Conditions: Neuropathic Back Pain Spinal Cord Injury
Keywords: Botulinum Toxin A Neuropathic pain Spinal cord injury Pain management Rehabilitation
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 8
Healthy volunteers: no

Brief summary:
Back pain is a common secondary condition of both acute and chronic spinal cord injury (SCI). Current existing treatment including both pharmacologic and non-pharmacologic are limited by marginal efficacy or intolerable side effects. The purpose of this study is to evaluate the potential of subcutaneous injections of botulinum toxin A to provide pain relief in spinal cord injury patients with back pain near the level of injury in the spine. Botulinum toxin A has been shown in both pre-clinical and clinical studies to help with nerve pain. The researchers propose a double blinded placebo controlled crossover study to study the effects of subcutaneous botulinum injections to at--level SCI back pain in patients with spinal cord injury.

Detailed description:
In this study, there will be 2 procedure performed. The first procedure will be named P1 and consists of subcutaneous injection of either placebo or Botulinum Toxin A. The second procedure will be the cross-over procedure named P2. For the cross-over procedure, the subjects who had initially received Botulinum Toxin A will receive placebo and the subjects who had initially received placebo will receive Botulinum Toxin A. This is a Randomized Double-Blinded Placebo Controlled Trial. Recruited subjects will be consented, enrolled and evaluated immediately prior to P1 (or during a visit prior to the visit for P1). After the initial pre-treatment evaluation, subjects will randomly receive either placebo or Botulinum Toxin A subcutaneously (P1). A telephone follow-up (or e-mail follow up) will be performed at 2 weeks and 8 weeks post- P1. An onsite follow up will be performed 4 weeks post P1 and 12 weeks post P1.

Cross-over Study: After the 3rd month on-site evaluation (12 weeks post P1), during the same visit, the subject will proceed to the cross-over study. At this time, the patient will have the option to receive a repeat subcutaneous injection of the cross-over agent. If they desire one, a subcutaneous injection of the cross-over agent will be performed at that same visit. If they wish to defer the repeat injection, they will be contacted and asked every 4 weeks - between 12 weeks and 24 weeks post P1 (no subject will receive P2 after week 24) if they would like to have the subcutaneous injection of the cross-over agent. If they desire one, a repeat injection will be scheduled for the following week.

The rationale for a variable length of time after the initial Botulinum Toxin A/Placebo injection (P1) is to document the variability of individuals' pain response after Botulinum Toxin A. It has been reported in literature, of the subjects that respond to subcutaneous Botulinum Toxin A injections for pain, most will return to their base-line pain score in 12--24 weeks.

Arms:
arm 1: Each vial of botulin toxin (100U, BOTOX, Allergan) will be reconstituted with 4ml non-preserved saline solution (0.9%) as recommended by the manufacturer (concentration of 5 units Botulinum Toxin A/0.2ml). Each injection will be 0.2mL (BOTOX, 5 units), administered through a 25 gauge needle. The marked area will have subcutaneous injections, each separated by a radius of 1 cm, from the other injections into the marked area,(maximum of 80 injections, 400 Units). arm 2: Placebo consists of 0.9% normal saline. Each injection will be 0.2mL, administered with a 25 gauge needle subcutaneously into the affected area. The marked area will have subcutaneous injections (maximum of 80) each separated from the surrounding ones by a radius of 1 cm.

Interventions: intervention 1: Botulinum Toxin A intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects will receive subcutaneous Botulinum Toxin A injections into the marked painful region. The syringes will be prepared by a third party prior to the injection and the administrator of the procedure will be blinded to syringe content. This physician will be performing the injections under sterile conditions. Local anesthesia, EMLA (lignocaine/prilocaine eutectic mixture) cream, up to 4 grams, will be applied topically for local anesthesia. After 50 minutes, the cream will be cleaned off. Overlying skin will be sterilized with either betadine or alcohol solution. intervention 2: Subjects will receive subcutaneous placebo injections into the marked painful region. The syringes will be prepared by a third party prior to the injection and the administrator of the procedure will be blinded to syringe content. This physician will be performing the injections under sterile conditions. Local anesthesia, EMLA (lignocaine/prilocaine eutectic mixture) cream, up to 4 grams, will be applied topically for local anesthesia. After 50 minutes, the cream will be cleaned off. Overlying skin will be sterilized with either betadine or alcohol solution.

Protocol document:
Prot_000.pdf: 




2 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
controlled cross- over study in which persons with SCI who report the presence of at-
level SCI pain of at least moderate intensity for at least 4 weeks (with or without 
musculoskeletal back pain that has been clearly differentiated by the subject from the at 
level SCI pain) will receive either subcutaneous BoNT or placebo through subcutaneous 
injections (maximum of 80) during one visit within the dermatomes where the pain is 
located. We predict that patients with one-time subcutaneous administration of BoNT at 
the site of pain will significantly decrease the average daily intensity of the pain for at 
least 12 weeks post treatment. 
 
Subjects will be evaluated at baseline and post-injection at 2 weeks, 4 weeks, 8 weeks, 
and 12 weeks. Subjects will be crossed over after 12 weeks. Subjects that had initially 
received subcutaneous BoNT will receive subcutaneous placebo and vice versa. Subjects 
can elect to have the repeat injection at the time of crossover or opt to postpone the 
injection each 4-week period, for up to 12 weeks if pain control is deemed adequate. 
Following the cross-over injection, subjects will be evaluated at 2 weeks, 4 weeks then 
every 4 weeks for 12 weeks to determine the magnitude and duration of pain relief. 
Depending on when the cross-over injection is administered, crossover follow-up could 
range from 12 to 24 weeks. 
 
1) Objectives: 
 
Research Question: Will subcutaneous injections of botulinum toxin A provide pain 
relief in spinal cord injury patients with back pain near the level of injury in the spine? 
 
We hypothesize that in persons who have at level SCI pain localized to the back, a 
one-time subcutaneous administration of BoNT at the site of pain will significantly 
decrease the average daily intensity of the pain for at least 12 weeks post treatment. 
 
