Comparison of Electrophysiologic And Ultrasound Guidance For Onabotulinum Toxin A Injections in Focal Upper Extremity Dystonia And Spasticity
Phase: NA
Conditions: Spasticity, Focal Dystonia, Tremor, Limb
Sponsor: Icahn School of Medicine at Mount Sinai

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Comparison of Electrophysiologic And Ultrasound Guidance For Onabotulinum Toxin A 
Injections in Focal Upper Extremity Dystonia And Spasticity 
PI: David Simpson, MD 
NCT02334683 
Document Date: 9-2-2014

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Protocol 
Comparison of Electrophysiologic Guidance and 
Ultrasound Guidance for Botulinum Toxin Injections 
 
Brief Summary of Research (250-400 words): 
This is a study to investigate the use of two targeting techniques for botulinum 
toxin (BoNT) injection for the treatment of focal hand dystonia and upper limb 
spasticity:  Electrophysiologic guidance, using electrical stimulation, and 
ultrasound.   Subjects will be selected from the clinical programs of both Icahn 
School of Medicine at Mount Sinai and the National Institutes of Health who are 
already receiving onabotulinum toxin A injections clinically.  The study will 
consist of four visits.  Visit one consists of screening subjects who will then be 
consented and randomized to one of the two treatment techniques for their ona-
BoNT injection: 1) Electrophysiologic guidance using electrical stimulation or 2) 
ultrasound.  Visit 2 will occur at week 4 where the subjects will return for a 
follow up visit to have blinded evaluator measurements of efficacy and strength 
and capture safety data.  Visit 3 will be at week 12 when subjects will cross over 
and have the alternate treatment technique during their ona-BoNT injection.  Visit 
4 will occur at week 16 as the final assessment where subjects will have 
measurements of efficacy and strength and capture safety data by the blinded 
evaluator.     
1) Objectives: 
Research Question: 
Hypothesis:  Neither Ultrasound or electrical stimulation will not show significant 
differences in the outcome measures.  
 
 
1) Improvement in dystonia or spasticity severity on visual analogue scale.  
Secondary objectives  
1. Duration of the injection procedure 
2. Weakness in targeted and adjacent muscles after the procedure 
3. Number of needle sticks and needle re-direction within a muscle required for delivery 
with each technique 
4. Side effects with each technique 
5. Patient self-reported satisfaction with each procedure 
6. Physician global impression of change 
7. For dystonia, physician rated “Arm Dystonia Disability Scale” 
8. For spasticity, physician rated Modified Ashworth scale 
9. Patient discomfort assessed on a visual analog scale. 
 
2) Background 

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Dystonia is characterized by muscle contractions causing abnormal movements or postures 
(Albanese, et al., 2013). Focal hand dystonia is a task-specific focal dystonia, occurring with 
one or several specific actions (Sheehy and Marsden, 1982). Assessment of dystonia depends 
largely on standardized clinical scales, like the Burke-Fahn-Marsden Dystonia Rating Scale 
(BFM DRS)(Burke et al., 1985). 
 
Spasticity is an upper motor neuron syndrome associated with lesions of the corticospinal 
system (Lance, 1981). Causes including traumatic brain injury, spinal cord injury, cerebral 
palsy, multiple sclerosis or stroke result in an imbalance of excitatory and inhibitory synaptic 
influences and hyperexcitability of the stretch reflexes. It is typically classified as 
generalized, regional, multifocal and focal (Ward, 2008). The most widely used assessment 
method is the Ashworth scale, which quantifies the increased tone across each joint on a 
scale from 0 (normal) to 4 (fixed position) (Bohannon and Smith, 1987).  
 
Botulinum neurotoxin (BoNT) injection therapy is the most effective established therapy for 
focal dystonia (Simpson et al., 2008). OnabotulinumtoxinA (Botox®, Allergan, Irvine, CA) 
has been approved by the FDA for treatment of upper extremity spasticity. Numerous 
controlled trials have shown improvement in muscle tone and functional outcomes using 
onabotulinumtoxinA in adults with upper extremity spasticity (Teasell et al., 2012).  
 
BoNT injections are ordinarily performed using anatomical landmarks, and additional 
instrumented localization methods include EMG, electrical stimulation and US guidance. 
Anatomical localization is insufficient for ideal muscle localization (Schnitzler et al., 2012, 
Molloy et al., 2002). Studies suggest that electrical stimulation guidance improves muscle 
localization and targeting (Molloy et al., 2002) and effectiveness of BoNT injection (Ploumis 
et al., 2013). Ultrasound-guided localization is a more recent development (Alter, 2010), that 
is gaining wider acceptance. Standardized techniques and additional information sources are 
now available (Alter et al., 2013).  
 
