) for upper extremity reach and grasp53.  SET-related improvements 
likely depend on the functional and structural integrity of area Spt prior to therapy.  
Nonetheless, SET-mediated recovery may be related to different brain regions 
depending on the aphasia type. More specifically, for subjects with intact repetition 
(transcortical aphasia), SET improvement may be related to recruitment of more anterior 
regions (frontal associative areas).  
It remains undefined for whom, why, and how much SET can be of benefit. It is very 
likely that, within the category of non-fluent aphasia, individuals with different aphasia types 
(and, thus, with different levels of repetition and comprehension impairment) may benefit 
differently. For this reason, this study will focus on evaluating whether SET is indeed associated 
with consistent results, and whether the improvement achieved with SET is comparable with an 
effect size reported in the literature for conventional speech therapy. If SET is indeed 
determined to be associated with therapeutic benefits, a “go” decision will be made for a 
future definitive clinical trial comparing SET with other forms of therapy. During this future 
study, it will be paramount to determine the individual determinants of therapy success, not 
only to better inform clinicians, but also to evaluate the mechanisms associated with 
differential responses from SET versus other forms of therapy.  
2.2.5 Evidence-based speech therapy for non-fluent aphasia 
One of the most important challenges in establishing evidence-based aphasia treatment 
is related to the fact that most of the existing literature is based on “small numbers of 
participants across a range of characteristics (age, time since stroke, and severity profiles), 
interventions, and outcomes” as described by the 2012 and 2016 Cochrane Reviews5, 25. This 
study aims to directly overcome this challenge by performing a controlled trial with a large 
number of subjects targeting a specific yet common form of aphasia (non-fluent aphasia).  
Although there is evidence suggesting that behavioral treatments for non-fluent aphasia 
can lead to improvements in spontaneous speech5, 6, 26-28, it is relatively uncommon for subjects 
with non-fluent aphasia to recover to a point where their speech could be considered fluent 
with the existing therapies, particularly in the chronic phases after the stroke5, 6.  
At the moment, there is no completely satisfactory approach for treating spontaneous 
speech production in non-fluent aphasia, which constitutes an important and unmet clinical gap 

v.14 
02MAY2024 
 
19
in the neurorehabilitation of stroke. This is a well-recognized area for improvement and past 
and current clinical trials have attempted to assess new approaches to treat aphasia, including 
Constrained-Induced Aphasia Therapy (CIAT)29 (ClinicalTrials.gov Identifier NCT00843427), 
Melodic Intonation Therapy30 (NCT00903266), transcranial direct current stimulation (tDCS) 
(NCT01686373), tDCS coupled with Dextroamphetamine (NCT02514044) and transcranial 
magnetic stimulation (TMS) (NCT00608582, NCT02241213, NCT01512264).  
While these are promising new avenues of treatment, we believe that the therapy being 
proposed in the current trial, speech entrainment therapy (SET), is unique and, perhaps, 
superior to other forms of therapy because it enables subjects with aphasia to practice 
relatively error-free, fluent speech. SET guides 
the reestablishment of speech fluency, thus 
overcoming the initial barrier between non-
fluent to fluent speech, which is not often 
observed with other therapies.  
Moreover, SET may circumvent 
speech errors that are commonly associated 
with conventional speech therapies31. To the 
best of our knowledge, the only other form of 
therapy that induces relatively error-free 
speech is Melodic Intonation Therapy (MIT)32, 
33. However, MIT propitiates practice in verbal 
output with a prosody that is different from 
actual speech and, therefore, is less 
ecologically realistic. For this reason, SET may 
be a better approach to permit practice in 
fluent speech. The significance and innovation 
of SET are further explained in detail below.  
2.2.6 Significance of SET 
 In a preliminary study7, we reported 
SET as a new form of speech therapy to enable individuals with non-fluent aphasia to produce 
fluent speech. During the SET session, the participant’s speech is “pulled along” (guided) by an 
audiovisual (A/V) model in which the therapist’s mouth is seen on a computer screen and the 
speech is heard via headphones (for an illustrational video, please refer to 
https://youtu.be/rseSnWq9C_U). 
It is important to point out that speech repetition ability and speech entrainment ability 
dissociate in most participants with non-fluent aphasia. That is, many participants with very 
poor repetition (as in the case of most non-fluent participants) can still produce fluent speech 
with speech entrainment. However, it is not known whether SET success depends on the 
degree of speech repetition impairment, or the degree of auditory comprehension deficits.  
Our preliminary data provided the “proof of concept” to justify a phase II clinical trial to achieve 
a detailed assessment of SET effect size and estimate type of linguistic improvements and 
response variability.  
 
Figure 2. Preliminary data - SET delivered once a day, 
5 times a week for three weeks was associated with 
significant gains in spontaneous speech production, 
which were sustained at 3 months after the 
conclusion of SET. The box-plot demonstrates the 
VPM data before and after SET (with the vertical 
histograms on the right side to further illustrate the 
distributions of the data points in the box-plots). 

v.14 
02MAY2024 
 
20
2.2.7 Preliminary study and pilot data for Specific Aim 1  
Our supporting data are based on two studies: the first one (preliminary published 
study, described in more detail below) was published by our group in 2012 in the journal Brain7, 
and the goal of that study was to determine the feasibility of SET as a clinical approach to treat 
non-fluent aphasia. That initial study focused on comparing delivery modes of SET and used 
speech metrics, such as the number of words per minute, and speech fluency ratings from the 
WAB-R. Subsequently, we determined that, while these measures may be adequate to assess 
aspects of discourse, they are possibly not the most sensitive measures of the effects of SET, 
and not the most reliable representations of speech abilities (e.g., a participant may repeat a 
noun several times but not improve communication). For this reason, we conducted a separate 
study (pilot data also described in more detail below), which was directly intended to provide 
preliminary data for this application. This second study used a similar dose of therapy as the 
current trial (3 weeks) and measured its effects on the same primary endpoint proposed here 
(VPM).  
2.2.8 Preliminary published study 
Fridriksson et al. (2012) was a preliminary study by our group, which provided the initial 
proof of principle for the effectiveness of SET. This study detailed: 1) the creation and 
implementation of SET using an A/V feedback system; 2) that SET using an A/V model is better 
than SET using an audio model alone; and 3) the effects of SET on speech production among 13 
subjects with chronic non-fluent aphasia after 6 weeks of daily therapy. During SET, the subject 
used a laptop to view a video of the therapist’s face (below the nose), listened to the audio via 
headphones, and mimicked the speech in real time. The topics were: the weather in the United 
States, how to make scrambled eggs, or describing the Thanksgiving holiday. Each subject 
underwent language testing 1 week before and 1 and 6 weeks after therapy. During SET, the 
subjects’ speech was more fluent than their speech outside of therapy. The subjects who 
underwent SET produced statistically significantly more words during discourse 1 week after 
treatment (p<0.05). They were also nearly better at producing more VPM at 6 weeks after 
treatment (p=0.06), but this effect was limited due to the reduced power from a small sample 
size.  
In Fridriksson et al. (2012), we observed that subjects with aphasia experienced an 
improvement in overall speech fluency associated with SET (standard deviation=1.7%, t= 2.76, 
p=0.009). Speech fluency was assessed by tallying the number of different words and recording 
the percent of correctly produced words per script7. In addition, SET was associated with an 
increase in ratings of information content. 
2.2.9 Telehealth as a mode of service delivery 
 
All visits will be performed via telehealth, with the exception of the optional MRI at 
study completion. The use of telehealth as a successful service delivery mode has been studied 
in the field of Speech Language Pathology for use with post-stroke aphasia73-76. A study by 
Woolf et al. (2016) compared the effects of Aphasia Remote Therapy (ART), In-Clinic Therapy (I-
CT), and attention therapy in a group of individuals with chronic aphasia and found no 
difference between ART and I-CT. A group study (N=44; 37 had aphasia) conducted by Meltzer 
et al. (2018) compared I-CT to a hybrid version of ART with one session a week of clinician 
administered therapy via telerehab, which was heavily supplemented with computerized 

v.14 
02MAY2024 
 
21
homework at least four times a week. This study found hybrid ART to be non-inferior to I-CT. 
The American Speech-Language Hearing Association (ASHA) also has set up guidelines for 
telepractice in Speech-Language Pathology77. 
Because SET is already an audiovisual computer program, telehealth will be compatible 
as a mode of service delivery. Our team has many experienced SLPs specializing in treatment of 
aphasia and, to our advantage, are already trained in the use of telehealth in aphasia research 
due to participation in an ongoing study that utilizes telehealth (C-STAR POLAR). This team 
developed an ART application that has been successfully utilized in POLAR, and this same team 
has developed an application specific for this trial. Technology support staff will provide on-call 
technology support for all sites during the trial. 
 
 
2.2.10 Significance of the knowledge to be gained 
Our pilot data suggest that SET can be a groundbreaking, innovative, and clinically 
feasible approach to treat aphasia. This study will provide a complete and controlled evaluation 
of SET and provide the important triage before costly head-to-head studies with other forms of 
speech therapy. 
 
