Treatment of Pain and Autonomic Dysreflexia in Spinal Cord Injury With Deep Brain Stimulation
Phase: NA
Conditions: Pain, Autonomic Dysreflexia
Sponsor: Jonathan Jagid

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CLINICAL  PROTOCOL VERSION   7.0 
TITLE OF STUDY: 
Study of Treatment of Pain and Autonomic Dysreflexia 
by Deep Brain Stimulation in Participants with Spinal 
Cord Injury 
DATE OF PROTOCOL: 
   June 30th , 2015 
PRINCIPAL INVESTIGATOR: 
Jonathan Jagid, MD 
Associate Professor of Neurological Surgery 
University of Miami, Miller School of Medicine 
1095 NW 14th Terrace, 
 Miami, FL, 33136.   
T:305-243-2359 
FAX: 305-243-3337 
SPONSOR / FUNDING AGENCY: 
Department of Defense: Department of the Army, 
US Army Medical Research Acquisition Activity, 
820 Chandler Street, 
Fort Detrick, MD 21702-5014 
Program information: FY11 SCIRP SC110131 
EMERGENCY 24-HOUR CONTACT: 
Jonathan Jagid, MD. 
FAX NUMBER FOR SENDING SAES: 
305-243-3337

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TABLE OF CONTENTS  
Page 
1 
CONTACTS ....................................................................................................................................................... 4 
1.1 
EMERGENCY CONTACTS .............................................................................................................................. 4 
1.2 
ADDITIONAL CONTACTS ............................................................................................................................. 4 
2 
PRINCIPAL INVESTIGATOR SIGNATURE ............................................................................................... 5 
3 
SYNOPSIS .......................................................................................................................................................... 6 
4 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................................................... 13 
5 
LIST OF ABBREVIATIONS .......................................................................................................................... 14 
6 
DEFINITION OF TERMS .............................................................................................................................. 16 
7 
INTRODUCTION / BACKGROUND ........................................................................................................... 19 
7.1 
TARGET DISEASE ...................................................................................................................................... 19 
7.2 
CONDUCT AND MONITORING OF STUDY: ................................................................................................... 20 
7.3 
OVERVIEW OF TARGET PATIENT POPULATION: ......................................................................................... 20 
8 
LITERATURE REVIEW ................................................................................................................................ 20 
8.1 
ANIMAL STUDIES ...................................................................................................................................... 20 
8.2 
EFFICACY AND SAFETY DATA FOR DBS IN HUMANS ................................................................................ 23 
9 
STUDY DEVICE .............................................................................................................................................. 25 
9.1 
DEVICE DESCRIPTION ................................................................................................................................ 25 
10 
RISK ANALYSIS ............................................................................................................................................. 27 
10.1 
RISK MINIMIZATION .................................................................................................................................. 27 
11 
STUDY OBJECTIVES AND PURPOSE ....................................................................................................... 28 
11.1 
PURPOSE/OBJECTIVE ................................................................................................................................. 28 
11.2 
CORE (NULL) HYPOTHESIS: ....................................................................................................................... 28 
11.3 
PRIMARY OBJECTIVES: .............................................................................................................................. 28 
11.4 
SECONDARY OBJECTIVES: ......................................................................................................................... 28 
12 
STUDY DESIGN .............................................................................................................................................. 29 
12.1 
TYPE OF STUDY ......................................................................................................................................... 29 
12.2 
EXPECTED NUMBER OF PARTICIPANTS ...................................................................................................... 29 
12.3 
TREATMENT GROUPS ................................................................................................................................ 29 
12.4 
SCHEMATIC DIAGRAM ("STUDY FLOW CHARTS") OF TRIAL DESIGN, AND PROCEDURES ............................ 29 
12.5 
DESCRIPTION OF THE MEASURES TAKEN TO MINIMIZE/AVOID BIAS ........................................................ 30 
12.6 
DURATION OF SUBJECT PARTICIPATION .................................................................................................... 30 
12.6.1 
Extension of study ........................................................................................................................... 30 
12.7 
DESCRIPTION OF THE "STOPPING RULES" OR "DISCONTINUATION CRITERIA" FOR INDIVIDUAL 
PARTICIPANTS, PARTS OF TRIAL, AND ENTIRE TRIAL. ............................................................................................. 34 
13 
SELECTION OF PARTICIPANTS ............................................................................................................... 35 
13.1 
RECRUITMENT PROCEDURE ....................................................................................................................... 35 
13.2 
CONSENT PROCEDURES ............................................................................................................................. 35 
13.3 
INCLUSION CRITERIA ................................................................................................................................. 35 
13.4 
EXCLUSION CRITERIA ............................................................................................................................... 36 
13.5 
WITHDRAWAL CRITERIA: .......................................................................................................................... 37 
14 
TREATMENT OF PARTICIPANTS ............................................................................................................. 38 