A limited number of recent studies have attempted a comparison of the currently available 
injection guidance techniques in spasticity patients (Picelli et al., 2013, Picelli et al., 2012). 
Within the limits of these studies, it was suggested that ultrasound guidance can improve 
outcomes of BoNT injections in limb spasticity.  
 
In this study we propose a direct comparison of E-stim-based and US-based injection 
guidance techniques in patients with focal upper extremity dystonia and spasticity. Both 
localization techniques are considered standard of care and to date one has not been proved 
superior to the other. Employing one or the other of the guidance techniques does not, in 
itself, change the risk/benefit balance of the standard injection treatment, based on currently 
available data.  
3) Setting of the Human Research 
This is a study being conducted at two sites: The Icahn School of Medicine at Mount Sinai. 
New York, NY and the National Institutes of Health, Bethesda, MD.  Both sites will recruit 
from patients who are currently receiving treatments with onabotulinumtoxin A within their 
clinical practices.  

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4) Resources Available to Conduct the Human Research 
Both sites have many patients that are being treated for focal hand dystonia and upper 
limb spasticity with onabotulinumtoxin A.  Each site will offer the study to their 
clinical patients by providing a copy of the consent form and answering questions 
about the study.   Each site anticipates randomizing 15 participants for a total of 30 
participants for the study.  We aim to have an equal number of subjects with upper 
extremity spasticity and focal dystonia randomized to each sequence of e-stim and US 
and at each site. 
The study teams will have an initial conference call meeting to launch the study once 
both sites have received IRB approval and all contractual obligations have been 
fulfilled.  Then the sites will have monthly conferences to review the status of 
enrollment and the study procedures.   
Both the Mount Sinai site under Dr. David Simpson, and the NIH site under the  Dr. 
Mark Hallett (NIH/NINDS) have considerable experience with research clinical trials 
including those with BoNT.    
NIH Biosketches will be provided to the IRB and the approved Human Subjects 
training for the entire study team.  
5) Study Design 
a) Recruitment Methods 
At the Icahn School of Medicine site, patients will be introduced to the research project from 
the Movement Disorders Program and from Drs. Simpson’s Shin’s and Frucht’s private 
practices, and by referral from other health care providers.   
 
At the NIH site, patients will be introduced to the research project from the BoNT clinic, 
including the neurology and movement disorders practitioners at Suburban Hospital, Holy 
Cross Hospital, George Washington University Medical Center, Georgetown University 
Hospital, Johns Hopkins University Medical Center, The Parkinson Disease and Movement 
Disorders Center of Maryland, University of Maryland and others.  
 
Subjects potentially interested will be provided information about the study, copy of the 
consent form will be provided which subjects can review and bring home for family or 
friends to review. They will have the opportunity to contact the investigators at the Icahn 
School of Medicine or the NIH for questions. We anticipate recruiting a total of 30 subjects 
with 15 subjects at each site within one year. 
b) Inclusion and Exclusion Criteria 
Inclusion criteria 
• Confirmed diagnosis of focal upper extremity dystonia (FHD) or upper limb 
spasticity 
• Stable onabotulinumtoxinA dose regimen with a stable response as judged by 
the physician and patient for at least 2 treatment sessions.  
• Age 18 and above 
 

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Exclusion criteria 
• Contraindications to botulinum toxin 
• Pregnancy or nursing  
• Cognitive impairment that prevents reliable outcome measures of self-report 
c) Number of Subjects 
The study will enroll a total of 30 patients, with 15 patients at each site.  Target number of 
patients to be treated and complete the study will be 18 subjects (to have sufficient statistical 
power.  
d) Study Timelines 
This is a randomized cross-over study, with two study sites. 4 outpatient visits of 
approximately 30-60 minutes each will take place over 16- 24 weeks. All NIH 
patients will also be enrolled in protocol 85-N-0195, and botulinum injections will 
be done under that protocol. 
 