2.3 Risk/Benefit Assessment 
2.3.1 Known Potential Risks 
For the current research, three areas are of paramount interest with regard to the 
protection of human subjects: 1) Potential adverse effects associated with MRI scanning; 2) 
Potential adverse effects associated with behavioral testing and treatment; and 3) Maintenance 
of participant confidentiality. We will address each of these below on a point-by-point basis. 
2.3.2 MRI Scanning  
All participants have the option to participate in an MRI once they have completed 
treatment. We find that most participants who have reported negative reaction to past MRI 
experiences do not have problems with our MRI setup. The MRI scanners used for this research 
are short-bore magnets (Siemens 3T Trio) with a wider bore than most older generation 
scanners. This allows the participant rather easily to see through either end of the scanner bore 
without shifting head position.  
All participants will undergo thorough screening to check for factors counter-indicative 
for MRI scanning. The optional MRI scanning will not be conducted in participants with 
contradications.  We will follow the same protocol that we have used with past participants. 
First, each person fills out a questionnaire in collaboration with a clinician and, when needed, a 
caregiver. Then, we give each participant ample time to get familiar with the scanner before the 
actual scanning session starts. We find that when taking this extra time to familiarize 
participants and, when appropriate, family members, with the MRI setup, participants usually 
feel comfortable with the MRI session. 
2.3.3 Participant Testing & Treatment 
 In our experience, occasional participants will have a negative reaction to 
neuropsychological testing. For example, this can be caused when participants realize that their 
performance on a given test is far worse than they would have expected. We always make sure 
that ample time is allotted for neuropsychological testing and that participants are allowed 

v.14 
02MAY2024 
 
22
breaks as needed. With regard to the behavioral treatment, the only adverse reaction that we 
occasionally see is fatigue. This is something that we warn participants about ahead of time. 
2.3.4 Participant Confidentiality 
All study investigators participating in the current project must ensure that the 
confidentiality of personal identity and all personal medical information of study participants 
will be maintained at all times. Additionally, the clinical sites are to follow privacy obligations to 
study participants under the Health Insurance Portability and Accountability Act (HIPAA). 
Because the DCU uses a web-based system, source documents will remain at site. The study 
database and any study documents submitted to the DCU will only identify study subjects by 
unique study identification codes. All data will be stored in a manner that is HIPAA compliant, 
without the ability to track the information back to a specific subject except through a 
password protected system (all collected information about a subject will be stored by a unique 
identification code). All DCU personnel have received GCP and Human Subject Protection 
training. All participants will be emailed invitations for telehealth appointments and given 
instructions in advance to join the telehealth session. Any video recordings made during the 
assessments will be saved to the researcher’s local computer and then transferred to a HIPAA-
compliant Box account. The central technology support specialist will have access to participant 
PHI across sites in order to monitor for video quality, manage Box storage, and call into 
participant sessions for technology assistance. 
2.3.5 Known Potential Benefits 
There is no real benefit to participation; however, the information gathered as a result 
of this study may help others with aphasia in the future. It is possible that the participant may 
benefit from SET treatment, but not guaranteed. 
 
3.0 
 Objectives and Endpoints 
 
Objectives 
Endpoint 
Justification 
Primary 
To estimate the dose of SET 
for individuals with non-
fluent aphasia that has the 
highest effect size on VPM. 
Verbs per minute (VPM) at 3 
months post-
treatment/control period. 
*See justification below 
Secondary 
To estimate the dose of SET 
for individuals with non-
fluent aphasia that has the 
highest effect size on SAQOL-
39g. 
SAQOL-39g at 3 months post-
treatment/control period 
To assess if improvements in 
fluency from SET are related 
to gains in quality of life. 
Safety and Tolerability 
To assess the tolerability and 
safety of SET 
Number of treatment 
sessions completed 
 
Adequate tolerability would 
be completion of at least 80% 
of the treatment sessions.  
 

v.14 
02MAY2024 
 
23
Adverse Events 
possibly/probably/definitely 
related to study treatment 
and Serious Adverse Events 
Although this study 
intervention is low-risk, there 
is the potential for risk in any 
clinical trial.  
Exploratory 
To estimate the dose of SET 
for individuals with non-
fluent aphasia that has the 
highest effect size on the 
WAB-R, CETI, and ASRS 3.0. 
Scores at 3 months post-
treatment/control period. 
To assess if improvements in 
fluency from SET are related 
to gains in other speech 
and/or quality of life 
measures. 
To estimate the effect of SET 
on VPM, WAB-R, SAQOL-39g 
at early and late time points. 
1-week post and 6 months 
post 
The primary time point of 
interest is the 3 months post, 
but the 1 week and 6 month 
post assessments will be 
explored to assess whether 
benefits are sustained over 
time 
 
*The primary endpoint for this trial is VPM at three months post-conclusion of SET or 
control. VPM is a measurable representation of spontaneous speech production. This primary 
endpoint was chosen for the following reasons:  
1) Spontaneous speech is an important “real-life” aspect of language. It has a direct effect on 
conversation and social aspects of language, and directly informs on practical and meaningful 
elements of communication.   
2) The use of verbs during spontaneous speech provides a reliable measure of language abilities 
and effectiveness of communication8.  
3) It is not surprising that many individuals with aphasia can achieve improved fluency during 
the SET session. However, for SET to have a clinical impact, it should lead to sustained benefits 
that remain after the therapy. Benefits that can last at least 3 months after therapy are highly 
important.  
4) Our preliminary data support that improvement in VPM is a feasible and achievable 
outcome. 
 
4.0 
Study Design 
 
4.1 Overall Design 
Approach: We propose a prospective, controlled, randomized, assessor-blinded, phase II 
clinical trial (n=80) entitled Speech entrainment for Aphasia Recovery (SpARc). The goals of the 
trial are to evaluate SET in comparison with no SET (control), and to determine SET’s best dose 
(duration of treatment in weeks). SET and assessments will be delivered via telehealth. We will 
enroll 80 participants and randomly assign them 1:1:1:1 to one of the 4 groups (A, B, C, D): 

v.14 
02MAY2024 
 
24
A - SET for 3 weeks (15 days, 1 hour daily, 5 x week)   
B - SET for 4.5 weeks (22 days, 1 hour daily, 5 x week)  
C - SET for 6 weeks (30 days, 1 hour daily, 5 x week) 
D - No SET for 6 weeks (control condition) 
4.1.1 Timing of Behavioral Assessments 
 The timing of behavioral assessments after the SET doses, or the control condition (no 
SET) will exactly mirror each other, so data can be directly compared, and also to permit 
blinding of the behavioral assessors. The participants will have behavioral assessments at 
baseline, 1-week post, 3-months post, and 6-months post.   
The research staff and the participants will obviously not be blinded to the groups, but 
the persons doing the scoring of the behavioral outcome measures will be. A scorer will be 
centrally located at UofSC and will not have contact with the research staff (who will perform 
the assessments and treatments) and the participants. Another scorer will be located at UoU 
and will perform scoring of the ASRS 3.0 only. The UoU scorer will not have contact with 
participants and will also be blinded to treatment arms and assessment time points. All scoring 
will be performed on videorecorded behavioral assessments stored on Box. By having the same 
number of follow-up visits, the scorer will not be able to discern the group in which the 
participant was included. We used this setup successfully in a recently completed randomized 
controlled trial35. 
4.1.2 Neuroimaging  
We will obtain a release of medical records from all participants and we will review the 
peri-stroke clinical neuroimaging to confirm that the aphasia was caused by a left hemisphere 
stroke. We will review brain MRI and/or head CT imaging depending on what modality was 
used during the stroke clinical care. We will use this information to exclude individuals with 
previous stroke outside the left hemisphere, and we will only include individuals whose aphasia 
was associated with a stroke diagnosed with neuroimaging. 
For neuroimaging fidelity, the PI will oversee review of participant peri-stroke clinical 
neuroimaging every six months by trained research staff to ensure that MRI/CT images: (1) are 
uploaded to the site-specific neuroimaging folder in Box, (2) are converted to Nifti files, (3) are 
anonymized, (4) are T1-weighted (if MRI scans), and (5) show a left hemisphere stroke (without 
evidence of right hemisphere stroke).      
The participants will be offered to take part in an optional research MRI at follow-up 
visit 2 or 3. The purpose of the research MRI is to study the brain anatomy in more detail, 
including the necrotic and gliotic cavity related to the previous stroke. 
 
4.2 Scientific Rationale for Study Design 
4.2.1 SET vs Control 
 For SET to be clinically useful, it has to be effective in comparison with a control, no SET 
condition. The goal of this study is to compare SET with a control condition, in which the 
individual with aphasia receives baseline and follow-up assessments at the same time-points as 
group C, however, does not receive therapy for 6 weeks.  
Since most individuals with aphasia do not receive continuous speech therapy in the 
chronic post-stroke stages, it is anticipated most of the control group will not receive treatment 

v.14 
02MAY2024 
 
25
as part of their current standard of care for chronic aphasia. The lack of continuous speech 
therapy in the chronic stages is, of course, different than in the acute and subacute stages, 
when continuous speech therapy is often employed. This trial will only assess individuals in the 
chronic stages. The control condition will provide an important benchmark against variability in 
speech production across time.  
 