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14.1 
RECRUITMENT AND SCREENING PROCEDURES AND ASSESSMENTS: .......................................................... 38 
14.2 
METHOD OF ASSIGNING PARTICIPANTS TO TREATMENT GROUPS: ............................................................ 38 
14.3 
PARTICIPANT PROCEDURES AND ASSESSMENTS ........................................................................................ 38 
14.3.1 
Baseline Assessments ...................................................................................................................... 38 
14.3.2 
Surgical Procedures and Assessments. ........................................................................................... 38 
14.3.3 
Targeting & Lead Placement .......................................................................................................... 39 
14.3.4 
Macrostimulation and Sensing ........................................................................................................ 40 
14.3.5 
Monitoring Participant for Comfort ............................................................................................... 40 
14.4 
LEAD AND OR DBS REMOVAL ................................................................................................................... 41 
14.5 
POST IMPLANTATION PROCEDURES & FOLLOW-UP ................................................................................... 41 
14.6 
MEDICATION(S)/TREATMENT(S) PERMITTED (CONCOMITANT MEDICATIONS) AND NOT PERMITTED 
BEFORE AND/OR DURING THE TRIAL: ...................................................................................................................... 42 
14.7 
PROCEDURES FOR MONITORING PARTICIPANT COMPLIANCE .................................................................... 42 
15 
SAFETY ............................................................................................................................................................ 42 
16 
ASSESSMENT OF TREND-TOWARD-EFFICACY .................................................................................. 43 
17 
STATISTICAL CONSIDERATIONS ............................................................................................................ 43 
17.1 
SAFETY ANALYSES: .................................................................................................................................. 43 
17.2 
EFFICACY ANALYSES: ............................................................................................................................... 44 
17.3 
POWER ANALYSES: ................................................................................................................................... 45 
17.4 
MISSING DATA .......................................................................................................................................... 45 
17.5 
PARTICIPANT ATTRITION........................................................................................................................... 45 
18 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................................................................ 45 
19 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................................................. 46 
19.1 
QUALITY CONTROL AND ASSURANCE CHECKS ......................................................................................... 46 
19.2 
STUDY CONDUCT ...................................................................................................................................... 46 
19.3 
MONITORING OF THE STUDY ..................................................................................................................... 46 
19.4 
PROTOCOL DEVIATIONS ............................................................................................................................ 46 
19.5 
PROGRESS REPORTS .................................................................................................................................. 46 
19.6 
AUDITS AND INSPECTIONS ......................................................................................................................... 47 
20 
ETHICS ............................................................................................................................................................ 47 
20.1 
INSTITUTIONAL REVIEW BOARD (IRB)/INDEPENDENT ETHICS COMMITTEE (IEC).................................... 47 
20.2 
INFORMED CONSENT ................................................................................................................................. 47 
20.3 
DECLARATION OF HELSINKI ...................................................................................................................... 47 
20.4 
PARTICIPANT CONFIDENTIALITY ............................................................................................................... 48 
21 
DATA HANDLING AND RECORDKEEPING ........................................................................................... 48 
21.1 
CASE REPORT FORMS ................................................................................................................................ 48 
21.2 
THE STUDY COORDINATOR ....................................................................................................................... 48 
21.3 
ADVERSE EVENT REPORTING .................................................................................................................... 49 
21.4 
PROTOCOL AMENDMENTS ......................................................................................................................... 49 
21.5 
FINAL STUDY REPORT ............................................................................................................................... 49 
21.6 
RECORDS RETENTION ................................................................................................................................ 49 
22 
FINANCING AND INSURANCE REGARDING PATIENT INJURY ...................................................... 50 
23 
PUBLICATION POLICY ............................................................................................................................... 50 
24 
APPENDICES .................................................................................................................................................. 50 
24.1 
APPENDIX 1 -- ADVERSE EVENTS REPORTING .............................................................................. 50 
24.2 
APPENDIX 2 – PROTOCOL REFERENCES ......................................................................................... 55 

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1 CONTACTS 
1.1 
Emergency Contacts 
Please contact the following for serious adverse events and other study-related emergencies: 
 
Primary Contact:  
Name:   
Jonathan Jagid, MD 
Phone (During Business Hours):  
305-243-2359 
Phone (After Business Hours): 
305-839-0521 
Fax:   
305-243-3337 
Email:   
jjagid@med.miami.edu 
 
Secondary Contact: 
Name:   
Corneliu C. Luca, MD 
Phone (During Business Hours):   
305-243-6732 
Phone (After Business Hours):   
305-321-3919 
Fax:   
305-243-4713 
Email:   
cluca@med.miami.edu 
 