 
An outline of the procedures is depicted in the figure below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The study anticipates enrollment of the first subject in February 2015.  The study 
team anticipates an enrollment period of approximately 36 months with the last 
patient to be enrolled  Dec. 2020 with the primary analysis completed by  June 
2021.  
Study Endpoints 
Outcome measures 
Primary outcome measures 
Improvement in dystonia or spasticity severity on a physician and patient self-
reported visual analog scale.  
Secondary outcome measures 
Visit 1: 
Enrollment, initial 
evaluation, BoNT 
injection using US 
or E-stim 
1 month 
Visit 2: 
Blinded 
evaluation 
2 months 
Visit 3: 
BoNT injection using 
alternate technique, E-stim 
or US if deemed clinically 
appropriate by the 
evaluating investigator 
Visit 3: 
Patients who remain 
clinically weak will return 
at weeks 14, 16, and 20 
post injection for re-
evaluation and re-injection 
with the alternate 
technique when clinically 
indicated 
1 month 
Final Visit: 
Blinded 
evaluation 
 
1month 
after re-
injection 
Final Visit: 
Blinded 
evaluation 
 

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(1) Duration of the injection procedure as follows: 
(a) E-Stim:  time from needle In to needle Out  
(b) Ultrasound: Time from transducer contact on skin to needleout  
(c) Number of needle sticks/muscle and needle redirection with muscle for E-stim 
and US   
(2) Weakness after the procedure in targeted and adjoining muscles 
(3) Side effect incidence with each technique 
(4) Patient self-reported satisfaction with each procedure 
(5) Physician global impression of change 
 
      (6) For dystonia, physician rated “Arm Dystonia Disability Scale” 
(7) For spasticity, physician rated Modified Ashworth Scale in targeted and adjoining 
muscles 
 
      (8) Patient discomfort assessed on a visual analog scale 
e) Procedures Involved in the Human Research 
Visit 1 - Screening  
At the time of the first visit, the protocol, procedures, and the entire consent 
document will be discussed with the subjects. If the subjects agree to participate, 
they will sign the consent form and a copy provided before any screening 
procedures are initiated. Eligibility will be determined by history and physical 
examination.  
The subjects’ history is reviewed and eligibility established. After signing the 
consent document, the subjects undergo a standard neurologic evaluation focusing 
on the dystonia and /or spasticity manifestations.  Before each treatment visit, 
women will be given a urine pregnancy test to confirm they are not pregnant.     
Patients are randomized by a computerized system with each site provided the 
sequence of treatments prior to the patient treatment.  Each patient will be 
scheduled to receive their stable, effective injections based upon prior stable 
regimen using either: a) Electrophysiologic guidance via electrical stimulation or 
b) US guidance. The same muscles, dose of onaBoNT-A formulation and dilution 
used previously during the patient’s clinical session will be employed. This 
treatment is standard of care, with the purpose of measuring the two different 
targeting techniques.  One injector and one blinded rater will be assigned for all of 
those taking part in the study.  Both having comparable experience with the 
necessary procedures.  Every effort will be made to reduce the patients discomfort 
during the process of measuring the two different muscle targeting techniques. 
Each injection site (as previously established) is approached using whichever 
above technique the patient has been randomized to. The number of attempts 
(sticks), and needle redirection or repositioning within the muscle to obtain the 
correct localization for each injection site will be recorded. Once the injector is 
satisfied with the placement based on the technique used, the injection proceeds 
as per standard of care. For e-stim technique, the time from initiation of the 
procedure (“needle in”) to completion (“needle out”) is documented. This will be 
measured from the time the needle is first inserted, until the time the injection is 
completed and needle removed.  For US technique, the time from application of 