4.3 Justification for Dose 
4.3.1 Treatment Groups 
              In a pilot study, we performed a subsequent and independent assessment of SET to 
directly mirror the approach proposed in this trial, with a similar endpoint, but uncontrolled 
and with a single group. Using assessors who were blinded to time of speech assessment (using 
videorecorded sessions), we examined 15 individuals with chronic non-fluent aphasia who were 
tested before and after 3 weeks of daily SET sessions. Similar to our published study described 
above, all participants were able to produce more fluent speech during SET therapy sessions. 
More importantly, there were considerable gains in spontaneous speech production that were 
sustained 3 months after SET.  
These data, shown in Figure 2, are the main preliminary evidence supporting this study. 
We observed an increase from an average ( SD) of 5.0 ( 3.9) VPM prior to therapy to 6.1 ( 
4.8) VPM at 3 months after the conclusion of SET. The average relative improvement was 22% 
(average post-pre difference of 1.11 SD = 1.98), with a standardized effect size (mean 
difference/SD of difference) of  0.56. This difference was statistically significant (paired t = 2.17, 
p = 0.047).  
4.3.2 Control Group 
The control group will be assessed before and after a six week no-SET condition. During 
the six weeks there will be weekly contact via phone for assessing AEs and concomitant aphasia 
therapy. This study will include individuals with chronic aphasia. In the chronic stage, large-scale 
spontaneous language recovery is not typically observed. External treatment for chronic 
aphasia is not prohibited in this trial. As discussed, there currently is not a standard of care for 
chronic aphasia. It is anticipated most participants will receive no treatment, some may 
participate in aphasia community groups, and a very few may receive individualized therapy. 
Therefore, the expected change in language functioning during the no-SET condition is 
expected to be very minimal, if any. Concomitant aphasia therapy will be captured (see Table 
5). 
The behavioral assessments in the control group will occur at the end of the 6-week no 
SET period. We will not perform behavioral assessments throughout the no-SET period. For 
example, in the SET for 3 weeks group, the first post-treatment behavioral assessment will be 
performed at 1 week after treatment conclusion (4 weeks after initiation of the SET). In the 
control group, there will not be a behavioral assessment in the middle of the no SET period at 4 
weeks (or at other times corresponding to the other groups) because multiple repeated 
assessments may lead to a training effect. They would also interfere with the blinded 
assessments. Since we do not anticipate any meaningful improvement in the control group, the 
treatment assessments at 1 week, 3 months, and 6 months after the no-SET condition will be 
considered equivalent to the post-SET assessments at the corresponding post SET times for 

v.14 
02MAY2024 
 
26
each SET dose. Using the longest possible control duration of 6 weeks ensures adequate 
sensitivity to any unanticipated improvement during that period. Having multiple control 
durations to match the SET durations is, therefore, unnecessary and would lead to a 
prohibitively and impractical sample sizes. 
 
4.4 End of Study Definition 
The randomization target for this study is 80 participants. This trial will be implemented 
in three aphasia clinical research laboratories across the United States: 1- MUSC, 2- UofSC, and 
3- UoU. Each site will enroll approximately 25-30 subjects over 4 years. 
 
5.0 
Study Population 
We will only include participants with chronic aphasia (>6 months post-stroke) as a 
result of an ischemic or hemorrhagic left hemisphere stroke. Clinical imaging (CT/MRI) will be 
used to verify the presence of a left hemisphere stroke and to exclude those with bilateral, 
brain stem or cerebellar strokes, or other structural neurological conditions (such as brain 
tumors or arteriovenous malformations). We will not exclude subjects with previous other left 
hemisphere strokes, but we will exclude subjects with clinical and radiological evidence of right 
hemisphere or brain stem or cerebellar strokes with persistent deficits. Subjects will not be 
excluded if they have received previous aphasia rehabilitation, either in the clinical or academic 
setting. 
 
5.1 Inclusion Criteria 
• Aphasia as a result of a left hemisphere ischemic or hemorrhagic 
stroke (WAB-R Aphasia Quotient <93.8). 
• Presence of left hemisphere stroke in clinical imaging (CT/MRI) 
and NIHSS 
• Participants must have spoken English as their primary language. 
• 21-81 years old 
• Pre-stroke modified Rankin Scale (mRS)= 2 or less 
• Post-stroke mRS= 4 or less. 
• At least 6 months post-stroke. 
• Non-fluent aphasia (WAB-R Comprehension score >4 and WAB-R 
Fluency score <6). 
• Technological compatibility (to be determined by clinical 
judgment of SLP) 
5.2 Exclusion Criteria 
• History of chronic neurological or psychiatric diseases (excluding 
migraines, depression, or post-stroke epilepsy).  
• Self-reported history of learning disability.  
• Severe dysarthria (determined via SLP clinical judgment from 
spontaneous speech tasks on the ASRS 3.0). 
• Global aphasia. 

v.14 
02MAY2024 
 
27
• History of right-hemisphere strokes or brain stem/cerebellar 
strokes with persistent deficits (as evidenced by MRI/CT and 
NIHSS). 
• Uncorrectable hearing as determined by the SLP’s clinical 
judgment. 
• Uncorrectable vision. 
 
5.3 Screen Failures 
 
Once a participant has consented, they will be screened for eligibility. This includes 
reviewing the criteria noted in sections 5.1 and 5.2. The team will review imaging (CT/MRI) 
obtained from the participant’s medical records to verify presence of left hemisphere stroke 
and absence of strokes involving the right hemisphere, cerebellum, and brainstem that have 
persistent deficits. The NIHSS will be administered by a trained clinician (e.g., SLP, neurologist) 
to assess for any persistent neurological deficits. The NIHSS will be used for research purposes 
only. The WAB-R will also be given to determine if eligible based on the Aphasia Quotient and 
aphasia classification as non-fluent. If the consenting participant fails either of these tests, it 
will be considered a screen failure and the participant will not be allowed to continue with the 
remainder of the trial. 
 
All screen failures will be documented in WebDCU, and a hard copy of the Screen Failure 
form will be stored in a Screen Failure folder, per IRB regulations. Re-screening of participants is 
not applicable. 
 
5.4 Strategies for Recruitment and Retention 
All three participating sites have active aphasia research programs and large 
recruitment pools for aphasic participants. We will utilize our established participant pool that 
has agreed to future contact for participation in studies to recruit for this study. These 
individuals will be contacted by telephone, email, or mail depending on their communication 
preference. The use of telehealth will likely facilitate strong participant retention rates due to 
the convenience of in-home therapy. 
5.4.1 Advertising 
 
Recruitment will also be performed through local advertisement. We will adopt a 
strategy that is similar to what was used previously in our large treatment studies where 
advertisement to rehabilitation centers and clinics has yielded sufficient recruitment.  An 
approved study flyer will be distributed to local clinics, hospitals and rehabilitation centers.  
Furthermore, we will also advertise to participants who have enrolled in previous aphasia 
clinical trials at all three sites. If our yield is low, we will update our recruitment plan to use 
local and state newspaper advertisements as needed. We also plan to advertise studies through 
statewide directories and site-specific lab websites in addition to university and/or site-specific 
lab social media accounts, per the IRB of records policies.   
5.4.2 Contacting Participants  
During the recruitment and initial scheduling period, participants and/or their 
caregiver/family (as applicable), may be contacted via telephone, email correspondence, or 
traditional mailing service (whichever is preferred by the participant). Upon establishing 

v.14 
02MAY2024 
 
28
preferred communication preferences, follow-up appointments, changes in schedule, or 
other pertinent study related information will be relayed in the same manner, as expressed 
by the participant.  
 