Tertiary Contact: 
Name:   
Alberto Martinez-Arizala, MD 
Phone (During Business Hours):   
305-575-3174 
Phone (After Business Hours):   
305-807-7322 
Fax:   
305-575-3161 
Email:   
amartine@med.miami.edu 
1.2 
Additional Contacts 
Contact the following for all other inquiries and information about this study: 
Name:   
Letitia Fisher 
Phone (During Business Hours):   
305-243-7108 
Phone (After Business Hours):   
305-775-8582 
Fax:   
305-243-3913  
Email:   
 LFisher@med.miami.edu 
 
 
 
 

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3 SYNOPSIS 
Study Title 
Phase 1 Study of Treatment of Pain and Autonomic Dysreflexia by Deep Brain 
Stimulation in Participants with Spinal Cord Injury 
Study Rationale 
Spinal cord injury (SCI) is a devastating disease, which exerts a 
disproportionate medical, social, and economic toll on society. Effective 
treatments are urgently needed for SCI, whether for immediate relief of 
symptoms or longer-lasting functional recovery. It (SCI) produces chronic loss 
of motor control, sensation and autonomic regulation below the level of the 
injury. Frequently disconnection is not total and some degree of below injury 
function remains. Unfortunately, the remaining functional connection can 
cause additional problems for patients (at least 20% of all SCI patients). In 
addition, dangerous rises in blood pressure can be produced by strong sensory 
input. This phenomenon is known as autonomic dysreflexia (AD). It occurs in 
48% to 90% of patients with tetraplegia or high quadriplegia. 
This study investigates the neurosurgical procedure of deep brain stimulation 
(DBS) in the midbrain’s periaqueductal and periventricular gray region 
(PAG/PVG). The use of DBS in PAG/PVG for drug-refractory non-metastatic 
chronic pain has been reported in the biomedical literature for at least several 
hundred patients, and continues to be used in many countries, including 
Germany and the United Kingdom. A small proportion of reported cases (about 
21) of DBS applied at any brain site involved pain from spinal cord injury 
(SCI), and only 3 or 4 for the PAG/PVG. These reports, some of them from the 
1970s, did not describe systematic studies. Extensive, modern pain testing was 
not done. The stimulation was not given time to work (it could require several 
weeks for effects to appear). The pathologies were in most cases inadequately 
characterized. Also, some preclinical evidence suggests PAG/PVG-DBS can 
also improve other SCI symptoms, such as motor deficits and autonomic 
dysreflexia (AD), which were never examined. The present study is designed 
to provide these missing details.  
Thus, our study seeks to examine whether the safety and efficacy of prolonged 
DBS for SCI are sufficient to warrant its larger-scale study as therapy for pain 
and AD in SCI patients. 
Trial Design 
 
Controlled, open label, non-randomized, investigation in twelve (12) 
participants. 
 
Two sites: (1) Miami Veterans Affairs Medical Center; (2) University of 
Miami Miller School of Medicine. 
 
Informed Consent will be obtained prior to enrollment in the study. 
Approximate 
Duration of Patient 
Participation  
 
52 weeks (±7 days) for each subject from Initial Visit until Final Visit. 
 
After implantation of the DBS device on the 8th week, scheduled safety 
and efficacy assessments will be performed at intervals of 4 weeks until 
study week 24, and at intervals of 8 weeks thereafter. 

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Approximate 
Duration of Study 
 
End of Study is Defined as Last Subject’s Final Visit 
 
Total period of study is 36 months, from when 1st subject enrolled. 
Study Objective(s) 
Primary: to determine whether Deep Brain Stimulation (DBS) applied 
bilaterally or unilaterally in the midbrain periaqueductal-periventricular gray 
(PAG/PVG) region provides acute or long-term relief of chronic SCI 
associated pain and autonomic dysreflexia. 
Secondary: to assess the clinical effects of DBS on  autonomic functioning; to 
determine with Activa PC+S whether local field potentials in the PAG/PVG 
can be used to predict the efficacy of DBS in this region 