This study will investigate whether BoNT is safe and effective for the control of at-level 
SCI pain. If BoNT is effective, this approach has significant advantages over the majority 
of existing treatment strategies in that systemic side effects are rare, has no abuse 
potential, and is minimally invasive. 
 
2) Background 
 
Back pain is a common secondary condition of acute and chronic spinal cord injury (SCI) 
which impacts activity, participation and quality of life.(1, 2) Back pain, which includes 
both neuropathic and nociceptive subtypes, has been reported to occur in 18-84% of 
persons with SCI. (2-12) Historically, it has been difficult to classify pain in patients with 
SCI and multiple classifications have been proposed . Recently, experts in the field


3 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
published a consensus classification, the International Spinal Cord Injury Pain (ISCIP) 
Classification system. Despite the ISCIP classification system, back pain in SCI located 
at the neurological level of injury can be difficult to classify in some patients. This may 
be because back pain in SCI can present with both neuropathic and nociceptive features. 
(26) 
 
At-level SCI (neuropathic) pain as defined within the ISCIP is a subtype of neuropathic 
pain that occurs within three dermatome levels at or below the neurological level of 
injury (NLI). It is believed to arise as a result of damage to the spinal cord or its nerve 
roots. (27) The presentation of neuropathic pain may include both evoked (allodynia and 
hyperalgesia) and non-evoked (spontaneous) pain. In SCI, the character of neuropathic 
pain is often described as “tightness”, “pressure” or “burning” in people with thoracic 
level injuries, and as “numbness”, “tingling”, “heat” or “cold” in those with cervical 
injuries. (1, 28) At-level (neuropathic) SCI pain is common, with a prevalence of about 
40% at all years post injury.(1) Despite current use of a wide variety of pharmacological 
treatments including anticonvulsants, tricyclic antidepressants, topical sodium channel 
blockers, gabapentinoids, serotonin-norepinephrine reuptake inhibitors, 
selective-serotonin reuptake inhibitors and opioid medication, it remains difficult to 
control. Most of the medications have limited efficacy, similar to placebo, or marginally 
better; therefore, there is a need for new treatments.(13-16, 29) 
 
Botulinum toxin A is a neurotoxin protein produced by the bacterium Clostridium 
botulinum. It is a neuropeptide that acts at the pre-synaptic SNARE complex at the 
neuronal endplate, specifically cleaving the SNAP-25 protein, preventing vesicular 
docking at neuronal endplates, thus inhibiting the release of acetylcholine at the 
neuromuscular junction. (47) On average, the onset of action of the toxin occurs 6 hours 
after administration, with the clinical effects evident within 2 to 3 days. (48) The peak 
clinical effect occurs about 2 weeks after administration, followed by approximately 10 
weeks of stable results. (48) It is commonly used in the treatment of myofascial diseases 
and neuromuscular hyperactivity diseases. Recently, animal model and clinical studies 
have shown that this mechanism of action can also be applied to neuropathic and 
nociceptive pain.(21-25, 47, 49-63) 
 
The exact mechanism of action of BoNT in pain is not fully understood. It has been 
shown that at the level of the peripheral nerves BoNT inhibits synaptic release of 
neuropeptides related to pain transmission. Glutamate, substance P, and calcitonin 
gene-related peptide are neuropeptides related to pain.(64-67) In rodent studies, 
administration of botulinum toxin is associated with the decreased secretion of glutamate,


4 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
substance P and calcitonin gene-related peptide (CGRP), as well as the increased 
appearance of cleaved SNARE proteins.(64-67) In normal physiology, neuropeptides are 
stored within vesicles at the nerve terminal. The SNARE protein complex allows docking 
of the vesicle to the nerve ending, followed by the release of the neuropeptides into the 
neuromuscular junction (NMJ). BoNT inhibits the secretion of the neuropeptides by 
cleaving the SNARE complex, thus preventing the docking and release of neuropeptides. 
(47) Neuropeptide release is not the only action within the cell that relies on intracellular 
vesicular docking. Ion receptor channels, like the transient receptor potential cation 
channel subfamily V member 1 (TRPV1), also rely on the vesicular docking to express 
itself.(68) The TRPV1 is a calcium-permeable, ionic receptor that is considered an 
integrator of heat perception and nociception (e.g. capsaicin) and has been shown to 
heighten the excitability of nociceptors. It is dependent on the SNARE protein for its 
expression on the cell membrane. In vitro studies with amphibian oocytes have 
demonstrated that the presence of BoNT reduces expression of TRPV1 on the cell 
surface.(68, 69) Together, these studies highlight the probable mechanism of BoNT at the 
peripheral nervous system and its basis for pain control at a cellular level. 
 
BoNT has been shown to act at the level of the central nervous system. When injected 
directly into the intrathecal space, BoNT decreases the pain in the peripheral limbs of 
rodents (54). An interesting concept is the transportation of the toxin from the peripheral 
limb to the central nervous system. This was demonstrated by Bach-Rojecky et al. after 
they had injected BoNT into one (ipsalateral) limb of rodents with painful diabetic 
neuropathy. (54, 55) They found that a pain-like behavioral response in both the 
ipsalateral and the contralateral side was reduced compared to control groups, suggesting 
that BoNT had an effect in the central nervous system despite it administration in the 
periphery. (54) Other studies have shown that BoNT can be transported both anterograde 
and retrograde along the nerve axon.(70, 71) These studies together demonstrate that 
peripherally administered BoNT can act at the central and peripheral nervous system to 
control the transmission of pain. 
 