6.0 
Study Intervention 
 
6.1 Study Intervention Administration  
The administration of SET is relatively simple: Subjects practice imitating in real-time 1-
minute scripts that consist of prerecorded videos (A/V speech model). Each video is presented 
through the SET treatment app made in house that is preloaded on the computer in the 
teletherapy kit. We will ask the participant or assistant to place the computer (with a high-
speed video card) at a comfortable distance in front of the subject, showing a speaker whose 
face is visible below the nose. Subjects are fitted with headphones to minimize distractions and 
to better focus on the auditory speech. The A/V speech model involves a relatively slow speech 
rate and a high-speed video frame rate and the subject is asked to mimic the speech as closely 
as possible. Subjects usually mimic the speech almost in real-time while seeing and hearing the 
A/V model. A trained research staff member is present during each session to provide guidance 
according to pre-established guidelines and to ensure treatment compliance. At the beginning 
of the first 2-3 treatment sessions, the research staff member models the manner in which the 
participant should imitate the A/V speech model. The subject instructions are as follows: “Your 
goal is to speak along with the video and try to match the timing of your speech as closely as 
possible to the video. If you miss words or fall behind, try to catch up with the video and 
continue speaking.”  
Once subjects understand the approach (as per the judgment of research staff trained 
by an SLP), the SET session is started. When treatment begins, the participant observes/listens 
as the videorecorded script is presented in its entirety without mimicking. On successive 
presentations, the participant mimics the script in real-time. Once a given script (video) has 
been mimicked three times, a new script is presented and then practiced three times, and so 
on. Practicing each script three times is based on our experience suggesting that subjects 
improve considerably from the first to the third practice of a given script. A total of 39 scripts 
addressing various topics will be constructed. During the treatment session, a new script video 
is selected at random. In-house computer software is used to accomplish stimulus presentation, 
start and stop the treatment session, and keep track of treatment data (e.g., the average 
number of scripts trained per session and how many times a given script was trained during the 
course of treatment).  
6.1.1 No SET condition 
During the no SET condition, the participant will not receive any specific form of therapy 
from the study. The purpose of the no SET condition is to assess whether SET provides a 
therapeutic benefit over the participants’ current standard of care.  
6.1.2 Treatment and assessment setting 
Once consent has been obtained and the local research team has established a study 
schedule for the participant, we will begin baseline testing and subsequent treatment. All 
baseline cognitive-linguistic testing will be performed via telehealth, and treatment will be 

v.14 
02MAY2024 
 
29
performed through the SET treatment app. We will request that a family member or friend be 
present during assessment and treatment sessions to assist with technology as needed. 
Headphones will be used to ensure high quality auditory stimuli. Breaks will be given as needed 
for those participants in testing or treatment as to not cause fatigue or stress in a new 
environment.   
The optional MRI (at either 3- or 6-months post-intervention) will be performed at the 
local site’s imaging center. Each participant will be provided ample time and orientation from 
the staff in order to feel comfortable with the scanner and time spent in the scanner.   
6.1.3 Dosing and Administration 
 
Treatment dose is dependent on particular group randomization (3 weeks, 4.5 weeks, 6 
weeks, no SET). 
 
6.2 Measures to Minimize Bias: Randomization and Blinding Instructions 
6.2.1 Randomization 
Once the participant is consented and enrolled in the study, his/her information is 
entered in the online clinical trial management system – Web Data Coordination Unit 
(WebDCUTM). Once the baseline data have been entered in WebDCU, the participant will be 
randomized to one of 3 SET groups (differing dose) or the control group (Figure 1). 
A “Real-Time” randomization procedure will be implemented via the trial website on the 
WebDCUTM system (located at MUSC). Using the WebDCUTM, the local site’s study staff will 
enter baseline and eligibility information for each subject prior to enrollment. If a subject’s 
eligibility status is confirmed, WebDCUTM will make the treatment assignment based on the 
current status of treatment group distribution at each site, age group (<70, >70 years), and 
aphasia severity (mild/moderate: AQ > 50, severe/very severe: AQ ≤ 50), as well as the overall 
balance of treatment assignments. Once a subject is randomized, the SLP or trained research 
staff will be made aware of the randomization assignment. The SLP or research staff will 
videorecord all behavioral assessments, and the recordings will be uploaded to Box at the 
conclusion of the treatment for centralized scoring.    
6.2.2 Blinded assessor 
We will employ centralized, blinded outcome assessors, who are comprehensively 
trained SLP graduate students located at UofSC, to score the videorecorded primary outcome 
measure (VPM) for all study subjects. Twenty percent of the assessments, including baseline 
testing and outcome measures, will be scored by a second, independent SLP graduate student 
assessor to establish inter-rater reliability. In addition, each SLP graduate student assessor will 
rescore at least 20% of all assessments, for which they were the original primary scorer, to 
establish intra-rater reliability. Our team has ample experience with aphasia assessments and 
every measure will be taken to maximize reliability of outcome testing. The primary and 
secondary coding SLP graduate student assessors will be blinded to the treatment arm. They 
will also be blinded to when the behavioral measures were obtained (i.e., there will be no time 
stamps on the assessments, and the assessor will not know if the sample was obtained before 
SET or no SET, or at which time point after SET or no SET they were obtained). 
 

v.14 
02MAY2024 
 
30
6.3 Study Intervention Compliance 
6.3.1 Subject enrollment, subject assessment, and data entry fidelity 
Across all project sites, we will standardize the training of SLPs and trained research 
staff who administer the cognitive-linguistic and outcome testing, beginning with the 
development of an assessment manual. We will monitor adherence to assessment 
administration procedures throughout the 5-year project period. Transcription and scoring of 
the video and discourse measures will be accomplished in the lab at UofSC, with the exception 
of transcription and scoring of the ASRS 3.0, which will be completed by an expert scorer at 
UoU. All discourse assessment sessions will be videorecorded and coded with a unique 
identifier and uploaded to Box. Scores from videos will be recorded on Case Report Forms 
(CRFs) maintained in WebDCUTM. To maintain reliability, at least 20% of all videorecorded 
discourse sessions will be re-scored by an SLP. 
6.3.2 Participant treatment fidelity 
Standardized clinician and research staff training relying upon a detailed manual of 
treatment procedures will be implemented.  Similar to the assessment manual, the purpose of 
explaining the project and emphasizing the importance of treatment activities is to promote 
clinician buy-in and subsequent adherence to procedures. The administration of SET is probably 
no more complex than that of aphasia treatment approaches practiced in everyday clinical 
practice; it is simply operationalized so that procedures will be standardized across subjects and 
sites. 
6.3.3 Testing and treatment fidelity 
It is imperative that we guard against the following threats at each site: variability in 
clinician and research staff qualifications, drift (gradual change in study procedures over time), 
contamination (systematic or variable influence of outside factors not controlled for in the 
study design), and clinician/research staff turnover. A Program/SLP Manager from MUSC will 
oversee testing and treatment fidelity procedures across all sites. 
Ratings of testing/assessment video recordings will be conducted by a Program/SLP 
Manager or another experienced SLP at MUSC. The rater will observe assessment and 
treatment video recordings for SLPs across each study site, document fidelity adherence via the 
SpARc SLP Assessment and Treatment Fidelity Observation Forms, and provide written 
feedback to clinicians to ensure fidelity of assessment and treatment administration across 
sites. If necessary, additional training and support will be provided to clinicians by the 
Program/SLP Manager or another experienced SLP at MUSC. 
 
 
7.0 
Study Intervention Discontinuation and Participant Discontinuation or 
Withdrawal 
 
7.1 Discontinuation of Study Intervention 
 
The Principal Investigator (PI) at each site has the authority to discontinue a person’s 
participation in the trial at any time if in the participant’s best interest; however, the failure to 
adhere to the study protocol should not be considered a reason for withdrawing a participant 
from the study. All participants randomized will be included in the analysis, and participants 

v.14 
02MAY2024 
 
31
who withdraw from the study will not be replaced. Participants who wish to discontinue the 
study intervention or who do not return for follow-up visits should be contacted about 
participating in follow-up visit(s), so that at a minimum the primary outcome can be collected. 
 
7.2 Participant Discontinuation/Withdrawal from Study: Instructions 
• During initial consent, it will be made clear that protocol adherence is of utmost 
importance to participation in the trial. This is clearly stated in the consent document. 
• During the trial, if the participant is not adhering to protocol (e.g., excessive tardiness 
and cancellations), this will be discussed with the participant and caregiver. 
• If the participant still does not comply, the PI will be notified. 
• The PI has the final decision to discontinue participation due to safety reasons. 
The participant can decide to withdraw at any time. If the participant withdraws from the study 
voluntarily: 
• The PI will be notified. 
• Withdrawal status will be appropriately documented, per IRB regulations 
• If they chose not to withdraw and still have missed appointments, we will continue the 
intervention until the planned duration while recording the number of missed 
appointments. We will utilize the number of missed appointments for statistical 
analysis. Refer to section 9.4.4. 
 
7.3 Lost to Follow-up 
 
A large number of our participants have already participated in previous aphasia studies 
and know that new studies will likely be available to them in the future; therefore, we typically 
get a small group of people that are lost to follow-up. All sites are also active in the local 
community, hosting events and support groups to advocate for those with aphasia. This is also 
beneficial and reduces the number of those lost to follow-up. 
 