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Diagnosis and Main 
Criteria for Inclusion 
Major Inclusion Criteria: 
Inclusion Criteria 
Measure 
Rationale 
Age > 22 
Years of age 
Higher rates of neurological 
recovery if younger. 
Age < 60 
Years of age 
Different injury patterns and 
higher risk of complications if 
older 
Level of injury at or 
above T12  
Neurological exam 
Eliminates injuries below 
thoracic level T12, which have 
different pain pattern 
1. Neuropathic pain at or below the level of injury, as determined based on pain in 
an area with neurological deficit and described as burning, shooting, electric, 
stinging etc. 
2. The injury must have occurred at least 1 year prior to entering the study and 
participants must have experienced chronic pain for a minimum of six months. 
3. The disability must have a grade of on the American Spinal Injury Association 
Impairment Scale (AIS) of ASIA-A, ASIA-B, ASIA-C or ASIA-D as determined 
by a qualified examiner. 
4. Autonomic dysreflexia can be present but is not a necessary requirement. This is 
defined as a rise of systolic pressure by more than 30 mm Hg during noxious skin 
stimulation or when the bladder or bowel is full, or apparently spontaneously over 
a period of minutes.  
5. Pain (neuropathic) of moderate severity or greater is present, when the patient is 
taking medication, with a score of at least 4 on a numerical rating scale (range of 
0 to 10). 
6. Treatment with at least two of the following drug classes must have failed to give 
satisfactory pain relief within the last two years: anticonvulsants (e.g., pregabalin, 
gabapentin); antidepressants (e.g., trazodone, amitriptyline); NSAIDS (e.g., 
ibuprofen). In addition, at least one of the following must have proved ineffective: 
exercise-based rehabilitation, massage therapy using a variety of methods, 
acupuncture using pressure, needles, heat, or electrical stimulation on specific 
points on the body and psychological interventions such as cognitive therapy. 
7. Participants on medications for other conditions, such as diabetes, will be 
considered as candidates for this study. The dose will be monitored throughout the 
trial. (They will be excluded if the drug is being used to treat epilepsy, Parkinson’s 
diseases, or other brain degenerative diseases.) 
8. The subject must be willing to comply with the protocol including all scheduled 
visits. 
9. Literate at 8th grade level or above. 
10. The subject must provide a letter of clearance for the DBS surgery from their 
primary physician. 

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Main Criteria for 
Exclusion 
Major Exclusion Criteria: Admission to study. 
Exclusion Criteria 
Measure 
Rationale 
Unable to give informed 
consent 
Clinical examination 
Protection of human subjects 
Prisoner or ward of the state 
History 
Vulnerable population 
Pregnancy 
Urine or serum 
pregnancy test 
Risk to fetus 
Prior history of abusing non-
prescribed drugs 
History 
Vulnerable population 
Recent (one-year) history of 
alcohol abuse 
History 
Vulnerable population 
ASIA motor exam 
unobtainable 
ASIA Motor Score 
Baseline scoring needed for 
determination of change in score 
History of cardiac arrhythmia 
History and ECG 
tracing  
Higher risks of arrhythmia with DBS 
Renal disease, heart disease 
or uncontrolled hypertension, 
liver disease or hepatic 
cirrhosis 
History 
Highly variable rates of recovery 
Active major medical or 
psychiatric illness 
(MMSE<25) 
History 
Vulnerable population 
Significant post-traumatic 
encephalopathy from head 
trauma sustained at SCI 
History 
Vulnerable population 
Languages without local 
expertise 
Family history 
Lack of personnel or appropriate 
outcomes scales 
Pain is only nociceptive, due 
to muscle spasm 
Physical 
examination 
Neuropathic pain is therapeutic target  
Major Exclusion Criteria: Treatment/Intervention procedure: 
1. Coagulopathy requiring anticoagulation therapy 
2. Thrombocytopenia or platelet dysfunction 
3. Peripheral vascular disease 
4. Comorbid neurological diseases or disorders, including a history of seizures 
5. Active systemic infection or concurrent immunosuppressive therapy 
6. Existing implantable cardiac pacemaker, defibrillator or neurostimulator 
7. Requiring short-wave or microwave diathermy treatment during the course 
of the study. 
8. Inability to cooperate 
9. Any contraindication to MRI studies (All future MRIs, with the exception of 
brain MRIs, are excluded.) 
10. Adverse reaction to stimulation (such as inability to stimulate at analgesic 
levels without causing clinical hypertension or hypotension) or allergy or 
hypersensitivity to any materials of the neurostimulation system  
11. Depression, as defined by a Beck Depression Inventory (BDI-1a) score of 
30 or above. 
12. Subjects with any clinically significant abnormality, not expected on the 
basis of age (age-related), that is seen in magnetic resonance imaging 
(MRI). 
 

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Approximate 
Number of Patients 
A maximum of 12 participants with incomplete or complete SCI and 
neuropathic pain at or below the level of injury. 
Approximate 
Number of Study 
Centers 
Two sites (VA Medical Center & University of Miami - Miller School of 
Medicine) 
Concomitant 
Medication 
Concomitant medications and treatments or procedures pertinent to the study 
treatment or to any adverse events will be recorded including: 
1) name of drug, treatment, or description of procedure, 
2) start and end dates and times, and 
3) clinical indication and/or findings.   
Investigational drugs and any other intervention (not part of the guidelines for 
management of SCI) known to have a potential impact on outcome will be 
prohibited. 
Participants will be allowed to utilize over-the-counter drugs such as NSAIDs, 
acetaminophen and aspirin. Their use will be documented in the weekly pain 
assessments. A list of “allowed” medications will be provided to study 
participants. After the surgery, patients will be allowed to stay on the protocol 
if they take Tramadol (50-100 mg, 2 times a day for up to 2 weeks) as a rescue 
drug in addition to their stable medication. 
The patient must be taking pain medication to maintain a stable level of 
medication from 4 weeks before surgery to 12 weeks after (the primary 
endpoint), except on the day of surgery. On the day of the surgery, in the 
presence of a physician who can provide immediate backup pain control if 
needed, medications will be stopped until the acute effects of DBS on analgesia 
have been evaluated. 
On week 20 during a patient visit under medical supervision, patients will be 
instructed to take one fewer tablet or a smaller dose tablet, wait 4 hours and 
then see if their pain becomes worse.  If it does become worse, they may take 
medication to reach the original dose. Subsequently, they may follow this 
procedure at home or during the following visits.  
 