In addition to the pre-clinical research that is performed on animal models, there have 
been a number of published clinical studies and case reports using subcutaneous 
administration of BoNT in the treatment of neuropathic pain. Randomized, 
double-blinded, placebo-controlled studies have shown efficacy in neuropathic pain 
control in subjects with post-herpetic neuralgia, (22, 72) post-traumatic/post- operative 
neuropathy(53, 58) and painful diabetic neuropathy.(24) In addition, there are multiple 
prospective studies showing possible efficacy of subcutaneous BoNT in the treatment of


5 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
trigeminal neuralgia, (21, 23, 47) and case reports reporting the benefit of BoNT in the 
treatment of complex regional pain syndrome (CRPS)-related neuropathic pain, (57, 73) 
post-thoracotomy neuropathic pain(58) and at-level SCI neuropathic pain. (25) In one 
case report, Jabbari et al. describes two patients with cervical spinal cord lesions (tumor 
and cord ischemia) who developed at-level (neuropathic) SCI pain and failed oral 
medications. After the administration of subcutaneous BoNT injections, there was 
clinically significant pain relief that continued to persist beyond 3 months.(25) 
 
BoNT has been shown to have a favorable safety and tolerability profile across a broad 
spectrum of therapeutic uses. (48, 74) Compared to gabapentin, a commonly prescribed 
medication for neuropathic pain, adverse events with BoNT are less frequent and less 
severe. (74) Adverse events reported to be associated with BoNT administration are 
generally related to the mechanism of action of the toxin, most commonly 
dose-dependent focal weakness. Other local side effects include short-duration injection- 
associated pain, edema, erythema, ecchymosis, headache and short-term hyperesthesia. 
(74) These side effects are usually temporary. Systemic side effects include nausea, 
fatigue, malaise, rash and flu-like symptoms. There has been a case report suggesting a 
possible anaphylaxis reaction to the toxin; (75) however, in clinical trials, there has not 
been any reported anaphylaxis or any serious systemic adverse effects related to BoNT. 
(74, 76) Long term studies on the safety of BoNT have found the appearance of primary 
and secondary resistance over a 10-year period (resistance defined as <25% improvement 
after 2- 3 consecutive treatments). (74) There was no other identified long term side 
effect. If we combine the reported data of clinical studies (21-25, 53) using subcutaneous 
BoNT injections (6 studies, total of 73 subjects receiving BoNT), the incidence of AE is 
under 5% (3AE out of 73 subjects), the most common being local swelling at the 
injection site. There were no permanent side effects reported. It is also noted in the 
literature that the subcutaneous injection may cause mild-moderate pain during the actual 
procedure itself.(22, 23) 
 
Sub-cutaneous administration of botulinum toxin A (BoNT) has been reported in the 
literature to decrease neuropathic pain in patients with a variety of conditions, including 
post-herpetic neuralgia, post- traumatic/post-operative neuropathy and diabetic 
neuropathy. Recent animal studies have demonstrated that BoNT has a significant effect 
on both the peripheral and the central nervous system. 
 
Of note, a few studies have demonstrated that intramuscular botulinum toxin 
administration has demonstrated pain relief in low back pain, and myofascial pain 
syndrome. (51, 59, 61-63)


6 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
3) Setting of the Human Research 
 
This study will be a randomized double-blinded placebo controlled cross-over study in 
which 32 human subjects with at-level SCI (neuropathic) back pain will receive either 
subcutaneous normal saline (placebo) or botulinum toxin injections. The subjects will 
have the procedure performed in an outpatient clinic setting at Mount Sinai Hospital with 
follow up (office visit, telephone or internet email follow-up) at 2 weeks, 4 weeks, 8 
weeks, and 12 weeks post-injection. Subjects will then be crossed-over. Those who had 
received placebo will receive BoNT and vice versa. They will be followed every 4 weeks 
after the cross-over agent (office visit, telephone or internet email follow-up) to 
determine the magnitude and duration of pain relief. 
 
4) Resources Available to Conduct the Human Research 
 
The proposed study aims to recruit 32 individuals with traumatic SCI. More than 110 
patients with SCI are admitted to Mount Sinai’s inpatient rehabilitation program each 
year, and many more return for outpatient medical and therapy services. Given past 
experience, we expect it will be feasible to recruit the desired number of subjects in a 
reasonable timeframe. 
 
Study procedures will be conducted by attending physicians and residents with support 
from one research assistant who is acting under the supervision of project investigators. 
All research staff have prior experience working with individuals with SCI at Mount 
Sinai Medical Center. All study staff have also completed all required PPHS education 
training modules related to Human Subjects Research Protections, Data Security, and 
HIPAA for Research. All investigators and research staff have been involved in the 
conduct of research studies with this participant pool, and are knowledgeable about the 
Mount Sinai study site and societal and cultural considerations relevant to those eligible 
for the study. Regular communications will occur between the investigators and all 
research team members to ensure that details of the protocol are communicated to all and 
that all staff are familiar with their study-related duties and functions. 
 
5) Study Design 
 
a)      Recruitment Methods 
 
Potential subjects will be recruited from a number of sources: 
 
1.         The outpatient SCI clinical practices at Mount Sinai Hospital and its affiliated Faculty 
Practice Associates. Most outpatients with SCI are seen by the investigator on this




8 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
2.  History of intolerance, hypersensitivity or known allergy to botulinum toxin or its 
preservatives 
 
3. History of intolerance, hypersensitivity or known allergy to EMLA cream 
(lignocaine/prilocaine  eutectic mixture) which is used as an analgesic during BoNT 
injection 
 
4. Recent history of administration of botulinum toxin (within previous 6 months) 
 
5. Contraindications to botulinum toxin (myasthenia gravis or other disease of the 
neuromuscular  junction) 
 
6. Coagulation disorder 
 
7. Current infection 
 
8. Insufficient command of English to complete self-report instruments. 
 
c)       Number of Subjects 
 
We conducted power analyses for the primary outcome of change on the Numeric Pain 
Rating Scale (NPRS) from baseline to the 4 week time point for proportions of 
participants expected to exceed the minimal clinical important difference (MCID). The 
analysis for a cross-over design was based on assumptions that the MCID value of a 
decrease in pain rating is 2/10 or more points (78) on NPRS, that 30% of participants in 
the placebo group would have a positive response to treatment (79), and that 40% more 
participants (70%) would respond in the treatment group.(24) Assuming two-sided alpha 
of 0.05, a sample size of 28 will provide 86% power that a difference will be fund. 
Assuming a 15% drop out rate, a sample size of 32 enrolled participants is necessary for 
the study to be sufficiently powered to detect a treatment effect. 
 
d)      Study Timelines 
 
In this study, there will be 2 procedure performed. The first procedure will be named P1 
and consists of subcutaneous injection of either placebo or BoNT. The second procedure 
will be the cross-over procedure named P2. For the cross-over procedure, the subjects 
who had initially received BoNT will receive placebo and the subjects who had initially 
received placebo will receive BoNT. 
 