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the US probe to the skin to needle out is recorded. During this process of 
completing the injection the subject will be videotaped at visits 1 and 3. . The 
subjects will be asked to rate their level of discomfort with the procedure, on a 
visual analog scale, after the injection is complete. 
Visit 2: 
The subjects return to the clinic one month after injection, at the anticipated peak 
effect of ona-BoNT-A therapy. They will complete self-rating forms (Patient 
Global Impression of Change and Visual Analog scale for pain) and be evaluated 
by a blinded rater, who will not know what injection technique has been used (the 
patients will be instructed to withhold that information). The evaluation will 
include: visual analog  benefit scale; visual analog weakness scale;  review of 
side-effects; standardized clinical scale assessment (by clinician):  Arm Dystonia 
Disability Scale for limb dystonia; Ashworth scale for spasticity; Global 
Assessment of Change/Clinical Global Impression of change; weakness assessed 
on the MRC scale; weakness of targeted and neighboring muscles as assessed 
with a mechanical force transducer (standard for both sites). 
The blinded rater is the non-injecting neurologist who will be one of the co-
investigators who did not participate in the subject’s study visit and will remain 
the blinded rater consistently for the subject for the study.  The blinded rater will 
provide an assessment of dystonia or spasticity without know the muscle targeting 
method used.  The visual analog scales will be used by the blinded rater but the 
patient will complete a satisfaction scale of the procedure on a 10 point scale (see 
the attached appendix 1)    
Visit 3: 
An interval history will be obtained, and a targeted examination repeated. If on re-
evaluation the patient’s dystonia or spasticity has increased and retreatment is 
deemed to be clinically indicated then the patient will be re-injected. The muscle 
pattern and dose will remain the same as on visit one. Muscle localization will be 
with the second technique (crossover). As in Visit 1, the process of completing 
the injection of the subject will be videotaped. If on clinical evaluation the 
patient’s severity of the patient’s dystonia or spasticity does not require treatment 
re-injection will be deferred. The patient will return when clinically symptomatic 
(16-24 weeks), re-evaluated and re-injection will occur when clinically 
appropriate, as described above.  
Visit 4: 
This will be identical to visit 2, i.e. 4 weeks post re-injection. The study ends after 
visit 4.  
End of Participation 
Subjects will be referred back to their clinical care.  If any new information 
pertaining to the patients’ care is obtained during the study, it will be shared with 
the patients and their healthcare providers. 
f) Specimen Banking 

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No samples are being stored. Data collected for research will be coded and stored 
on MSSM and NIH secured servers. Only the investigators will have access to the 
data and only the PI will have access to the code key.  Any data that is shared 
between the sites will be done with a process that is encrypted and de-identified. 
g) Data Management and Confidentiality 
Data Collection  
All data will be collected about each enrolled subject, e.g., Demographics, 
Standard clinical regimen, medical history, medications, randomly selected 
targeting method (ultrasound or e-stimulation), results of the blinded rater’s 
review of muscle strength and response to post-treatment.  A subject’s response 
about discomfort during the study at each visit.  The data will be documented on 
de-identified documents. This de-identified data will be shared by the two sites 
using an encrypted process with the NIH site inputting the data points into a 
statistical software for final analysis. The data to be stored indefinitely will be de-
identified data. We will only need the link to patient files until the database is 
locked. We anticipate the link can be destroyed once the database is locked. This 
would be approximately 1 year after the last patient’s last visit. 
Analysis of data/ study outcomes 
The investigators have scheduled an initial investigator’s meeting (August 8, 
2014) where training, data collection and verification process will be defined, 
protection, encryption, physical controls, and separation of identifiers and a 
system of data sharing). The intent is to de-identify all shared data, during storage, 
use, and transmission. Transmission would occur using an encrypted system. 
Quality control measures would be those which are customary by each research 
site and reviewed by the principal investigator of each site on a quarterly basis for 
of all collected data.  Aggregate data will be reviewed quarterly by the team and 
discuss any unresolved outstanding issues to be addressed prior to the next 
quarterly review.  Once all data is collected, the study team will review the 
completed data, address any items that need clarification.  Data will be finalized 
and locked once all information is confirmed by each site and all outstanding 
queries have been resolved.   
Repeated measures ANOVA will be used for the primary outcome. Patients who 
do not complete all 4 visits will be replaced, and all subjects will be included in 
the safety analysis. We will use p<0.05 as significance threshold. No interim 
analysis is planned. 
Power analysis  
Calculations are based on a α of 5% and a β of 80%, and the published SD for 
ona-BoNT-A therapy of 20%.  There is an expected variation of 15% for the 
procedure.  We hypothesize that US will demonstrate non-inferiority in 
comparison to E-stim based on previous experience performing the procedures.  A 
total of 18 subjects (9 from each site) are needed to show the desired 15% 
variation.  15 subjects will be enrolled at each site to allow for screen failures and 
dropouts. 

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h) Provisions to Monitor the Data to Ensure the Safety of subjects 
Adverse events will be reviewed at every visit. Patients will be asked specifically about 
pain or weakness. Patients will also have the option to contact the investigators between 
scheduled visits to report unanticipated events.  
 
The procedures will be stopped if an individual reports any unexpected adverse event 
NCI grade 3 or higher.  
 