8.0 
Study Assessments and Procedures 
 
8.1 Efficacy Assessments 
8.1.1 Baseline measures 
The WAB-R will be obtained at participant screening to determine if the participant fits 
criteria for non-fluent aphasia (WAB-R Comprehension score > 4 and WAB-R Fluency score < 6). 
See Table 6 for aphasia classification chart. If the participant does not classify as having non-
fluent aphasia, this is considered a screen failure. The participant will undergo an MRI to 
determine stroke eligibility criteria, unless MRI images from the stroke are made available to 
the study team for review. The ASRS 3.0, PPTT, and WAIS-III will be obtained for the purpose of 
linguistic assessments and participant description in publications. The ASRS 3.0 measures the 
presence and severity of AOS57; the PPTT assesses amodal semantic processing of nouns58; and 
the WAIS-III measures non-verbal abstract problem solving and inductive and spatial 
reasoning59. The SAQOL-39g will be given to assess quality of life for each individual with 
aphasia. All baseline language assessments will be videorecorded for offline scoring. Recording 
will include the participant from head to torso, and all recordings will be stored on Box. 

v.14 
02MAY2024 
 
32
Speech repetition and comprehension: We will employ detailed measures of speech 
repetition and comprehension to refine the identification of subtypes of aphasia and improve 
the evaluation of the influence of these variables on the effectiveness of SET. As part of the 
WAB-R, participants will complete the repetition subtest involving single words, phrases, as well 
as shorter and longer sentences. In addition, all participants will be administered the PRT, 
involving real words. For detailed assessment of auditory comprehension, we will rely on 
subtests from the WAB-R. 
The mechanisms of action of SET will be determined from the comprehensive behavioral 
assessment as described in Table 1 above. More specifically, we will define whether fluency 
improvements with SET are supported by repetition, speech comprehension, or residual 
fluency, based on the multi-faceted speech and cognitive evaluations. 
8.1.2 Primary outcome – VPM 
All recorded discourse measures will be stored on Box and scored centrally in the lab at 
UofSC using automated coding analysis systems available through AphasiaBank. We have 
already used this setup to assess outcome in our original study of speech entrainment7. 
AphasiaBank includes computerized tools to accomplish discourse transcription and analyses, 
such as Codes for the Human Analysis of Transcripts (CHAT) and Computerized Language 
Analysis (CLAN)64.  
Speech samples for VPM scoring will be assessed through procedural storytelling and 
narrative – with four items in each category. The procedural storytelling items are: 1) how to 
make a peanut butter and jelly sandwich, 2) how to make scrambled eggs, 3) how to brew 
coffee, and 4) how to wash dishes. The subject will be recorded while describing each 
procedure. A two-minute time limit will be imposed for each item. The four topics will be 
randomized with only one topic being presented each time VPM is being assessed without topic 
repetition. Randomization of topics will be performed in WebDCUTM. 
The narrative items will be: 1) Cinderella story, 2) Little Red Riding Hood, 3) The Three 
Little Pigs, and 4) Goldilocks. The participant will be provided with a picture book without text 
to guide and serve as a reminder of the story, and the participant will be asked to recount the 
passages of the story as depicted in the book. Similarly, one narrative will be presented at each 
VPM assessment, and they will be randomized for each participant in WebDCUTM.  
By combining procedural storytelling and narratives ranging from different topics, a 
broad sample of discourse abilities will be obtained. They will be scored using automated 
coding analysis (CLAN) systems available through AphasiaBank. Words Per Minute (WPM) is 
included in AphasiaBank and our data will be compared against the data from >440 aphasic 
subjects already included in AphasiaBank. This feature is especially important for determining 
variance across participants. The outcome assessor will be blinded to group assignment and to 
when the sample was acquired (at baseline or after each treatment interval).   
 
8.2 Adverse Events and Serious Adverse Events 
 
* Refer to MUSC IRB Human Research Protection Program (HRPP) Guide, Unanticipated 
Problems and Adverse Events Policy and Procedures, section 4.7 found at 
https://research.musc.edu/resources/ori/irb/forms. 

v.14 
02MAY2024 
 
33
8.2.1 Definition of Adverse Event 
 
An AE or adverse experience is any untoward or unfavorable medical occurrence in a 
human subject, including any abnormal sign (e.g., abnormal physical exam or laboratory 
finding), symptom, or disease, temporally associated with the subject’s participation in the 
research, whether or not considered related to the subject’s participation in the research. AEs 
encompass both physical and psychological harms and occur most frequently in the context of 
biomedical research, although they can occur in the context of social and behavioral research. 
 
An internal AE is an SE experienced by subjects enrolled by the investigator(s) at MUSC 
or at a site for which MUSC has oversight. 
 
An external AE is an AE experienced by subjects enrolled by investigators at other 
institutions engaged in a multi-site clinical trial. 
8.2.2 Definition of Serious Adverse Events 
 
A serious adverse event (SAE) is any AE temporally associated with the subject’s 
participation in research that meets any of the following criteria: 
• Results in death 
• Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred) 
• Requires participant hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
• Any other AE that, based upon appropriate medical judgment, that may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the 
other outcomes listed in this definition (examples of such events include allergic 
bronchospasm requiring intensive treatment in the emergency room or at home, blood 
dyscrasias or convulsions that do not result in participant hospitalization, or the 
development of drug dependency or drug abuse). 
8.2.3 Adverse Event and Serious Adverse Event Reporting 
 
AEs will be documented in the participant’s chart. An AE will only be reported if it is 
related to the intervention. The relation to intervention will be determined by the site PI.   
 
SAEs will be documented in the participant’s chart AND reported. 
8.2.4 Time Period and Frequency for Event Assessment and Follow Up 
 
AEs will be followed up until stabilized or resolution from study entry through end of 
study. 
 
9.0 
Statistical Considerations  
 
9.1 Statistical Hypotheses 
• Primary Endpoint:  
VPM at 3 months post treatment 
 
We hypothesize that, compared to participants who receive control, participants who receive 
SET for 3, 4.5, or 6 weeks for aphasia will have improved VPM at 3 months and that there is 
an optimal duration of SET therapy. However, this study was not designed to formally test 

v.14 
02MAY2024 
 
34
SET versus control. This study represents the first step in a series of studies which will 
ultimately test this hypothesis; however, for this study no formal hypothesis tests are 
planned. The primary analyses will be descriptive statistics of VPM at 3 months and will 
estimate the effect size of each SET duration and the pooled SET durations versus control 
adjusting for baseline. 
 
9.2 Sample Size Determination 
9.2.1 Sample Size Considerations for Comparison with Control group 
This study is not powered to detect statistically significant differences between the 
chosen SET dose and the control group. The sample size was determined by administrative 
reasons. This will be the focus of a later and dedicated comparison study once the best dose 
has been defined.  
9.2.2 Sample Size Considerations for Effect Size of SET versus Control group 
For each treatment group versus control, we will estimate the standardized mean 
difference (effect size). The criterion needed to accept any duration is that the effect size is at 
least 0.36 (a “small” effect size). The rationale for this criterion is that if the pooled standard 
deviation estimate is large, because of the small sample size, then the effect size may be 
smaller than expected. We consider a 20% improvement from control to be the the minimum 
clinically important difference (MCID). This corresponds to an increase of 1 VPM based on our 
pilot data (20% of 5 VPM). Given the MCID and the common SD of change in the VPM estimate 
from pilot data (SD=2), the expected effect size is 0.5. However, with n=20 per group, the 
observed SD may be as large as 2.74 based on the one-sided upper 95% confidence interval for 
the common SD; thus, the observed effect size may be only 0.36. 
 
9.3 Populations for Analyses 
The primary analysis will be intent-to-treat (ITT). Under this principle, the evaluable 
sample will include all participants who are randomized.  
 
9.4 Statistical Analyses 
9.4.1 General Approach 
In general, descriptive statistics will be presented by treatment group. Dichotomous 
variables will be summarized as number (%). Percentages will be calculated based on the number 
of participants with available data for that variable. Continuous variables will be summarized by 
the mean and standard deviation (SD). Ordinal data will be presented as median (IQR).  
9.4.2 Analysis of the Primary Endpoint 
The primary outcome is VPM, which is a continuous value greater than 0. It is collected at 
baseline, 1 week, 3, and 6 months post treatment period. The primary analysis will calculate the 
change from baseline. The statistical model will be a repeated measures model (SAS® MIXED 
procedure with REPEATED subcommand). The model will include the following fixed effects: 
categorical visit (1 week, 3, and 6 months post treatment period) by treatment group (class 
variable) interaction, site, baseline aphasia severity score, baseline VPM and age. The estimated 
difference (95% confidence intervals) in change between each SET duration group  and control 

v.14 
02MAY2024 
 
35
group will be reported as the primary analysis. The standardized mean difference for each SET 
duration versus control will also be reported and will be used to select the best dose of SET. Since 
this study is not powered for direct comparison with control, no p-values will be reported. 
Estimates of the change at 1-week and 6 months obtained from this model are exploratory 
analyses. Additionally, as an exploratory analysis, the combined SET duration versus control 
comparison will be tested at a two-sided alpha of 0.05. 
9.4.3 Missing Data 
The primary analysis will be ITT. All participants randomized will be included in the 
primary analysis regardless of whether or not they dropped out or discontinued treatment. For 
the primary analysis, a repeated measures linear mixed model will be fit; this is considered an 
implicit imputation approach if at least 1 post-baseline assessment is available. However, if 
baseline is the only assessment available (or if baseline is missing but follow-up available), then 
a nearest neighbor approach will be used to impute the missing values. 
9.4.4 Pre-specified rule to select best SET duration 
1- Highest standardized mean difference (effect size) in VPM from baseline to three months 
post treatment; 
2- Adequate tolerability: group average participation in at least 80% of the treatment sessions;    
We will select the duration associated with the highest group average VPM at 3 months post 
treatment, but also had adequate tolerability. 
9.4.5 Analysis of the Secondary Endpoint(s) 
• Secondary Endpoints:  
o Quality of life assessment - SAQOL-39g 
o Individual components of the primary outcome:  
▪ VPM on Narrative Story Telling Task 
▪ VPM on Procedural Story Telling Task 
 