Randomized Double-Blinded Placebo Controlled 
 
Recruited subjects will be consented, enrolled and evaluated immediately prior to P1 (or 
during a visit prior to the visit for procedure P1). After the initial pre-treatment


9 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
evaluation, subjects will randomly receive either placebo or BoNT subcutaneously (P1). 
A telephone follow-up (or e-mail follow up) will be performed at 2 weeks and 8 weeks 
post-P1. An onsite follow up will be performed 4 weeks post P1 and 12 weeks post P1. 
 
Cross-over Study 
After the 3rd month on-site evaluation (12 weeks post P1), during the same visit, the 
subject will proceed to the cross-over study. At this time, the patient will have the option 
to receive a repeat subcutaneous injection of the cross-over agent. If they desire one, a 
subcutaneous injection of the cross-over agent will be performed at that same visit. If 
they wish to defer the repeat injection, they will be contacted and asked every 4 weeks 
(between 12 weeks and 24 weeks post P1 (no subject will receive P2 after week 24) if 
they would like to have the subcutaneous injection of the cross-over agent. If they desire 
one, a repeat injection will be scheduled for the following week. 
 
The rationale for a variable length of time after the initial BoNT/Placebo injection (P1) is 
to document the variability of individuals’ pain response after BoNT. It has been reported 
in literature, of the subjects that respond to subcutaneous BoNT injections for pain, most 
will return to their base-line pain score in 12-24 weeks.(24, 25, 51, 52) 
 
After P2, a telephone follow-up (or e-mail follow up) will be performed at 2 weeks and 2 
8 weeks. An onsite follow up will be performed 4 weeks post P2 and 12 weeks post P2. 
Subjects will be continued to follow monthly until 24 weeks post P2 to determine 
duration of effectiveness. 
 
The following outlines the sequence of study procedures for four groups of subjects, 
those asking for reinjection at 12 weeks (group 1), 16 weeks (group 2), 20 weeks (group 
3) or 24 weeks (group 4), respectively


10 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
P1 = procedure 1 
P2 = procedure 2 
Office = onsite evaluation 
Tel = telephone contact, evaluation or internet evaluation 
 
 
 


11 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
 
 
The anticipated enrollment end date is December 2018. The study data collection will be 
completed within 6 months following the last participant enrollment.


12 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
e)        Study Endpoints 
 
A number of outcome measures will be used, as listed below: 
 
1. Pain intensity – past week. Average pain intensity over the past week will be the 
primary outcome measure for determining treatment effect. Subjects will be asked to 
rate their average pain over the past week on a 0-10 numeric pain rating scale (NPRS) 
with end points 0=“no pain” and 10=“pain as bad as you can imagine.” Average pain 
over the past week is part of the International Spinal Cord Injury Pain Basic Data Set 
(ISCIPDS) (80) whose validity and utility in persons with SCI has been demonstrated 
(81); it also is among measures recommended for use in SCI clinical trials. (82) The 
lowest and highest pain intensity over the past week will also be recorded to provide 
additional descriptive information about the pain the participants are experiencing. 
 
2. Douleur Neuropathique 4 Questions (DN4) – This is an originally French instrument 
designed to discriminate between neuropathic and non-neuropathic pain. No 
psychometric testing in the English version of the instrument has been performed for 
SCI. In French and Swedish versions, it has shown good inter-rater reliability and 
validity. (82) It consists of 10 items, each scored on a binary scale. This test will be 
used to distinguish between at level (neuropathic) pain and nociceptive pain in SCI 
subjects. 
 
3. Spinal Cord Injury Pain Instrument (SCIPI Version 1.1). The SCIPI is an interview 
based screening instrument consisting of 7 items designed to differentiate neuropathic 
from non- neuropathic pain in individuals with SCI. 
 
4. International Basic Pain Dataset. The International Basic Pain Dataset is an 
assessment tool which includes several components including: location of pain, 
temporal qualities of the pain, type of pain, pain interference measures of activity, 
sleep, and mood. It has been shown to be valid in an interview/self-report format.(81) 
This will be collected for up to 3 pains localized to the back which can be 
differentiated as unique pains. These pains may or may not be neuropathic. 
 
5. 7­Point Guy/Farrar Patient Global Impression of Change (PGIC) – This scale 
measures the global treatment effect from very much improved to very much worse. 
Subjects will be asked to rate the treatment’s effect at each re-evaluation. In this 
investigation, the PGIC rating will take the form of, “Taking into account your pain 
level and how it affects your life, are you feeling better, the same or worse than when 
you started treatment?” If the individual states that there is no change, then the rating 
is complete. If he or she is worse or better, the individual is asked to quantify the


13 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
magnitude of the change as 1-very much better; 2-better; 3-somewhat better; or 5- 
somewhat worse; 6-worse; 7-very much worse. The PGIC will be a secondary 
outcome measure of treatment effect. The PGIC one of the recommended scales for 
measuring the global treatment effect and can be used to complement the 
one-dimensional pain intensity scales. (82) 
 
6. Adverse Effects (AE) – Subjects will be monitored for adverse effects. As mentioned in 
the literature review, the most common side effects are focal weakness, local edema, 
short-term hyperesthesia, fatigue, malaise, and flu-like symptoms. There are no 
expected serious side effects. 
 
7. Pain Medication Usage/Other treatments – Subjects will be asked to report the use or 
lack of use or changes in dose or use of other pain medications and other treatments 
they are receiving. 
 