Serious or unexpected adverse events and other unanticipated problems will be reported 
orally as soon as possible and in writing within 7 days if life-threatening and within 15 
days otherwise.  Expected or non-serious adverse events will be reported at the time of 
continuing review. Adverse events will be reviewed at every visit. Patients will be asked 
specifically about pain or weakness. Patients will also have the option to contact the 
investigators between scheduled visits to report unanticipated events.  
 
The procedures will be stopped if an individual reports any unexpected adverse event 
NCI grade 3 or higher.  
 
 
Serious or unexpected adverse events and other unanticipated problems will be reported 
orally as soon as possible and in writing within 7 days if life-threatening and within 15 
days otherwise.  Expected or non-serious adverse events will be reported at the time of 
continuing review. 
 
Videos will be captured at Visits 1 and 3 of the injection process only.  Every attempt 
will be made to videotape the study visits without showing a participant’s face nor will 
names be used.  The videos will be identified with the study subject number and stored in 
the locked cabinet and locked office in Dr. Simpson’s research area.  The de-identified 
videos will be downloaded on the password-protected database that is on the secure, 
encrypted Mount Sinai network drive within four weeks of study visit.  Only the study 
team will have access to these videos.  At the time of the analysis only the study team 
will exam these videos and confirm the capture of the data of timing, and muscles 
injected.  These videos will be kept indefinitely for the purposes of research and 
education.  The study subject will be asked to sign the Icahn School of Medicine Video 
consent form that will be discussed with the subject prior to any recording  
 
 
Part I: Elements of a Data and Safety Monitoring Plan 
i) Drs. Simpson and Lungu will share the responsibility for monitoring the data to ensure 
the safety of all the participants in the study. 
MSSM Principal Monitor:– PI – Icahn School of Medicine  
Last Name: Simpson  
First Name: David  
 
Academic Title: Professor  
Department: Neurology  
Mailing Address: 1468 Madison Ave., 
Box 1052, NYC, NY 10029  
Phone: 212-241-8748 
Fax: 212-987-3301 
E-mail:david.simpson@mssm.edu   
MSSM Additional Monitor: PI- NIH Site  

 
Protocol Name: 
Comparison of Electrophysiologic Guidance  and Ultrasound 
Guidance for Botulinum Toxin Injections   
Principal Investigator:  
David M. Simpson, MD 
Primary Contact 
Name/Contact Info: 
Mary Catherine George/ mary-catherine.george@mssm.edu; 212-
241-0784 
Date Revised: 
9-16-14  
Study Number: 
HSM# 14-00492 GCO#14-1113 
 
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     Last Name: Lungu  
    First Name: Codrin 
    Academic Title: Chief 
                Department: NIH, Parkinson Clinic 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Mailing Address: NIH, 10 Center Drive, 
Bethesda, MD 20892-1428 
Phone: 301-402-0976 
Fax: 301-480-2286 
E-mail: lunguci@ninds.nih.gov 
 
 
 
1) Drs. Simpson and Lungu have special expertise in caring for patients 
with movement disorders and treating patients with onabotulinum 
toxin.  This knowledge and experience will ensure patient safety 
throughout the study for each of the individual sites as well as 
collaborate when reviewing the study processes. 
2) Adverse events (AE) will be monitored for safety.  At each visit subjects will 
be asked non-leading questions such as “do you feel different in any way since 
the last visit?”  All observed or volunteered AE’s will be documented in the 
AE log.  
3) Accumulated safety and data information will be reviewed by the monitors 
during the monthly study team calls. 
4) The study does not require any stopping rules for interrupting the study or 
altering the study design. The treatments are standard of care.   
5) Onabotulinumtoxin A is not under study.  The subjects will receive their 
standard clinical treatment. 
6) AEs will be classified as mild, moderate or severe based upon the 
following criteria:  Mild = symptoms do not alter the subject’s normal 
functioning, Moderate= symptoms produced some degree of 
impairment to function but are not dangerous, uncomfortable or 
embarrassing to the subject, Severe = symptoms are dangerous to the 
subject’s well-being and causes significant impairment of function or 
incapacitation. 
 
The relationship of the AE to the treatment will be classified as follows:  
Related:  there is good reason(s) and sufficient evidence to assume that 
there is a causal relationship with the treatment and the AE.  Not related:  
there is good reason(s) and sufficient evidence to exclude a causal 
relationship with the treatment.  
 