 
Study Intervention  (Device Usage Protocol) 
Device 
The study will use PMA authorized, Class III, implantable, Neurostimulation 
Systems for Deep Brain Stimulation. The Medtronic Activa PC and PC+S 
DBS device systems will be used as designed without any modifications. 

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Study Intervention  (Device Usage Protocol) 
Device Implant 
Procedure 
 
 
Participants presenting to the trial site with a history and mechanism 
consistent with chronic SCI with neuropathic pain below the level of injury, 
will be assessed using defined screening tests. Eligible participants will also 
undergo a multi-step consent process. 
Upon successful consent, trained and certified study personnel will perform 
imaging and neurological systems exams. The neurological systems exams 
will be utilized as the baseline measure of neurological status including 
neuropathic pain and autonomic dysreflexia. 
Upon successful completion of screening and baseline measurements, 
participants will undergo surgery to implant unilateral or bilateral DBS Leads 
(Model 3387S), extensions (Model # 37085 or 37086) and implantable 
neurostimulator (IFN) (Model 37601, or Model 37604).  
After successful implantation and one week recovery, subjects will participate 
for 44 weeks in the study. 
Treatment group 
Single treatment group. Ethical considerations forbid a control group that 
receives implant surgery without stimulation. Hence participants must serve 
as their own controls. 
Frequency 
One-time implantation of Activa PC or Activa PC+S Deep Brain Stimulation 
device system. Continuous stimulation, or cycled in 12-hour on/off periods, 
or in shorter on/off periods, for ~ 40 weeks. Voltage range 0.1-10V. 
Safety Evaluation 
1) 
Although preclinical data and clinical experience suggests DBS and 
device implantation is relatively safe, several adverse events are 
possible and will be noted,  
2) 
Comprehensive pain, motor and autonomic assessment will occur on 
screening and enrollment (baseline) and then at every on-site visit week 
throughout the study.  
3) 
The correct functioning of the DBS apparatus will be monitored at 4-
week intervals after implantation until study week 24, and at 8-week 
intervals thereafter.  
4) 
Pain Assessments using the ISCIPDS:B will evaluate development of 
neuropathic pain syndromes. 
Secondary outcomes 
1) 
Tilt table response exam  
2) 
Autonomic Standards Assessment (BP, HR, sympathetic skin response)  
 
 
 
 
 

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Safety Analysis Plan 
Primary Safety 
Analysis 
The analyses for safety will focus on changes in reported pain intensity 
during routine patient visits.  All AEs and SAEs will be listed and their 
incidence compared to historical controls.  The primary endpoint analyses 
will occur at 44 weeks post-implantation. 
Secondary Outcomes 
and Analyses 
The secondary hypothesis concerns autonomic assessment that will also take 
place during routine patient visits.  Heart rate, blood pressure, sweating, 
body temperature and breathing will also be classified as normal, abnormal, 
unknown or not obtainable. Lower urinary tract, bowel and sexual function 
will also be scored. 
Comprehensive testing sessions will analyze vagal and sympathetic 
influences on the cardiovascular system, measuring blood pressure and heart 
rate variability (power spectrum analysis) during sit-up or tilt-table 
challenge. 
Assessment of motor and non-pain somatosensory function will be done 
during visits every 4 weeks. Clinical sensory testing will include Light 
Touch and Pin Prick tests defined in the ASIA standards [1]. The Beck 
Depression Inventory (BDI-1a) will also be used, to assess emotional 
function in neuropathic pain [4]. If BDI assessment (>30) suggests suicidal 
thoughts, the Columbia Suicide Severity Rating Scale will be used in 
consultation with a clinical psychologist. 
 