8. Static and Dynamic Mechanical Allodynia testing. Mechanical allodynia is a 
characteristic of evoked pain in subjects with neuropathic pain. Static allodynia to 
mechanical stimuli will be defined as a sensation of pain evoked by the pressure of 
the end of a wooden stick. The end of a wooden stick will touch the affected region 
with enough pressure to indent the skin, for 10 seconds. Afterwards, the subject will 
be asked to rate the perceived pain on an 11-point NRS. Dynamic allodynia will be 
tested by stroking the affected region gently with a cotton swab, 4 times at a rate of 
3-5cm per second over an area of 5cm. If there is an evoked clear sensation of pain, 
the subject is asked to rate the intensity of dynamic allodynia using the 11-point NRS. 
The region of static and dynamic allodynia, if present, will be marked and recorded. 
 
9. Punctate Hyperalgesia. Punctate hyperalgesia will be defined as the altered sensation 
produced with a safety pin when applied to the marked identified painful region as 
compared to a reference region (an area of normal sensation above the level of 
injury). The reference region will be tapped twice with a safety pin for about half a 
second with a 5 second interval between taps. The subject will rate his or her pain 
with the 11-point NRS. Then, the test will be repeated on the affected region and the 
subject will be asked to rate their pain again. The test is considered positive if there is 
an increase of at least 2 points on the 11-point NRS for pain. 
 
10.  
Wind­up pain/Temporal Summation. Mechanical wind-up pain will be defined as 
the perceived increase in pain intensity when a painful stimulus is delivery 
repeatedly. To test for mechanical wind-up pain, the reference region (an area of 
normal sensation above the level of injury) will be tapped with the safety pin at a rate


14 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
of approximately 2-3 taps per second (2Hz) for 30 seconds. The subject will rate his 
or her pain on the 11-point NRS. Then, the test will be repeated on the affected 
region. The subject will be asked to rate the pain caused by the safety pin at the end 
of the test using the 11-point NRS for pain. The test is considered positive if there is 
an increase of at least 2 points on the 11-point NRS for pain. 
 
11.  
Patient Generated Index (PGI). Activity is highly individual-specific, and it is not 
thought that any of the standard validated functional instruments, such as the 
Functional Independence Measure (FIM), would be sensitive in detecting changes in 
activity due to decreasing pain. We will adapt the Patient-Generated Index (83, 84) to 
develop an individualized measure of activity that is sensitive to short-term changes 
in activity levels due to a change in pain severity. In the PGI, subjects are asked to: 
(1) list five activities that are affected by their pain (a listing of activities nominated 
by many SCI subjects with pain may be used to stimulate their memory); (2) rate how 
they function in each chosen area, on a scale from 0 to 100, where 0 represents the 
worst they can imagine, and 100 means “exactly as they would like to be”; and (3) 
quantify the relative importance of these five areas by distributing 50 points over 
them, thus assigning importance weights. The PGI score is calculated as the sum 
(across the five areas) of the products of importance and rating of pain effect. A 
decrease in pain resulting in improvement in activity level would result in a higher 
PGI score. As in other studies utilizing “customized” functional or quality of life 
measures (85, 86) the PGI was found to be more sensitive to low back pain 
interventions than were other standard measures. (84) To accomplish a high level of 
sensitivity, the subject-identified activities in the present study must be ones that (1) 
are completed at least weekly (actually or preferentially), (2) at baseline, are rated at 
75 or less on the 0-100 scale (to offer room for gain), and (3) are not limited by the 
SCI itself, but are stated to be limited by the pain. We will ask subjects to complete 
the PGI first at the initial assessment visit (Visit 1). At all later follow up, subjects 
will perform only steps (2) and (3) above, guaranteeing that the activities considered 
are the same throughout the study. Statistical analysis will consider the effect, if any, 
of changes in importance weights over time (step 3). If these are significant, either the 
baseline weights will be used throughout, or an average of the weights for the same 
activity will be used at all time points. The PGI will serve as a secondary outcome 
measure of treatment effect. 
 
12.  
Back pain impact. For many patients, the (almost) continuous presence of pain in 
the back from the moment of getting up in the morning is what in its cumulative


15 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
effect limits their activity level. Thus, even if the maximum pain severity remains 
unchanged with BoNT injection, pain over a shorter time may be a worthwhile 
outcome. To assess this, participants will be asked to report on the day of evaluation 
(1) on average, for the past week, what time did you get up; (2) on average, for the 
past week, about what time, if at all, did your pain become so problematic or 
significant that you stopped the activity you were doing, or at least modified it (going 
slower, etc.) or took a rest; (3) on average, for the past week, how often did the pain 
become so significant that you stopped what you were doing and took a rest? (4) If 
you did take a rest, how long of a rest do you have to take before you are able to 
resume the activity you were doing? 
 
f)       Procedures Involved in the Human Research 
 
Study Design 
 
This is a randomized double-blind placebo controlled cross-over study. 
 
Study Procedure 
 
Recruited subjects will be consented, enrolled and evaluated. During the pre-procedure 
evaluation, subject history and a physical exam will provide information about the pain, 
including localization, pain characteristics, and current analgesics medication use. The 
subjects’ existing medical therapy (including analgesics) will be continued during the 
study period (but changes, e.g. decrease in analgesic intake, will be noted). 
 
During the physical exam, the painful region will be identified with palpation. The 
borders of the painful region will be marked with a marker. Using a plastic circle cutout 
with a 1cm radius, injection sites will be measured out and clearly marked. Photographs 
of the marked painful region with the identified injection sites will be taken, printed out 
and kept on file. For the cross-over injection procedure, the images will be used to 
replicate the injection pattern. Subjects can elect to have the procedure performed on the 
same day as their evaluation or return at a later date to have the procedure performed. 
 
Subjects will receive subcutaneous injections into the marked painful region. The 
injection will consist of either placebo or BoNT. The syringes will be prepared by a third 
party prior to the injection and the administrator of the procedure will be blinded to 
syringe content. This physician will be performing the injections under sterile conditions. 
Local anesthesia, EMLA (lignocaine/prilocaine eutectic mixture) cream, up to 4 grams, 
will be applied topically for local anesthesia. After 50 minutes, the cream will be cleaned 
off. Overlying skin will be sterilized with either betadine or alcohol solution.