All AEs will require the investigator to obtain adequate information to 
determine the outcome of the AE and to assess whether it meets criteria as 
a serious adverse event (SAE), which requires immediate notification to the 
funding agency and ethics review board.  The investigator will obtain 
sufficient information to determine the causality of the AE (i.e. treatment or 

 
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other cause); and provide their opinion on causal association (i.e., whether 
they consider the AE related or not related to the study intervention).  
Subjects will receive follow up until the AE either resolves completely or 
stabilizes to a level acceptable to the investigator.  
 
All SAEs will be reported within 24 hours of the investigator’s knowledge 
of the event to the ethics review board and/or funding agency.  An SAE is 
any AE during the time period of the study that:  1) results in death, 2) is 
life threatening and places the subject  at immediate risk of death, 3) results 
in in-patient hospitalization, 4) results in significant disability/incapacity, 
where the disability is a substantial disruption of a person’s ability to 
conduct normal daily life functions, 5) is an important medical event that 
may not result in death, be life threatening, or require inpatient 
hospitalization, but which based upon the appropriate medical judgment 
may require medical and/or surgical intervention to prevent one of the 
outcomes listed above. 
 
7) All data will be reviewed by Drs. Simpson and Lungu for completeness 
and accuracy  
8) Should a temporary or permanent suspension of the study occur, in 
addition to the PPHS, we would need to inform the funding agency and 
the NIH. 
 
j) Withdrawal of Subjects 
Participants may withdraw from the study at any time, with an early withdrawal, a 
follow-up visit to examine and ensure patient safety.  Withdrawal or 
discontinuation due to an AE will be distinguished from 
withdrawal/discontinuation due to an insufficient response to the study treatment.  
It is rare that the study team will request a subject be withdrawn from the study 
because the treatment is standard of care, but if an adverse event does occur 
requiring the subject be withdrawn, a follow up visit to examine and ensure 
patient safety will be performed. 
6) Risks to Subjects 
The risks of BoNT injection will be reviewed with patients again at time of 
enrollment in this protocol. The possible side effects are:  
• Over relaxation or muscle weakness of the targeted muscles. Furthermore, non-
targeted muscles may be affected.  
• Participants may experience pain and discomfort while receiving the injections.  
• Infection at the injection site. 
• A possibility the muscles will not be targeted similar to your previous treatments and 
you may not experience the same results as previous clinical treatments. 

 
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• Treatment of BoNT to subjects with breathing or swallowing problems poses 
substantial risks. Muscles in the neck that help in breathing and swallowing may be 
over relaxed.  Subjects may experience severe breathing problems, and inability to 
swallow.  Food and water may also enter the lungs.  This potential risk is limited in 
this study because the muscles being injected are not in the neck but in the arm and 
hand. 
• Allergic reaction, and/or skin or eye irritation  
• Nausea 
• Skin inflammation (dermatitis) 
• The spread of BoNT may be life-threatening and may even lead to death, but this 
would be a rare occurrence due to the location of the study drug being injected. 
• Bad effects have been seen in pregnant animals who were given Botox.  Please tell 
your study doctors immediately if you get pregnant while on this study.  If you 
become pregnant, you will be removed from the study.  
• Risk of being videotaped is loss of confidentiality. To reduce this we will not include 
any personal information, such as your name, with the recording. We will discuss this 
with you prior to any recording and we will ask you to sign a separate video 
agreement for this. 
There is no difference in procedures and associated risks due to participation in 
this protocol then treatment for clinical care.  
There is some discomfort and local pain associated with insulated EMG injection 
needles or wire insertions as well as with the current delivered during electrical 
stimulation. Some patients have discomfort for 1-3 hours after hooked wire 
insertion, but most tolerate the procedure well. Patients are free to discontinue 
diagnostic testing or injection at any time. 
There is no medical risk with ultrasound. There may be mild discomfort or skin 
irritation with the coupling gel used on the transducer. 
There is a very small risk that the muscles will not be targeted equally due to 
using only one of the targeting methods to identify the muscle and subject could 
possibly not have results of previous clinical treatments.   
There is a risk should a subject be pregnant or become pregnant during the study. 
These risks are unknown and could minor or major (death). Women of 
childbearing potential will have a pregnancy test prior to treatments and reminded 
to continue to use two forms of contraception. Men should not father a child while 
on this research study and will be requested to use condoms while participating in 
this study.   
The patients have a potential risk for loss of privacy  
There is always the possibility for unknown risks to occur 
7) Provisions for Research Related Injury 