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4 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
1. Jonathan Jagid, MD, is an Associate Professor in the Department of Neurological Surgery 
University of Miami. He will serve as a Principal Investigator and have overall responsibility for 
the conduct of the study, including study and database design, data and statistical analysis, and 
publication of results. 
2. Ian Hentall, PhD is an Associate Professor in the Departments of Neurological Surgery / Miami 
Project to Cure Paralysis, University of Miami. He will serve as a Co-investigator and share 
responsibility for clinical protocol compliance. 
3. Corneliu C. Luca, MD, is an Assistant Professor of Neurology in the Department of Neurology, 
University of Miami. He will serve as a Co-investigator, share responsibility for clinical protocol 
compliance and adjust the stimulators during subject visits in accordance to the protocol timeline. 
4. Alberto Martinez-Arizala, MD, is the Chief of the Spinal Cord Injury Service at the Miami VA 
Medical Center. He will serve as a Co-investigator, share responsibility for clinical protocol 
compliance and will be involved in patient screening, and performing evaluations of neurological 
status in all participants. 
5. Gustavo Alameda, MD, is a Neurologist specialized in spinal cord injury at the Miami VA Medical 
Center. He will serve as Co-investigator, and share the responsibilities for clinical protocol 
compliance and clinical assessment of subjects with Dr. Martinez-Arizala at the MVAMC.  
6. Eva Widerstrom-Noga, PhD, is a Research Professor in the Department of Neurological Surgery / 
Miami Project to Cure Paralysis, University of Miami. She will serve as a Co-investigator and, as 
an expert on the psychology and measurement of spinal cord injury pain; she will conduct and 
interpret comprehensive pain and other psychological assessment on patients. 
7. James Adcock, ChE, MBS, is a Senior Research Associate at the Miami Project to Cure Paralysis. 
He will assist Dr. Widerstrom-Noga on pain measurement by presenting stimuli and capturing data. 
8. Letitia Fisher, is a Clinical Research Coordinator in the Department of Neurosurgery / Miami 
Project to Cure Paralysis, University of Miami.  She will serve as Study Coordinator and will be 
responsible for regulatory compliance, ethical approvals, data collection and entry in the study case 
report forms, monitoring study staff for protocol compliance, scheduling and conducting visits with 
participants.   
9. Diana D. Cardenas, MD, MHA, is Professor and Chair of the Department of Rehabilitation 
Medicine, University of Miami and Chief of Service & Medical Director, Rehabilitation Medicine 
Hospital, Jackson Memorial Hospital. She will serve as Medical Monitor and will perform the 
following duties:  assess all participants for significant potential adverse events throughout the trial, 
determine if an adverse event requires reporting to the Principal Investigator, Sponsor, IRB, and 
FDA, and report findings and recommendations to the Principal Investigator. 
10. M. Ross Bullock, MD, PhD, is Clinical Director of the Neurotrauma Program at The Miami Project 
to Cure Paralysis, University of Miami Miller School of Medicine. He will serve as Medical 
Monitor and will perform the following duties:  assess all participants for significant potential 
adverse events throughout the trial, determine if an adverse event requires reporting to the Principal 
Investigator, Sponsor, IRB, and FDA, and report findings and recommendations to the Principal 
Investigator. 

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5 LIST OF ABBREVIATIONS  
Abbreviation 
Term 
AEs 
Adverse Events 
AIS 
ASIA Impairment Scale 
ASIA 
American Spinal Injury Association 
BPI 
Brief Pain Inventory 
CNS 
Central Nervous System 
CRFs 
Case Report Forms 
CT Scan 
Computerized Axial Tomography 
DBS 
Deep Brain Stimulation 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
ICH 
International Conference on Harmonization  
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
INS 
Implantable Neurostimulator 
ISCI 
International Spinal Cord Injury 
ISNCSI 
International Standards for Neurological Classification of Spinal Cord Injury 
LANNS 
Leeds assessment of neuropathic symptoms and signs (Pain scale drawings) 
LFP 
Local field potential 
LUT 
Lower Urinary Tract 
MPCP 
Miami Project to Cure Paralysis  
MPI 
Multidimensional Pain Inventory  
MRI 
Magnetic Resonance Imaging 
MVAMC 
Miami Veterans Administration Medical Center 
NRS 
Numerical rating scale (0-10) 
PI 
Principal Investigator 
QLI 
Quality of Life Index 
QoL 
Quality of Life assessments 
SAEs 
Serious Adverse Events 
SCI 
Spinal Cord Injury 

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Abbreviation 
Term 
SCIM III 
Spinal Cord Independence Measure 
TBD 
To be Determined 
TEAE 
Treatment Emergent Adverse Event 
UM HSRO 
University of Miami Human Subject Research Office 
UMH 
University of Miami Hospital 
UMMSM 
University of Miami Miller School of Medicine 
 

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6 DEFINITION OF TERMS 
 
Term 
Definition 
6.1 
Adverse Experience (AE) 
The term "adverse event," as used by the Sponsor, is synonymous 
with the term "adverse experience," which is used by the FDA.  
An adverse event is any untoward, undesired, unplanned clinical 
event in the form of signs, symptoms, disease, or laboratory or 
physiological observations occurring in a human being 
participating in a clinical study with a Sponsor study drug, 
regardless of causal relationship.  This includes but is not limited 
to the following: 
 
Any clinically significant worsening of a preexisting 
condition. 
 
Any recurrence of a preexisting condition. 
 
