A Randomized, Single Blind, Controlled, Longitudinal Study of the Effects of Venlafaxine Hydrochloride Capsules on the Language Function of Stroke Patients With Subcortical Aphasia Using fMRI
Phase: NA
Conditions: Subcortical Aphasia, Ischemic Stroke
Sponsor: Guangzhou General Hospital of Guangzhou Military Command

The Effect of Venlafaxine on Language Function in Patients
With Subcortical Aphasia: A fMRI Study
NCT03588572
Study Protocol
Guangzhou General Hospital of Guangzhou
Military Command
No. 111, Liuhua Road, Yuexiu District,
Guangzhou, China
August 2018

Study Protocol
1. Research object and Study design
1.1
Research object
The cases will recruit from patients with acute ischemic stroke in Department of
Cerebrovascular, the Guangzhou General Hospital of Guangzhou Military Command
from August 2018 to June 2019. The diagnose of ischemic stroke is base on the
diagnostic criteria of the International Association of Neurological Diseases and
Stroke Association in 1982. The classification criteria for subcortical ischemic stroke
are based on the current international TOAST etiological classification method.
1.1.1
Inclusion criteria
（1）The first stroke of the left single subcortical areas, within 72 hours.
（2）Primary school or higher level, aged between 18-75, native language Chinese.
（3）According to the commonly used eye chart examination, the corrected visual
acuity is more than 1.0.
（4）According to the Edinburgh Handedness Questionnaire (EHQ), participants are
identified as right-handed.
（5）The language function is normal before the stroke onset. After the onset, the
language function was mildly to moderately impaired with Western Aphasia Battery
(WAB) ,which Aphasia Quotient (AQ) between in 60 to 88.
（6）The patient cooperate with the examination, they or their guardian sign
the informed consent.
1.1.2
Exclusion criteria
（1）History of organic diseases of nervous system and history of TBI(Traumatic
brain injuries)
（2）History of epilepsy and psychosis.
（3）History of material abuse.
（4）Decompensation of important organic function.
（5）Hamilton Depression Scale(HAMD )>8 points.
（6）Hamilton Anxiety Scale(HAMA )>7 points.

（7）The Mini-Mental State Examination (MMSE)score <20 points.
（8）Dysphagia(difficult to take capsules).
（9）A history of allergens in component of venlafaxine capsule.
（10）Pregnant women and breast-feeding women.
（11）Any contraindication of MRI.
1.2
Study design
It is a randomized, controlled, single-blind, longitudinal trial which has approved
by the ethics committee of Guangzhou General Hospital of Guangzhou Military
Command. All patients and their guardian will sign an informed consent. The patients
will divid into the venlafaxine group and the control group according to the principle
of randomization (random number table). The patients in the venlafaxine group begin
to take a venlafaxine hydrochloride capsule(EFFEXOR XR: each containing
venlafaxine 75mg, qd) after enrollment, until 4 weeks after randomization, and the
control group do not. Assessments of language functional behavior and examines of
functional magnetic resonance imaging (fMRI) should be performed on the first days
(Visit1,V1), 28±3 days (Visit2, V2) and 90±3 days (Visit3, V3) after randomization.
Language functional behavioral assessments include the Chinese version of Western
Aphasia Battery(WAB), spontaneous language frequency test(SLFT) and picture
naming test(PNT). Examines of fMRI include task-state fMRI, resting-state fMRI,
and DTI(Diffusion Tensor Imaging). All patients will receive language rehabilitation
training (twice a week, one hour each) which are conducted by a professional
rehabilitation physiotherapist from the V1 to the V3. The blood pressure and heart rate
of each patient will be monitored and recorded on each visit. Two routine blood tests
are performed at V0 and V3, including the blood routine and the liver and kidney
function.The technical roadmap is shown in Figure1.
The sample size is estimated by the professional software nQuery Advisor7.0.
According to the previous literature on the efficacy of venlafaxine, the main
evaluation index of the effect of the experimental group and the control group are
7.5±3.8 and 4.3±2.6 respectively. The standard deviation are 3.26, and the statistical
meaning level(double tail) is 0.05. The test efficiency are set to 0.83. The balance