16 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
1. Placebo: Placebo consists of 0.9% normal saline. Each injection will be 0.2mL, 
administered with a 25 gauge needle subcutaneously into the affected area. The marked 
area will have subcutaneous injections (maximum of 80) each separated from the 
surrounding ones by a radius of 1 cm. 
 
2. Botulinum Toxin: Each vial of botulin toxin (100U, BOTOX, Allergan) will be 
reconstituted with 4ml non-preserved saline solution (0.9%) as recommended by the 
manufacturer (concentration of 5 units BoNT/0.2ml). Each injection will be 0.2mL 
(BOTOX, 5 units), administered through a 25 gauge needle. The marked area will have 
subcutaneous injections, each separated by a radius of 1 cm, from the other injections into 
the marked area, (maximum of 80 injections, 400 Units). 
 
The procedure described above, adapted from recent studies using subcutaneous 
injections of BoNT, is estimated to last about 45 to 60 minutes. (22-24). Patients will be 
monitored for 5 minutes post-procedure for immediate adverse effects. There are no 
expected serious adverse effects. 
 
The procedure above will be repeated for the cross-over portion of the study. 
 
Procedures to Lessen the Probability or Magnitude of Risk 
 
Risks are expected to be low because no reported significant adverse events have been 
reported in the literature. The procedure will be performed under sterile condition and 
patient will be monitored 5 minutes post procedure for any adverse effects. Patients will 
be educated on known adverse events of BoNT and will be provided a contact number 
should there be any questions. For serious adverse events they will be referred to the 
nearest emergency room. 
 
g)      Specimen Banking 
 
Not Applicable 
 
h)      Data Management and Confidentiality 
 
All research data will be kept in password-protected files on the Mount Sinai network or 
in hard copy form in locked files in the offices of research staff. All research data will be 
labeled with a study ID number rather than subject name. Subject contact information and 
a list matching subject names with IDs (linking file)* will be kept separate from research 
data. Data will be stored until the conclusion of the project (including composition of 
manuscripts) and as long as necessary to ensure compliance with regulatory 
requirements. Data will be accessible to Mount Sinai investigators only.


17 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
* The linking file will be stored electronically on a Mount Sinai server. As with all other 
electronic files containing data or participant information, the file will be secured by two 
levels of password protection, one at the level of the workstation from which the server 
will be accessed and another at the level of the file itself. 
 
i)       Provisions to Monitor the Data to Ensure the Safety of subjects 
 
Part I: Elements of a Data and Safety Monitoring Plan 
 
1. MSSM Principal Monitor: 
 
Principle Investigator: 
Last Name: Bryce 
First Name: Thomas 
 
Academic Title: MD 
 
Department: Rehabilitation Medicine 
 
 
 
 
 
 
Phone: 212-241-6321 
 
Fax: 212-369-6389 
 
E-mail: Thomas.bryce@mountsinai.org 
 
2. Patient monitoring will be conducted by the principal investigator. The principal 
investigator has prior experience working with individuals with SCI at Mount Sinai 
Medical Center, as well as experience with botulinum toxin in intramuscular injections. 
3. Adverse events, subject compliance with the protocol and drop outs will be monitored 
for safety. 
 
4. Significant adverse events are not expected to occur. Thus, accumulated adverse events 
will be reviewed quarterly. 
 
5. There is no expected interruption or alteration of the study design. 
 
6. There are no expected dose selection procedures to be performed to minimize toxicity. 
 
7. There is no specialized grading system that will be used to evaluate adverse events. 
 
8. Physicians will complete case forms, and turn them over to the research assistant. The 
assistants will review them for completeness, legibility and clarity, and return them to the


18 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
physician as necessary. The research assistant will enter the data in an Excel file; all 
entries will be compared by an investigator against the case report form (CRF), and errors 
corrected. The PI will monitor the presence of all CRFs to be completed over time for 
each subject. 
 
9. In addition to the PPHS, the FDA, sponsor and IRB will be notified should there be a 
temporary or permanent suspension of the study. 
 
j)       Withdrawal of Subjects 
 
Participants may withdraw voluntarily from the study at any time. No negative effects are 
expected to be experienced by participants who choose to withdraw from the study. 
Participants may be withdrawn from the study by the investigators without their consent 
if it is determined that their eligibility or appropriateness for inclusion changes after 
enrollment. Once a participant withdraws (or is withdrawn) from study participation, all 
study procedures for that participant will cease. The participant will continued to be 
followed for adverse events. 
 
6)      Risks to Subjects 
 
BoNT has been shown to have a favorable safety and tolerability profile across a broad 
spectrum of therapeutic uses. (48, 74) Compared to gabapentin, adverse events in BoNT 
are less frequent and less severe. (74) Adverse events reported to be associated with 
BoNT administration are generally related to the mechanism of action of the toxin, most 
commonly dose-dependent focal weakness. Other local side effects include 
injection-associated pain, edema, erythema, ecchymosis, headache and short-term 
hyperesthesia. (74) These side effects are usually temporary. Systemic side effects 
include nausea, fatigue, malaise, rash and flu-like symptoms. There has been a case 
report suggesting a possible anaphylaxis reaction to the toxin; (75) however, in clinical 
trials, there has not been any reported anaphylaxis or any serious systemic adverse effects 
related to BoNT. (74, 76) Long term studies in the safety of BoNT have found the 
appearance of primary and secondary resistance over a 10-year period (resistance defined 
as <25% improvement after 2-3 consecutive treatments). (74) There was no other 
identified long term side effect. If we combine the reported data of clinical studies 
(21-25, 53) using subcutaneous BoNT injections (6 studies, total of 73 subjects receiving 
BoNT), the incidence of AE is 5% (3AE out of 73 subjects), the most common being 
local swelling at the injection site. There were no permanent side effects reported. It is 
also noted in the literature that the subcutaneous injection may cause mild-moderate pain 
during the actual procedure itself.(22, 23)


19 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
7)      Provisions for Research Related Injury 
 
The physicians performing the procedure are trained and experienced clinicians and can 
take action if they observe any signs of harm. In case of adverse events, subjects will be 
referred to their own physician, to the Mount Sinai Emergency Room, or to a 
psychological counselor in their own community, as deemed appropriate. 
 