An AE occurring from overdose of a Sponsor study drug 
whether accidental or intentional (e.g., a dose higher than 
that prescribed by a health care professional for clinical 
reasons). 
 
An AE occurring from abuse of a Sponsor study drug (e.g., 
use for nonclinical reasons). 
 
An AE that has been associated with the discontinuation of 
the use of a Sponsor study drug. 
6.2 
Clinical Trial/Study 
Any investigation in human patients intended to discover or verify 
the clinical, pharmacological and/or other pharmacodynamic 
effects of an investigational product or device, and/or to identify 
any adverse reactions to an investigational product or device, 
and/or to study absorption, distribution, metabolism and excretion 
of an investigational product with the object of ascertaining its 
safety and/or efficacy. 
6.3 
Co-investigator 
An individual member of the clinical trial team (e.g. MD, DO, 
PA) designated and supervised by the Principal Investigator at a 
trial site to perform critical trial-related medical procedures 
and/or to make important trial-related decisions. 
6.4 
Good Clinical Practice 
(GCP) 
A standard for the design, conduct, performance, monitoring, 
auditing, recording, analysis and reporting of clinical trials that 
provides assurance that the data and reportable results are credible 
and accurate, and that the rights, integrity and confidentiality of 
trial patients are protected. 

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Term 
Definition 
6.5 
Informed Consent 
A process by which a patient voluntarily confirms his or her 
willingness to participate in a particular trial, after having been 
informed of all aspects of the trial that are relevant to the patient’s 
decision to participate.  Informed consent is documented by 
means of a written, signed, and dated informed consent form. 
6.6 
Institutional Review 
Board (IRB) or 
Independent Ethics 
Committee (IEC) 
An independent body of medical professionals and non-medical 
members, whose responsibility it is to ensure the rights, safety and 
wellbeing of patients involved in a trial.  This is accomplished by, 
among other things, reviewing, approving and providing 
continuing review of trial protocol and amendments and of the 
methods and materials to be used in obtaining and documenting 
informed consent of the trial patients. 
6.7 
Investigator Brochure 
A written document that contains a detailed and current review 
of all relevant clinical trials.  It includes when applicable, 
chemical and pharmaceutical data, toxicological, 
pharmacokinetic, and pharmacodynamic data in animals, and the 
results of earlier clinical trials. 
6.8 
Monitoring 
The act of overseeing the process of a clinical trial, and of 
ensuring that it is conducted, recorded and reported in accordance 
with the protocol, standard operating procedures (SOPs), GCP 
and the applicable regulatory requirements.   
6.9 
Patient 
A person who receives medical care. 
6.10 
Principal Investigator 
The person responsible for the conduct of the clinical trial at a 
trial site.  If a trial is conducted by a team of individuals at a trial 
site, the Investigator recorded in box 1 of the Form FDA 1572 is 
the responsible leader of the team and may be called the Principal 
Investigator.  (See Subinvestigator) 
6.11 
Quality Assurance (QA) 
All those planned and systematic actions that are established to 
ensure that the study is performed and the data are generated, 
documented (recorded), and reported in compliance with 
applicable regulatory requirements. 
6.12 
Regulation 
Regulation refers to all applicable regulations, laws, and 
guidelines.  This study will be conducted according to all 
applicable regulations.  The regulations include but are not 
limited to the Code of Federal Regulations (United States); Good 
Clinical Practice; the International Conference on Harmonization 
(ICH) and the World Medical Association Declaration of 
Helsinki:  Ethical Principles for Medical Research Involving 
Human Patients. 

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Term 
Definition 
6.13 
Regulatory Agency 
Regulatory Agency refers to all appropriate health and regulatory 
agencies.  These may be local, national, or international and 
include, but is not limited to, the US Food and Drug 
Administration (FDA). 
6.14 
SAE (Serious Adverse 
Event) 
Any adverse drug/device experience occurring at any dose that 
results in any of the following outcomes:  death, a life-threatening 
adverse drug experience, inpatient hospitalization or prolongation 
of 
existing 
hospitalization, 
a 
persistent 
or 
significant 
disability/incapacity, or a congenital anomaly/birth defect. 
6.15 
Serious Adverse Event 
(SAE) Report 
A special form completed by the Investigator and forwarded to 
COMPASS for reporting all serious adverse experiences 
(regardless of cause) and for any death (regardless of cause) that 
occurs while on study or within 30 days of study completion. 
6.16 
Sponsor 
Sponsor refers to Sponsor and representatives such as contract 
research organizations that are being used for the study. 
6.17 
Statement of Investigator 
(Form FDA 1572) 
A form that represents a contract between a clinical Investigator 
and the FDA.  This contract represents the investigators' 
commitment to conduct the clinical trial in accordance to all the 
regulations and laws that govern the conduct of clinical trials. 
6.18 
Study Device 
Any drug, device or biological agent (including placebo) required 
by the protocol and supplied by the Sponsor for use in the 
Sponsor's clinical research and development studies. 
6.19 
Study Start Date 
Date on which first patient signs informed consent form. 
6.20 
Subinvestigator 
(See Co-investigator) 
6.21 
Unexpected Adverse 
Experience 
Any adverse experience, the specificity or severity of which is not 
consistent with the current Investigator’s Brochure. 