 
The SAQOL-39g will be analyzed similarly to the primary endpoint. The same approach will 
be used to define the analysis sample and handling of missing data. The mean change from 
baseline of each SET group will be compared to control with 95% confidence intervals. Since this 
study is not powered for direct comparison with control, no p-values will be reported.  
9.4.6 Safety Analyses 
 
Monitoring Plan for Worsening in the Primary Outcome: If SET leads to substantially 
worse outcome than the no SET arm, early stopping may be considered. The unblinded 
statistician will fit the primary analysis model semi-annually in order to compare VPM between 
the combined SET durations versus No SET (one-sided α=0.025). As part of this analysis, outliers 
will be explored to ensure that the results are not driven by a specific individual. Should the null 
hypothesis be rejected, an investigation of dose response among the SET arms based on 
qualitative evaluation (i.e. not statistical) when ordered in terms of dose level will occur. Should 
a dose response relationship be detected, the unblinded statistician will bring this to the 
attention of the DSMB and investigators. 
 

v.14 
02MAY2024 
 
36
All AEs and SAEs are summarized by preferred term according to the Medical Dictionary 
for Regulatory Activities (MedDRA) adverse reaction dictionary in terms of frequency of the 
event, number of subjects having the event. For the Closed DSMB report, severity, and 
relatedness to the treatment will also be shown by treatment group.  
 
At the end of the trial, the cumulative incidences of the specific SAEs related to 
treatment, as well as all SAEs, will be compared across groups. 
9.4.7 Baseline Descriptive Statistics 
Summary statistics of baseline variables (e.g., demographics, time from stroke onset, 
aphasia type, WAB-R AQ, all baseline assessments) will be compared by treatment groups. 
Dichotomous variables will be summarized as number (%). Percentages will be calculated based 
on the number of participants with available data for that variable. Continuous variables will be 
summarized by the mean and standard deviation (SD). Ordinal data will be presented as median 
(IQR).  
9.4.8 Sub-Group Analyses 
Gender, Race, Ethnicity: All eligible subjects of both sexes and all races and ethnic 
groups will be approached to participate in the trial. Recruitment and retention of women and 
minorities will be monitored throughout the trial. Although we do not anticipate differential 
treatment effects based on sex, race, or ethnicity, our analyses will explore clinically important 
differences in these subgroups. Randomization should ensure that the allocation to treatment 
groups is unbiased and balanced between males and females and different racial and ethnic 
groups. At the end of the trial, the primary analysis will be repeated within sex subgroups and 
within race/ethnicity groups. If differences in the magnitude of the treatment effect are 
observed within a sex, race, or ethnicity subgroup, they will be reported to the scientific 
community.  
9.4.9 Tabulation of Individual Participant Data 
Individual participant data will not be listed by measure and time point in the final 
analysis; however, individual participant listings may be included in Data and Safety Monitoring 
Board (DSMB) reports for purposes of monitoring trial quality. 
9.4.10 Exploratory Analyses 
Exploratory Endpoints: 
Communicative Effectiveness Index (CETI) 
Apraxia of Speech Rating Scale (ASRS 3.0) 
WAB-R 
For the exploratory endpoints, the mean change from baseline to 1 week and 3 months 
post of each SET group will be compared to control with 95% confidence intervals.  
9.4.11 Scoring of speech samples and evaluation of potential confounders 
As described above, all baseline and treatment videorecorded discourse samples will be 
scored centrally at the Aphasia Lab at UofSC using AphasiaBank, with the exception of 
transcription and scoring of the ASRS 3.0, which will be completed by an expert scorer at UoU. 
Special care will be taken to evaluate the influence of potential confounders, such as AOS (rated 

v.14 
02MAY2024 
 
37
on the ASRS), speech repetition scores (WAB-R, PRT), single word (WAB-R), and sentence level 
comprehension65. These will be input into the multiple linear regression analyses used to define 
determinants of the primary outcome as a sensitivity analysis. Since SET has not been 
systematically studied as a potential clinical treatment, the goal of this project is to determine if 
SET is associated with a robust effect size regardless of the underlying source of impairment, 
but it is very likely that cognitive and linguistic factors that vary across persons with non-fluent 
aphasia may influence SET outcome to different degrees. We will assess these variations and 
the overall benefit of SET by systematically assessing the effect size of SET and examining 
individual characteristics that relate to treatment response. 
 
10.0 Regulatory, Ethical, and Study Operational Considerations 
 
10.1 Informed Consent Process 
 
The consent documentation contains all required regulatory elements and has been 
approved by the central IRB. The consent also contains HIPAA authorization to use and disclose 
(release) medical information. 
 
10.2 Consent Procedures and Documentation 
Informed consent can be obtained in written fashion by one of the members of the 
study team. Participants will be provided with ample time to review the consent document 
prior to discussion with a member of the study team. The nature of the study will be explained 
by a member of the study team in lay terms. If the potential participant agrees to participate in 
the study, they will sign and date the informed consent and HIPAA forms (or combined 
consent/HIPAA if applicable). They will also be informed that they may choose to withdraw 
from the study at any time. Participants will be informed that their decision regarding 
participation will not affect their clinical care in any way. A copy of the signed informed consent 
and HIPAA will be provided to participants. 
Alternatively, electronic consent (eConsent) will be obtained through the REDCap 
system. A member of the research team will reach out to the participant by phone to provide 
details of the study. If the participant agrees to participate, a link to the REDCap eConsent will 
be provided to the participant via a hyperlink (text or email), and a member of the study team 
will review the consent document over the phone or via videoconferencing with the 
participant. The participant will electronically sign the eConsent and submit the REDCap survey. 
The study team member will then electronically sign the eConsent and print a PDF of the 
document. The signed PDF willl be emailed or mailed to participants for their records. eConsent 
will be implemented at sites that support this method of consent. 
 
10.3 Study Discontinuation and Closure 
 
If the study is prematurely terminated or temporarily suspended, the PI will promptly 
inform study participants, the IRB, and sponsor and provide the reason(s) for the termination or 
temporary suspension. When a study is prematurely terminated, refer to Section 7, Study 
Intervention Discontinuation and Participant Discontinuation/Withdrawal, for handling of 
enrolled study participants. 

v.14 
02MAY2024 
 
38
 
10.4 Confidentiality and Privacy 
Each participant will be given an identification number through the WebDCUTM and all 
baseline and outcome measure data will be linked to this number without any identifying 
information of the participant. Each participant will have a binder that will contain demographic 
and baseline characteristics (refer to Table 3). The person obtaining this information will have 
gone through CITI research ethics training and been approved by the IRB. All binders with 
identifying information will be stored in a locked location at the site. Assessments will be 
performed via telehealth and videos of participants that have been recorded will be stored on 
Box, MUSC’s approved cloud storage device. Only those who are IRB approved will have access 
to these videos. A central technology support specialist will have access to participant PHI 
across sites in order to monitor audio/visual quality of videos and assist with technology with 
participants in real-time 
 
10.5 Future Use of Stored Data 
 
Data stored on Box and WebDCUTM will be used for data analyses while the study is 
actively enrolling and after enrollment has ended. All data stored on WebDCUTM will be de-
identified with each participant having their own unique identifier. Audio-video recordings of 
participants will be stored on Box, and only those who are IRB approved will have access to 
these recordings. 
 
10.6 Key Roles and Study Governance 
The clinical trial will be centrally coordinated by the Lead Investigator, Leonardo 
Bonilha. Participating sites include UofSC and UoU. The Data Coordination Unit (DCU) at MUSC 
is a nationally renowned center that provides assistance with the design of clinical trials, 
analysis of clinical trial data, as well as establishing, implementing, and maintaining data and 
project management systems for multicenter clinical trials, administrative, and statistical 
support. The DCU will provide the data management backbone for this trial, including online 
data collection forms,  data collection guidelines, continuous data surveillance, and AE 
reporting.  
 
10.7 Safety Oversight 
A DSMB will provide the safety oversight for this trial. The DSMB meets annually to 
review safety data and trial progress.  
 
10.8 Clinical Monitoring 
10.8.1 Site Initiation Procedure 
 A site initiation visit by the PI and Project Manager will occur to ensure that the 
following steps are performed in accordance with a unified protocol: 1) participant enrollment, 
2) use of the WebDCUTM system, 3) behavioral assessments, 4) intake of individual 
characteristics, 5) neuroimaging acquisition, and 6) speech therapy. We also implement yearly 
online recertification for the SLPs and trained research staff to review the SET procedures with 
the site SLPs and study coordinators and ensure continued proficiency of the study protocol.  

v.14 
02MAY2024 
 
39
10.8.2 Treatment manual, on-site training and online recertifications 
The SLP Manager and the Project Manager will create a manual for standard operating 
procedures (SOPs), and for the administration of the behavioral assessments and of SET. This 
manual will be shared at the initiation of the study and subsequently throughout the study. The 
manual and the SOPs will be reviewed through site recertifications.  
The SLP Manager and the Project Manager will perform site recertifications every 6 
months. This will be done separately and more frequently than site visits, and will be performed 
via teleconference through the MUSC’s Telehealth Center. The MUSC’s Telehealth Center is an 
initiative that supports telehealth activities in diverse applications including health care and 
research. The Center coordinates training in the use of telehealth technologies for each site, 
assists with ongoing quality maintenance, and facilitates the administrative management of 
telehealth activities. We will use a HIPAA-compliant virtual platform for site communication and 
recertifications. During the recertification process, the SLP Manager and the Project Manager 
will teleconference with the site study coordinator, and the site SLP and review the manual and 
SOPs. They will run through case scenarios to ensure understanding of the procedures and 
answer questions. They will also review data entry and storage compliance, whilst data 
management is performed independently by the MUSC DCU. 
 