8)      Potential Benefits to Subjects 
 
Participants in this study may or may not experience direct benefits. The direct benefit 
would be temporary (12+ weeks) relief of at-level back pain. 
 
9)      Provisions to Protect the Privacy Interests of Subjects 
 
Communications with participants will take place at a place and time of their choosing. 
Conversations with and physical examinations of participants will take place in private 
locations (i.e. exam room with closed door) to avoid participants being seen or overheard 
by others not involved with the study. Participants will be asked if they are comfortable 
with the setting of the examination before it begins. Research team members will have 
received training in appropriate interactions with research participants and will approach 
all participants in a respectful manner. 
 
10)    Economic Impact on Subjects 
 
No medical costs will be incurred as part of participation in this study. Participants will 
be expected to travel to Mount Sinai Hospital either three or four times. There are no 
plans for reimbursement at this time. 
 
11)    Payment to Subjects 
 
There will be no payments to the subject at this time. 
 
12)    Consent Process 
 
Interested subjects will be pre-screened to confirm that they meet the inclusion and 
exclusion criteria. The inclusion and exclusion criteria will be read to the subject in full 
without interruption. The subject will be instructed not to give any information. If the 
subject does not meet the inclusion and exclusion criteria, he or she will withdraw from 
the screening process without the interviewer knowing which of the criteria they did not 
meet. 
 
Consent will be obtained prior to the initial assessment, in a suitable meeting room at


20 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
Mount Sinai (most likely a private office or conference room in the Rehabilitation 
Medicine Dept.), or in a private room in the outpatient clinic area. Either one of the 
investigators or a consent delegate will explain the study and obtain consent. Potential 
participants may ask questions about the study at any time, and will be given as much 
time as they feel they need to decide about participation. 
 
Subjects will be asked to state in their own words the following: purpose of the study; 
methods; risks and benefits; voluntary nature of participation and alternatives. If their 
response indicates a lack of understanding, explanations will be repeated, and potential 
participants will again be asked to describe the study in their own words. Subjects who 
after a second explanation fail to grasp the nature, method and risks of the study will not 
be allowed to participate. 
 
If a potential participant decides to enroll in the study, s/he and the research team member 
will complete the consent form, a copy of which will be provided to the subject for 
his/her records. Consent procedures will take place in accordance with Standard 
Operating Procedure HRP- 090 Informed Consent Process for Research. 
 
Children, cognitively-impaired adults, and non-English speakers are excluded from 
participation in this study. 
 
13)    Process to Document Consent in Writing 
 
The standard PPHS consent template will be used to document informed consent. 
 
In cases where a signature is being sought from the participant, but s/he is unable to 
physically sign the consent form due to upper extremity impairment, consent will be 
documented on the signature page of the consent form, to which a section has been added 
to document the circumstances of the situation, the method used by the subject to 
demonstrate understanding and consent to participation, and the signature of an impartial 
witness to the consent process. The content of this section was designed to address the 
policy described in section 3.3 of PPHS SOP-091. 
 
14)    Vulnerable Populations 
 
Include 
Exclude 
Vulnerable Population Type 
X 
Adults unable to consent 
X 
Individuals who are not yet adults (e.g. infants, children, teenagers) 


21 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
X 
Wards of the State (e.g. foster children) 
X 
Pregnant women 
X 
Prisoners 
 
 
15)    Multi-Site Human Research (Coordinating Center) 
 
Not applicable 
 
16)    Community-Based Participatory Research 
 
Not Applicable 
 
17)    Sharing of Results with Subjects 
 
Findings of the study will shared with study participants and others with SCI via the SCI 
rehabilitation program’s newsletter, and other similar venues. 
 
18)    External IRB Review History 
 
Not applicable 
 
19)    Control of Drugs, Biologics, or Devices 
 
BOTOX (onabotulinumtoxinA, Allergan) will be provided for research subjects at no 
charge to them or their insurance providers. The study drug/agent will be shipped by the 
manufacturer to: 
 
Thomas Bryce, MD 
Rehabilitation Medicine Associates 
 
  
 
 
 
 
Placebo consists of 0.9% normal saline. It will be supplied by Allergan. Both placebo and 
BOTOX will be stored in a locked refrigerator (2‐8 degrees Celsius) at a Mount Sinai 
Hospital. The principal investigator will be the only person with access to the key. The 
labels for the study drug will include the following: “Store at”, “Keep Out of Reach of 
Children”, “For Clinical Trial Use Only”, "Caution: New Drug: Limited by Federal 
(USA) Law to Investigational Use Only". In addition, a black box warning will read: 
POTENTIAL FOR HUMAN BIRTH DEFECTS.


22 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
 
 
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2. Cardenas DD, Bryce TN, Shem K, Richards JS, Elhefni H. Gender and minority 
differences in the pain experience of people with spinal cord injury. Arch Phys Med 
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3. Rintala DH, Loubser PG, Castro J, Hart KA, Fuhrer MJ. Chronic pain in a 
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11. Walter JS, Sacks J, Othman R, Rankin AZ, Nemchausky B, Chintam R, et al. A 
database of self- reported secondary medical problems among VA spinal cord injury


23 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
patients: Its role in clinical care and management. J Rehabil Res Dev. 2002 
Jan-Feb;39(1):53-61. 
 