design will be used to estimate the sample size. Finally, the sample size of the
experimental group and the control group are 16 cases respectively. In addition,
considering the 20% missing rate, a total of 45 samples will be included in the study.
Figure 1
Technical roadmap for research and design
1.3
Functional magnetic resonance (fMRI)
1.3.1
Functional magnetic resonance (fMRI) design
Task-state fMRI: an fMRI block design will be adopted, and DMDX software
will be used to present each picture in series alternated between baseline (B) and
activation (A) [B–A–B–A–B…]. Thirty-six animal pictures and 36 tool pictures from
the Snodgrass picture database will be recognized by all subjects. Six blocks of
animal naming and six blocks of tool naming will be repeated, and each block
continue for 18s with six pictures. The abstract picture of an American skunk which is
unrecognized by all the subjects will be selected for baseline of animal naming. A
schematic drawn arrow will be chosen for baseline of tool naming. Patients will be
required to silently name the object in each picture without moving their lips. To
avoid practice effects, the pictures used for fMRI will not appear in the behavioral
Venlafaxine
Withdraw
V1
V2
V3
Grouping
Test1+fMRI1
Test2+fMRI2
Test3+fMRI3
V1
V2
V3
Grouping
Test1+fMRI1
Test2+fMRI2
Test3+fMRI3
Venlafaxine Group
Control Group

evaluation. In the baseline phase, the participants will be asked to identify the
orientation of the pictures by silently saying ‘upright’ or ‘inverted’. The subjects will
receive task familiarization training prior to the test to ensure that there will be no
substantive picture naming but only positional judgment in the baseline task. The
design as shown in Figure 2.
Rest-state fMRI: During the rest-state fMRI scan, no task instruction will be
given to the patient, and the patient will be completely relaxing, closing his eyes,
breathing calmly, keeping his head still, but can not fall asleep, try to avoid any
systematic thinking activities, scanning 8min.
DTI: The patient will remain quiet and awake during the DTI data scan.
3000ms×6
picture naming task（3000ms×12）
3000ms×6
B
A
B
A
B
A
B
A
B
A
B
A
24s
18s
18s
18s
18s
18s
18s
18s
18s
18s
18s
18s
18s
Figure 2
Picture naming task group block design sketch map
1.3.2
Functional magnetic resonance data acquisition
The fMRI scan will be performed by using the US GE HDX3.0 Tesla superconducting
magnetic resonance imaging system. The scanning sequence and parameters are as
follows:
(1)In
order
to
obtain
the
whole
brain
anatomical
structure
image
data,
a
three-dimensional fast spoiler gradient echo (FSPGR BRAVO sequence) is used.. The
parameters included: time of repetition, 8.86 ms; time of echo, 3.52 ms; field of view,
24×24 cm2; in-plane resolution,256×256; slice thickness, 1mm;interslice gap, 1 mm;
Activation
Baseline

and number of slices, 176.
(2)Echo-Planar Imaging (EPI) is used to acquire task-state fMRI data. The parameters
included: time of repetition, 3000ms; time of echo, 40 ms; field of view, 24×24 cm2;
in-plane resolution,64×64; slice thickness, 4mm; interslice gap, 1 mm; and number of
slices, 34. Scan a sequence of 240s, a total of 12 min.
(3) Echo-Planar Imaging (EPI) is used to acquire rest-state fMRI data.The parameters
included: time of repetition, 3000ms; time of echo, 40 ms; field of view, 24×24 cm2;
in-plane resolution,64×64; slice thickness, 4mm; interslice gap, 1 mm; and number of
slices, 34. A total of 8 min.
(4)Echo-Planar Imaging (EPI) is used to acquire DTI data. The parameters included:
time of repetition, 8500ms; time of echo, 93 ms; field of view, 24×24 cm2; in-plane
resolution,128×128; slice thickness, 3mm; interslice gap, 0 mm; b-value=1000mm2/s.
1.4
Outcome Measures
1.4.1
Primary Outcome Measure:
(1)A change of outcome measure: the Chinese version of Western Aphasia
Battery(WAB)
The main outcome measure for this scale is Aphasia Quotient(AQ) which mainly
tests the ability of spontaneous speech, oral comprehension, repetition, and naming,
and reflects the severity of aphasia, and can be used as a reliable indicator to evaluate
the improvement and deterioration of aphasia. Score fluctuation is 0-100 points, the
normal value is 98.4-100 points, AQ<93.8 can be judged as language dysfunction.
Time Frame: This is an outcome measure to assess the improvement of language
function from onset to 3 months after treatment. Thus, participates will undergo this
assessment on the first days (V1), 28±3 days (V2), and 90±3 days(V3) after
randomization.
1.4.2
Secondary Outcome Measure:
(1)A change of outcome measure: Spontaneous Language Frequency Test(SLFT)
This test mainly assesses spontaneous speech fluency of participants. It requires
participants name as many food names as possible within one minute, and each
correct one to give one point. The higher the score, the better the language function.