10.9 Data Collection and Management Responsibilities 
 
The research team will be trained by the SLP Manager on methods for data collection. 
Source documents for assessments will be stored in local site’s lab. Training will be provided to 
research team for use of WebDCUTM online data storage. The SLP Manager will do routine, 
periodic review of source documents and data stored on WebDCUTM to ensure proper 
documentation and storage of all data.  
10.9.1 Sharing of Results with Subjects 
 
If there are any significant new findings during the course of the study, the participants 
will be notified. Participant may also request copies of assessment documentation or MRI for 
their own use or to provide to their primary care physicians. Informal verbal request is all that 
will be required to obtain documents. All assessments are de-identified as they are recorded by 
participant number. Each participant will receive a follow-up appointment after study 
completion to discuss results of study participation. This is not mandatory, but with experience 
from previous aphasia trials, participants typically request this meeting. 
10.9.2 Protocol Deviations 
 
A Protocol Deviation is any variance from the protocol involving a subject or subjects 
that is not approved by the IRB prior to its initial implementation and occurs when a member of 
the study departs from the IRB-approved protocol in any way without the investigator first 
obtaining IRB approval. 
 
What are not considered to be protocol deviations are changes or departures from the 
study design or procedures that are due to a study participant’s non-adherence. This should not 
be submitted to the IRB. This should be documented in a Note to File for the participant 
records. 

v.14 
02MAY2024 
 
40
 
In the event of a Protocol Deviation, the research team member should contact the SLP 
Manager at MUSC and provide details of the deviation. The SLP Manager will then initiate the 
protocol deviation procedure. 
 
 
 
11.0 References 
 
1. 
Damasio AR. Aphasia. The New England journal of medicine 1992;326:531-539 
2. 
Engelter ST, Gostynski M, Papa S, Frei M, Born C, Ajdacic-Gross V, Gutzwiller F, Lyrer PA. 
Epidemiology of aphasia attributable to first ischemic stroke: incidence, severity, fluency, 
etiology, and thrombolysis. Stroke 2006;37:1379-1384 
3. 
Poeck K. Fluency. In: Code C, ed. The characteristics of aphasia. Philadelphia: Taylor & 
Francis, 1989: 23-32. 
4. 
MacWhinney BF, D.;Forbes,M.;Holland,A. AphasiaBank: Methods for Studying 
Discourse. . Aphasiology 2011;25:1286-1307 
5. 
Brady MC, Kelly H, Godwin J, Enderby P. Speech and language therapy for aphasia 
following stroke. Cochrane Database Syst Rev 2012;5:CD000425 
6. 
Kelly H, Brady MC, Enderby P. Speech and language therapy for aphasia following 
stroke. Cochrane Database Syst Rev 2010:CD000425 
7. 
Fridriksson J, Hubbard HI, Hudspeth SG, Holland AL, Bonilha L, Fromm D, Rorden C. 
Speech entrainment enables participants with Broca's aphasia to produce fluent speech. Brain 
2012;135:3815-3829.3525061 
8. 
Rofes A, Capasso R, Miceli G. Verb production tasks in the measurement of 
communicative abilities in aphasia. Journal of clinical and experimental neuropsychology 
2015;37:483-502 
9. 
Croquelois A, Bogousslavsky J. Stroke aphasia: 1,500 consecutive cases. Cerebrovascular 
diseases 2011;31:392-399 
10. 
Pedersen PM, Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS. Aphasia in acute 
stroke: incidence, determinants, and recovery. Annals of neurology 1995;38:659-666 
11. 
Wade DT, Hewer RL, David RM, Enderby PM. Aphasia after stroke: natural history and 
associated deficits. J Neurol Neurosurg Psychiatry 1986;49:11-16.1028640 
12. 
Siirtola M, Narva EV, Siirtola T. On the occurrence and prognosis of aphasia in 
participants with cerebral infarction. Scand J Soc Med Suppl 1977;14:128-133 
13. 
Hilari K, Needle JJ, Harrison KL. What are the important factors in health-related quality 
of life for people with aphasia? A systematic review. Archives of physical medicine and 
rehabilitation 2012;93:S86-95 
14. 
Hilari K, Byng S. Health-related quality of life in people with severe aphasia. Int J Lang 
Commun Disord 2009;44:193-205 
15. 
Kauhanen ML, Korpelainen JT, Hiltunen P, Maatta R, Mononen H, Brusin E, Sotaniemi 
KA, Myllyla VV. Aphasia, depression, and non-verbal cognitive impairment in ischaemic stroke. 
Cerebrovascular diseases 2000;10:455-461 
16. 
Black-Schaffer RM, Osberg JS. Return to work after stroke: development of a predictive 
model. Archives of physical medicine and rehabilitation 1990;71:285-290 

v.14 
02MAY2024 
 
41
17. 
Code C, Hemsley G, Herrmann M. The emotional impact of aphasia. Seminars in speech 
and language 1999;20:19-31 
18. 
Hilari K. The impact of stroke: are people with aphasia different to those without? 
Disabil Rehabil 2011;33:211-218 
19. 
Carson AJ, MacHale S, Allen K, Lawrie SM, Dennis M, House A, Sharpe M. Depression 
after stroke and lesion location: a systematic review. Lancet 2000;356:122-126 
20. 
de Freitas GR. Aphasia and other language disorders. Front Neurol Neurosci 2012;30:41-
45 
21. 
Holland AL, Fromm DS, DeRuyter F, Stein M. Treatment efficacy: aphasia. Journal of 
speech and hearing research 1996;39:S27-36 
22. 
Geschwind N. The Organization of Language and the Brain: Language disorders after 
brain damage help in elucidating the neural basis of verbal behavior. Science 1970;170:940-944 
23. 
Gleason JB, Goodglass H, Green E, Ackerman N, Hyde MR. The retrieval of syntax in 
Broca's aphasia. Brain Lang 1975;2:451-471 
24. 
Kertesz A. The Western Aphasia Battery - Revised. New York: Grune & Stratton, 2007. 
25. 
Brady MC, Kelly H, Godwin J, Enderby P, Campbell P. Speech and language therapy for 
aphasia following stroke. Cochrane Database Syst Rev 2016:CD000425 
26. 
Fridriksson J. Preservation and modulation of specific left hemisphere regions is vital for 
treated recovery from anomia in stroke. J Neurosci 2010;30:11558-11564.2938788 
27. 
Fridriksson J, Baker JM, Whiteside J, Eoute D, Jr., Moser D, Vesselinov R, Rorden C. 
Treating visual speech perception to improve speech production in nonfluent aphasia. Stroke 
2009;40:853-858.2679690 
28. 
Schlaug G, Marchina S, Norton A. Evidence for plasticity in white-matter tracts of 
participants with chronic Broca's aphasia undergoing intense intonation-based speech therapy. 
Ann N Y Acad Sci 2009;1169:385-394.2777670 
29. 
Szaflarski JP, Ball AL, Vannest J, Dietz AR, Allendorfer JB, Martin AN, Hart K, Lindsell CJ. 
Constraint-Induced Aphasia Therapy for Treatment of Chronic Post-Stroke Aphasia: A 
Randomized, Blinded, Controlled Pilot Trial. Medical science monitor : international medical 
journal of experimental and clinical research 2015;21:2861-2869.PMC4588672 
30. 
Norton A, Zipse L, Marchina S, Schlaug G. Melodic intonation therapy: shared insights on 
how it is done and why it might help. Ann N Y Acad Sci 2009;1169:431-436.PMC2780359 
31. 
Boyle M. Stability of Word-Retrieval Errors With the AphasiaBank Stimuli. Am J Speech 
Lang Pathol 2015;24:S953-960 
32. 
Albert ML, Sparks RW, Helm NA. Melodic intonation therapy for aphasia. Archives of 
neurology 1973;29:130-131 
33. 
Sparks RW, Holland AL. Method: melodic intonation therapy for aphasia. J Speech Hear 
Disord 1976;41:287-297 
34. 
Cramer SC. Stimulating Dialogue Through Treatment of Poststroke Aphasia With 
Transcranial Direct Current Stimulation. JAMA Neurol 2018 
35. 
Fridriksson J, Rorden C, Elm J, Sen S, George MS, Bonilha L. Transcranial Direct Current 
Stimulation vs Sham Stimulation to Treat Aphasia After Stroke: A Randomized Clinical Trial. 
JAMA Neurol 2018 
36. 
Hebb DO. The organization of behavior; a neuropsychological theory. New York,: Wiley, 
1949. 