12. Rintala DH, Hart KA, Priebe MM. Predicting consistency of pain over a 10-year 
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13. Cardenas DD, Jensen MP. Treatments for chronic pain in persons with spinal cord 
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14. Cardenas DD, Warms CA, Turner JA, Marshall H, Brooke MM, Loeser JD. Efficacy 
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15. Levendoglu F, Ogun CO, Ozerbil O, Ogun TC, Ugurlu H. Gabapentin is a first line 
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16. Norrbrink C, Lundeberg T. Tramadol in neuropathic pain after spinal cord injury: A 
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17. Elia AE, Filippini G, Calandrella D, Albanese A. Botulinum neurotoxins for 
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18. Novak I, Campbell L, Boyce M, Fung VS, Cerebral Palsy Institute. Botulinum toxin 
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19. Sheean G, Lannin NA, Turner-Stokes L, Rawicki B, Snow BJ, Cerebral Palsy 
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20. Olver J, Esquenazi A, Fung VS, Singer BJ, Ward AB, Cerebral Palsy Institute. 
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21. Piovesan EJ, Teive HG, Kowacs PA, Della Coletta MV, Werneck LC, Silberstein SD. 
An open study of botulinum-A toxin treatment of trigeminal neuralgia. Neurology. 2005


24 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
Oct 25;65(8):1306-8. 
 
22. Xiao L, Mackey S, Hui H, Xong D, Zhang Q, Zhang D. Subcutaneous injection of 
botulinum toxin a is beneficial in postherpetic neuralgia. Pain Med. 2010 
Dec;11(12):1827-33. 
 
23. Wu CJ, Lian YJ, Zheng YK, Zhang HF, Chen Y, Xie NC, et al. Botulinum toxin type 
A for the treatment of trigeminal neuralgia: Results from a randomized, double-blind, 
placebo-controlled trial. Cephalalgia. 2012 Apr;32(6):443-50. 
 
24. Yuan RY, Sheu JJ, Yu JM, Chen WT, Tseng IJ, Chang HH, et al. Botulinum toxin for 
diabetic neuropathic pain: A randomized double-blind crossover trial. Neurology. 2009 
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25. Jabbari B, Maher N, Difazio MP. Botulinum toxin a improved burning pain and 
allodynia in two patients with spinal cord pathology. Pain Med. 2003 Jun;4(2):206-10. 
 
26. Bryce TN, Budh CN, Cardenas DD, Dijkers M, Felix ER, Finnerup NB, et al. Pain 
after spinal cord injury: An evidence-based review for clinical practice and research. 
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measures meeting. J Spinal Cord Med. 2007;30(5):421-40. 
 
27. Bryce TN, Biering-Sorensen F, Finnerup NB, Cardenas DD, Defrin R, Ivan E, et al. 
International spinal cord injury pain (ISCIP) classification: Part 2. initial validation using 
vignettes. Spinal Cord. 2012 Jun;50(6):404-12. 
 
28. Bryce TN, Ragnarsson KT. Pain after spinal cord injury. Phys Med Rehabil Clin N 
Am. 2000 Feb;11(1):157-68. 
 
29. Vranken JH, Hollmann MW, van der Vegt MH, Kruis MR, Heesen M, Vos K, et al. 
Duloxetine in patients with central neuropathic pain caused by spinal cord injury or 
stroke: A randomized, double-blind, placebo-controlled trial. Pain. 2011 
Feb;152(2):267-73. 
 
30. Lis AM, Black KM, Korn H, Nordin M. Association between sitting and occupational 
LBP. Eur Spine J. 2007 Feb;16(2):283-98. 
 
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25 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
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Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
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27 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
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Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
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29 
Revised 9/2/14 
 
 
 
Protocol Title: 
Subcutaneous Injection of Botulinum Toxin A for At-Level 
Back Pain in Patients with Spinal Cord Injury 
Principal Investigator 
Name/Contact Info: 
Thomas Bryce, MD 
Primary Contact 
Name/Contact Info 
Ajax Yang, MD, MPT 
Department of Rehabilitation Medicine 
One Gustave L. Levy Place, Box 1240 
New York, NY 10029 
 
Date Revised: 
12/29/2015 
Study Number: 
HS: 14-01107    GCO: 14-2212(0001) 
 
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SAP_001.pdf: 
Subcutaneous Injection of Botulinum Toxin A for At-Level Back Pain in Patients 
with Spinal Cord Injury   
PI: Thomas Bryce, MD 
NCT02736890 
Document Date: 12/29/2015


"Data analysis plan: 
The primary outcome measure used to determine treatment effect in this study was patient reported
average pain intensity over the prior week. This measure is part of the International SCI Pain Basic Data Set
(ISCIPBDS), whose validity and utility in individuals with SCI has been demonstrated, and is also among the
measures recommended for use in SCI clinical trials. Subjects were asked to rate their average pain using the
0-10 NPRS with endpoints of 0 (“no pain”) to 10 (“worst pain imaginable”). Secondary outcome measures
included other items from the ISCIPBDS such as the degree to which pain interfered with: (1) day to day
activities, (2) mood, and (3) sleep, all on 0-10 numeric scales with endpoints of 0 (“no interference”) to 10
(“extreme interference”). At each follow-up time point, subjects were also asked to quantify the change in
quality of life appreciated after injections on a 0-6 numeric scale based on the Patient Global Impression of
Change (PGIC) scale. Our adaptation of this scale had endpoints of 0 (“no change, or condition got worse”)
to 6 (“a great deal better, a considerable improvement that has made all the difference”). Lastly, subjects
were asked about and monitored for any AEs.  
All collected research data were stored in a password-protected REDCap database and all hard copy forms
were kept in locked files in the offices of research staff.  Statistical analyses were performed using SPSS
version 22.0. Power analyses were conducted based on the primary outcome of change in pain intensity on
the NPRS from baseline. We determined that a minimal clinical important difference (MCID) on the NPRS
would be ≥ 3 points on the 0-10 point scale, that 30% of participants in the placebo group would have a
positive response to treatment, and that 40% more participants (i.e. 70%) would respond in the treatment
group. Assuming a two-sided alpha of 0.05, a sample size of 28 would have provided 86% power that a
difference will be found. Assuming a 15% drop out rate, a sample size of 32 enrolled participants was
deemed necessary for sufficient power to detect treatment effect. Our study failed to meet this target
sample size and it was ultimately determined that our findings would be best presented as a descriptive
case series."