 
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Medical care will be available to participants in the occurrence of any adverse events.  
NIH will provide medical coverage for research-related injury in accordance with 
NIH policy.  For those enrolled the Icahn School of Medicine site, the participant and 
his/her insurance company will be responsible for the medical costs 
8) Potential Benefits to Subjects 
Indirect benefits: 
This study does not offer direct benefit to participants but is likely to yield 
generalizable knowledge about the best therapy paradigms using ona-BoNT. 
While there are no direct benefits to the participants, injections of BoNT may 
alleviate over-active muscles. 
9) Provisions to Protect the Privacy Interests of Subjects 
All study visits will occur in private exam rooms.  Phone calls and any 
information concerning the participant’s involvement of the study will be 
conducted with sensitivity of maintaining the participant’s privacy. 
10) 
Economic Impact on Subjects 
Participants will not be responsible for any costs, and the drug for the treatment 
visit will be provided without cost to the participants. 
11) 
Payment to Subjects 
Participants will receive payments for each study visit for travel in the amount of 
$75 to be provided by check in approximately 4-6 weeks after each completed 
visit.  If extra visits are required, these visits will receive compensation at 
$75/visit. 
12) 
Consent Process 
Consent procedures 
The study teams will use the standard operating procedure for conducting the 
consent form process per the institutional guidelines.  Prior to any study activities, 
participants will be provided a copy of the consent form, and undergo a consent 
process, which includes signing the consent and providing a copy to the subject 
prior to any screening activities. Once the consent process is completed, the 
screening process will be completed.  
All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures and potential risks of the study and of 
their rights as research participants. Participants will have the opportunity to 
carefully review the written consent form and ask questions regarding this study 
prior to signing and at each study visit.   
Consent documents 
The consent document contains all required elements as required by regulations 
and will be provided to the respective institutions for ethical review. . 
Children – N/A;  Cognitively Impaired Adults  - N/A  

 
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Non-English Speaking Subjects 
For non-English speaking subjects at Mount Sinai – currently all subjects treated 
by Drs. Simpson, Frucht and Shin are English speaking  Should a participate 
become eligible that does speak another language other than English, the IRB will 
be contacted and the appropriate translation of the consent will be requested from 
the IRB for approval. The subject will then be included and follow standard 
procedures for non-English speaking according to MSSMs consent SOP (i.e. 
include translator during each study visit). The NIH will follow standard 
procedures for their site when managing non-English speaking subjects.  The NIH 
has a short form consent and the English consent form will be used as the script 
for the short form consent process.   
Waiver or Alteration of the Consent Process – N/A 
13) 
Process to Document Consent in Writing 
The Icahn School of Medicine site will use the SOP-091 and the consent will be 
documented in writing using the standard PPHS consent template. 
The NIH will use the standard consent process in writing as required to meet NIH 
guidelines. 
14) 
Vulnerable Populations 
Indicate specifically whether you will include or exclude each of the following 
populations: 
Include 
Exclude 
Vulnerable Population Type 
 
x 
Adults unable to consent 
 
x 
Individuals who are not yet adults (e.g. infants, children, 
teenagers) 
 
x 
Wards of the State (e.g. foster children) 
 
x 
Pregnant women 
 
x 
Prisoners 
 
15) 
Multi-Site Human Research (Coordinating Center) 
There will not be a coordinating center, but the grant will be managed by Mount 
Sinai, the data will be coordinated by the NIH site.  Drug will be shipped from the 
funding agency as a donation to both sites for the study.   
16) 
Community-Based Participatory Research 
Not/Applicable 

 
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Revised  9/2/14 
17) 
Sharing of Results with Subjects 
Any results which are part of the treatment are available to share with the patient and 
their clinician.  
18) 
IRB Review History 
N/A 
19) 
Control of Drugs, Biologics, or Devices 
Note: The IDS has its own forms that must be completed and a review process that 
must be followed before the IDS representative will sign off on Appendix B for 
submission to the PPHS. 
 