v.14 
02MAY2024 
 
42
37. 
Lowel S, Singer W. Selection of intrinsic horizontal connections in the visual cortex by 
correlated neuronal activity. Science 1992;255:209-212 
38. 
Taub E, Uswatte G, Mark VW, Morris DM. The learned nonuse phenomenon: 
implications for rehabilitation. Eura Medicophys 2006;42:241-256 
39. 
Mark VW, Taub E. Constraint-induced movement therapy for chronic stroke hemiparesis 
and other disabilities. Restor Neurol Neurosci 2004;22:317-336 
40. 
Dimyan MA, Cohen LG. Neuroplasticity in the context of motor rehabilitation after 
stroke. Nature reviews Neurology 2011;7:76-85 
41. 
Starkey ML, Schwab ME. How Plastic Is the Brain after a Stroke? Neuroscientist 
2014;20:359-371 
42. 
Wittenberg GF. Experience, cortical remapping, and recovery in brain disease. 
Neurobiology of disease 2010;37:252-258.2818208 
43. 
Gauthier LV, Taub E, Perkins C, Ortmann M, Mark VW, Uswatte G. Remodeling the brain: 
plastic structural brain changes produced by different motor therapies after stroke. Stroke 
2008;39:1520-1525.2574634 
44. 
Lindenberger U. Human cognitive aging: corriger la fortune? Science 2014;346:572-578 
45. 
Popa-Wagner A, Badan I, Vintilescu R, Walker L, Kessler C. Premature cellular 
proliferation following cortical infarct in aged rats. Romanian journal of morphology and 
embryology = Revue roumaine de morphologie et embryologie 2006;47:215-228 
46. 
Popa-Wagner A, Carmichael ST, Kokaia Z, Kessler C, Walker LC. The response of the aged 
brain to stroke: too much, too soon? Current neurovascular research 2007;4:216-227 
47. 
Blanke O. Multisensory brain mechanisms of bodily self-consciousness. Nature reviews 
Neuroscience 2012;13:556-571 
48. 
Hickok G, Buchsbaum B, Humphries C, Muftuler T. Auditory-motor interaction revealed 
by fMRI: speech, music, and working memory in area Spt. J Cogn Neurosci 2003;15:673-682 
49. 
Hickok G, Okada K, Serences JT. Area Spt in the human planum temporale supports 
sensory-motor integration for speech processing. J Neurophysiol 2009;101:2725-2732 
50. 
Isenberg AL, Vaden KI, Jr., Saberi K, Muftuler LT, Hickok G. Functionally distinct regions 
for spatial processing and sensory motor integration in the planum temporale. Hum Brain Mapp 
2012;33:2453-2463 
51. 
Pa J, Hickok G. A parietal-temporal sensory-motor integration area for the human vocal 
tract: evidence from an fMRI study of skilled musicians. Neuropsychologia 2008;46:362-
368.PMC2278046 
52. 
Ipata AE, Gee AL, Goldberg ME, Bisley JW. Activity in the lateral intraparietal area 
predicts the goal and latency of saccades in a free-viewing visual search task. J Neurosci 
2006;26:3656-3661.PMC2367056 
53. 
Grefkes C, Ritzl A, Zilles K, Fink GR. Human medial intraparietal cortex subserves 
visuomotor coordinate transformation. Neuroimage 2004;23:1494-1506 
54. 
Hilari K, Byng S, Lamping DL, Smith SC. Stroke and Aphasia Quality of Life Scale-39 
(SAQOL-39): evaluation of acceptability, reliability, and validity. Stroke 2003;34:1944-1950 
55. 
Holland AL, Frattali C, Fromm D. CADL-2 communication activities of daily living : 
examiner's manual, 2nd ed. Austin, Tex.: pro-ed, 1999. 

v.14 
02MAY2024 
 
43
56. 
Lomas J, Pickard L, Bester S, Elbard H, Finlayson A, Zoghaib C. The communicative 
effectiveness index: development and psychometric evaluation of a functional communication 
measure for adult aphasia. J Speech Hear Disord 1989;54:113-124 
57. 
Strand EA, Duffy JR, Clark HM, Josephs K. The Apraxia of Speech Rating Scale: a tool for 
diagnosis and description of apraxia of speech. J Commun Disord 2014;51:43-50.PMC4254321 
58. 
Howard D, Patterson K. The Pyramids and Palm Trees Test: A test of semantic access 
from words and pictures. . London: Harcourt Assessment, 1992. 
59. 
Kaufman AS, Lichtenberger EO. Assessing adolescent and adult intelligence, 3rd ed. 
Hoboken, N.J.: Wiley, 2006. 
60. 
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic 
comorbidity in longitudinal studies: development and validation. Journal of chronic diseases 
1987;40:373-383 
61. 
Leritz EC, McGlinchey RE, Lundgren K, Grande LJ, Milberg WP. Using lexical familiarity 
judgments to assess verbally mediated intelligence in aphasia. Neuropsychology 2008;22:687-
696.PMC2910429 
62. 
Laures-Gore JS, Farina M, Moore E, Russell S. Stress and depression scales in aphasia: 
relation between the aphasia depression rating scale, stroke aphasia depression questionnaire-
10, and the perceived stress scale. Topics in stroke rehabilitation 2016:1-5 
63. 
Choi-Kwon S, Han SW, Kwon SU, Kim JS. Poststroke fatigue: characteristics and related 
factors. Cerebrovascular diseases 2005;19:84-90 
64. 
Forbes MM, Fromm D, Macwhinney B. AphasiaBank: a resource for clinicians. Seminars 
in speech and language 2012;33:217-222.PMC4073291 
65. 
Magnusdottir S, Fillmore P, den Ouden DB, Hjaltason H, Rorden C, Kjartansson O, 
Bonilha L, Fridriksson J. Damage to left anterior temporal cortex predicts impairment of 
complex syntactic processing: a lesion-symptom mapping study. Hum Brain Mapp 
2013;34:2715-2723 
66. 
Proschan MA. Two-stage sample size re-estimation based on a nuisance parameter: a 
review. J Biopharm Stat 2005;15:559-574 
67. 
Rubin DB, Schenker N. Multiple imputation in health-care databases: an overview and 
some applications. Stat Med 1991;10:585-598 
68.  
Roach A, Schwartz MF, Martin N, Grewal RS, Brecher A. The Philadelphia naming test: 
Scoring and rationale. Clinical Aphasiology. 1996;24:121-34. 
69.  
Dell GS, Schwartz MF, Martin N, Saffran EM, Gagnon DA. Lexical access in aphasic and 
nonaphasic speakers. Psychol Rev. 1997;104(4):801-38. PubMed PMID: 9337631. 
70.  
Johns MW. A new method for measuring daytime sleepiness: The Epworth Sleepiness 
Scale. Sleep 1991;14(6):540-545 
71.  
Tseng BY, Gajewski BJ, Kluding PM. Reliability, responsiveness, and validity of the Visual 
Analog Fatigue Scale to measure exertion fatigue in people with chronic stroke: A preliminary 
study. Stroke Research and Treatment 2010;1-7. 
72. 
Riley EA, Owora A, McCleary J, Anderson A. Sleepiness, Exertion Fatigue, Arousal, and 
Vigilant Attention in Persons with Chronic Aphasia. American Journal of Speech-Language 
Pathology 2019;29;1S;375-576. 

v.14 
02MAY2024 
 
44
73. Laver KE, Schoene D, Crotty M, George S, Lannin NA, Sherrington C. Telerehabilitation 
services for stroke. Cochrane Database System Rev. 2013; 12 (CD010255). doi: 
10.1002/14561858.CD010255.pub2. 
74. Zheng C, Lynch L, Taylor N. Effect of computer therapy in aphasia: A systematic review. 
Aphasiology. 2016; 30(2-3):211-244. doi: 10.1080/02687038.2014.996521. 
75. Meltzer JA, Baird AJ, Steele RD, Harvey SJ. Computer-based treatment of post-stroke 
language disorders: A non-inferiority study of telerehabilitation compared to in-service delivery. 
Aphasiology. 2018;32(3):290-311. doi: 10.1080/02687038.2017.1355440 
76. Woolf C, Caute A, Haigh Z, Galliers J, Wilson S, Kessie A, Hirani S, et al. A comparison of 
remote therapy, face to face therapy and an attention control intervention for people with 
aphasia: A quasi-randomised controlled feasibility study. Clinical Rehabilitation. 2016;30(4):359-
373. doi: 10.1177/0269215515582074 
77. American Speech-Language-Hearing Association. Telepractice [Professional Issues]. 
Available from: www.asha.org/practice-portal. 
78. Cassarly C, Matthews LJ, Simpson, AN, Dubno JR. The Revised Hearing Handicap Inventory 
and Screening Tool Based on Psychometric Reevaluation of the Hearing Hadnicap Inventories 
for the Elderly and Adults. Ear and Hearing. 2020; 21(1):95-105 doi: 
10.1097/AUD.0000000000000746