Time
Frame: This is an outcome measure to assess the improvement of language function
from onset to 3 months after treatment. Thus, participates will undergo this
assessment on the first days (V1), 28±3 days (V2), and 90±3 days(V3) after
randomization.
(2) A change of outcome measure: Picture Naming Test(PNT)
This test mainly assesses the ability of picture name of participants. we used a
program for displaying named pictures
on a computer screen (60 photos in total, of which 20 were Chinese celebrity faces).
Each image was displayed in 3 seconds, and 1 point was correctly named for an
image. The faces of celebrities were selected from the picture database of Chinese
celebrities in the State Key Laboratory of Cognitive Neuroscience and Learning at
Beijing Normal University. Score fluctuation is 0-60 points, the higher the score,
the better the ability of picture name.
Time Frame: This is an outcome measure to assess the improvement of
language function from onset to 3 months after treatment. Thus, participates will
undergo this assessment on the first days (V1), 28±3 days (V2), and 90±3 days(V3)
after randomization.
(3)Follow-up measurement: Hamilton Depression Rating Scale (HAMD)
The Hamilton Depression Rating Scale (HAMD) has proven useful for many
years as a way of determining a patient’s level of depression before, during, and
after treatment. It generally takes 15-20 minutes to complete the interview and
score the results. Eight items are scored on a 5-point scale, ranging from 0 = not
present to 4 = severe. Nine items are scored from 0-2. HAMD Scoring
Instructions:0-7=Normal, 8-13 = Mild Depression, 14-18 = Moderate Depression,
19-22 = Severe Depression, ≥23 = Very Severe Depression(i.e., the higher the
score, the greater the likelihood of depression).
Time Frame: We must determine that the participant is not in depression at
each follow-up. Thus, participates will undergo this assessment on the first days
(V1), 28±3 days (V2), and 90±3 days (V3) after randomization.

(4) Follow-up measurement: Hamilton Anxiety Rating Scale (HAMA)
The Hamilton Anxiety Rating Scale (HAMA) is a widely used and
well-validated tool for measuring the severity of a patient's anxiety. The HAMA is
composed of 14 items and takes 15-20 minutes to complete the interview and
score the results. Each item is scored on a 5-point scale, ranging from 0=not present
to 4=severe. HAMA Scoring Instructions:0-8=Normal, 8-13= Possible Anxiety,
14-17 = Mild Anxiety, 18-24 = Moderate Anxiety, 25-30 = Severe Anxiety(i.e., the
higher the score, the greater the likelihood of anxiety).
Time Frame: We must determine that the participant is not in anxiety at each
follow-up. Thus, participates will undergo this assessment on the first days (V1),
28±3 days (V2), and 90±3 days (V3) after randomization.
(5) Follow-up measurement: Mini-Mental State Examination (MMSE)
The Mini–Mental State Examination (MMSE) is a 30-point questionnaire that
is used extensively in clinical and research settings to measure cognitive
impairment. Administration of the test takes between 5 and 10 minutes. The MMSE
test includes simple questions and problems in a number of areas: the time and
place of the test, repeating lists of words, arithmetic such as the serial sevens,
language use and comprehension, and basic motor skills. Any score greater than or
equal to 24 points (out of 30) indicates a normal cognition. Below this, scores can
indicate severe(≤9 points), moderate (10–18 points) or mild (19–23 points)
cognitive impairment. The raw score may also need to be corrected for educational
attainment and age.
Time Frame: We must determine that the participant is not in moderate or
more cognitive impairment at each follow aup. Thus, participates will undergo this
assessment on the first days (V1), 28±3 days (V2), and 90±3 days (V3) after
randomization.
(6) Other observational outcome
Edinburgh hand check（EHQ）：It is used to assess the habitual hand of patient.
National Institute of Health stroke scale(NIHSS )：It is used to assess
neurological deficits in patients with aphasia

Water swallow test(WST）：It is used to assess the swallowing function of
patients with aphasia.