N/A  
References 
• 
ALTER, K. E. 2010. High-frequency ultrasound guidance for neurotoxin 
injections. Phys Med Rehabil Clin N Am, 21, 607-30. 
• 
ALTER, K. E., HALLETT, M., KARP, B. I. & LUNGU, C. 2013. 
Ultrasound-guided chemodenervation procedures : text and atlas, New York, 
Demos Medical Pub. 
• 
BOHANNON, R. W. & SMITH, M. B. 1987. Interrater reliability of a 
modified Ashworth scale of muscle spasticity. Phys Ther, 67, 206-7. 
• 
BURKE, R. E., FAHN, S., MARSDEN, C. D., BRESSMAN, S. B., 
MOSKOWITZ, C. & FRIEDMAN, J. 1985. Validity and reliability of a rating 
scale for the primary torsion dystonias. Neurology, 35, 73-7. 
• 
LANCE, J. W. 1981. Disordered muscle tone and movement. Clin Exp 
Neurol, 18, 27-35. 
• 
MOLLOY, F. M., SHILL, H. A., KAELIN-LANG, A. & KARP, B. I. 
2002. Accuracy of muscle localization without EMG: implications for treatment 
of limb dystonia. Neurology, 58, 805-7. 
• 
PICELLI, A., LOBBA, D., MIDIRI, A., PRANDI, P., MELOTTI, C., 
BALDESSARELLI, S. & SMANIA, N. 2013. Botulinum toxin injection into the 
forearm muscles for wrist and fingers spastic overactivity in adults with chronic 
stroke: a randomized controlled trial comparing three injection techniques. Clin 
Rehabil. 
• 
PICELLI, A., TAMBURIN, S., BONETTI, P., FONTANA, C., 
BARAUSSE, M., DAMBRUOSO, F., GAJOFATTO, F., SANTILLI, V. & 
SMANIA, N. 2012. Botulinum toxin type A injection into the gastrocnemius 
muscle for spastic equinus in adults with stroke: a randomized controlled trial 
comparing manual needle placement, electrical stimulation and ultrasonography-
guided injection techniques. Am J Phys Med Rehabil, 91, 957-64. 
• 
PLOUMIS, A., VARVAROUSIS, D., KONITSIOTIS, S. & BERIS, A. 
2013. Effectiveness of botulinum toxin injection with and without needle 

 
16 
Revised  9/2/14 
electromyographic guidance for the treatment of spasticity in hemiplegic patients: 
a randomized controlled trial. Disabil Rehabil. 
• 
SCHNITZLER, A., ROCHE, N., DENORMANDIE, P., LAUTRIDOU, 
C., PARRATTE, B. & GENET, F. 2012. Manual needle placement: accuracy of 
botulinum toxin A injections. Muscle Nerve, 46, 531-4. 
• 
SIMPSON, D. M., BLITZER, A., BRASHEAR, A., COMELLA, C., 
DUBINSKY, R., HALLETT, M., JANKOVIC, J., KARP, B., LUDLOW, C. L., 
MIYASAKI, J. M., NAUMANN, M. & SO, Y. 2008. Assessment: Botulinum 
neurotoxin for the treatment of movement disorders (an evidence-based review): 
report of the Therapeutics and Technology Assessment Subcommittee of the 
American Academy of Neurology. Neurology, 70, 1699-706. 
• 
TEASELL, R., FOLEY, N., PEREIRA, S., SEQUEIRA, K. & MILLER, 
T. 2012. Evidence to practice: botulinum toxin in the treatment of spasticity post 
stroke. Top Stroke Rehabil, 19, 115-21. 
• 
WARD, A. B. 2008. Spasticity treatment with botulinum toxins. J Neural 
Transm, 115, 607-16. 

 
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Revised  9/2/14 
 
Appendix 1  
 
Visual analog scales: Benefit, Weakness, Discomfort  
 
Visit 2 and 4  
 
Benefit 
 
Mark a vertical line that best demonstrates how beneficial you found the injections. 
 
 
No improvement 
 
 
 
 
 
 
   Normal use 
 
 
 
 
 
 
How long after the injection was any benefit first noted?  
 
 
How long until maximal benefit was reached? 
 
 
How long did the maximal benefit last? 
 
 
How long did any benefit last? 
 
 
 
Weakness 
 
Mark a vertical line that best demonstrates how weak you have felt after the injections. 
 
 
No weakness 
 
 
 
 
 
 
         Unable to move 
 
 
 
 
 
 
How long after the injection was weakness first noticed?  
 
 
How long until maximal weakness was reached? 
 
 
How long did the maximal weakness last? 
 
 

 
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How long did any weakness last? 
 
 
 
Visit 1 and 3  
 
Discomfort 
 
Mark a vertical line where you feel best represents your pain or discomfort during the treatment. 
 
No Pain  
 
 
   
 
 
  Worst possible pain