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7 INTRODUCTION / BACKGROUND 
7.1 
Target Disease 
Chronic spinal cord injury (SCI) entails loss or abnormality of autonomic regulation, motor control and 
body sensation at and below the dermatomal level of injury. When disconnection is incomplete, some 
degree of below-injury function remains. About one half of all new cases in the US are incomplete [5]. In 
principle, surviving functional connections are a hopeful sign, offering a target for possible therapies, as 
well as giving the patient some possibility of control distal to the lesion. In practice, unfortunately, these 
connections often entail dysfunction. For example, persistent pain below or at the injury level is experienced 
in 2/3rd of chronic SCI patients. As a result of this pain at least 1/3rd of this sub-population faces a severely 
reduced quality of life [6]; some authorities consider this rate to be much higher, based on surveyed pain 
ratings [7]. It was reported that 23% of a sample patients with cervical or high thoracic SCI and 37% with 
low thoracic or lumbosacral SCI would sacrifice sexual, bowel and bladder function for good pain relief 
[8]. 
SCI pain is typically a mixture of nociceptive pain, which is caused by activation of primary afferents’ 
receptors, and neuropathic pain, which is caused by damage to the nervous system. The neuropathic pain 
of SCI is most frequently treated by anticonvulsant agents. There is good evidence from randomized control 
trials for some degree of effectiveness of gabapentin [9-11] and pregabalin [12,13], with weaker evidence 
for valproic acid [14]. Tricyclic antidepressants are also used to control SCI pain, but the supporting 
evidence is not as strong. Thus amitriptyline has proved somewhat effective when the patient is depressed 
[15,16], but trazodone was reported not to reduce post-SCI neuropathic pain more than placebo [17]. 
Traditional analgesics are also useful. Morphine can provide effective relief of neuropathic pain due to SCI, 
and can be combined with the alpha-2 agonist clonidine for this purpose [18,19]. Subarachnoid or epidural 
lidocaine has been used to obtain short-term relief [20]. For the musculoskeletal pain in SCI, which 
nociceptive, antispasticity agents are frequently used; intrathecal baclofen, for example, can be fairly 
effective [21,22]. Despite this considerable range of choices, pharmacological treatment for the pain of SCI 
remains inadequate. Low effectiveness, tolerance, side effects or difficulties with prolonged local 
administration (e.g., subdural) are among problems encountered [23].  
Autonomic functioning after SCI depends on the injury level. Visceral efferents are damaged directly by 
mid-thoracic or sacral injuries. Higher control of autonomic function is degraded after cervical or high 
thoracic SCI, when only vagal control remains. Autonomic dysreflexia (AD) is a frequent consequence of 
cervical or high thoracic injuries. It mostly occurs when the lesion is above the 6th thoracic segment. Its 
estimated frequency is 48-90% in patients with tetraplegia or high quadriplegia [24-26]. AD is a cluster of 
symptoms caused by a massive sympathetic outflow, which includes elevated blood pressure, headache, 
flushing, sweating above the lesion level and abnormal heart rhythms.  It is typically provoked by activity 
in visceral or cutaneous afferents below the injury. Distension of bladder or colon, such as occurs from loss 
of control of evacuation, may precipitate AD.  It can occur sporadically, triggered several times each day, 
but sometimes it lasts for many days, since the patient is generally unaware of aggravating stimuli below 
the injury level.  
Various categories of antihypertensive agents are used for symptomatic control of AD, in particular nitrates 
(e.g., topical nitroglycerin), calcium blockers (e.g., nifedipine) and selective alpha-adrenergic antagonists 
(e.g., prazosin, terazosin) [27]. In the short-term, these treatments are generally adequate. However, because 
AD can present as an acute crisis, long-term treatment with an effective blocking dose is poorly matched 
to the breakthrough of symptoms and their chronic sequelae. Alpha-adrenergics, for example, in addition 
to their adverse acute effects and contraindications, produce receptor upregulation with long-term use. 
Additional problems are specific to SCI. Norepinephrine facilitates movement generation in the spinal cord 
and is a transmitter at sphincter muscles of hollow organs. Blockade of its principal alpha-1 receptors can 
therefore exacerbate functional deficits in SCI.  

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Deep brain stimulation (DBS) is increasingly being used instead of drugs (or in combination with them) for 
several neurological problems. Its most common application at present is to control the symptoms of 
advanced Parkinson’s disease and essential tremor by stimulation in the basal ganglia or sub-thalamic 
nucleus [28,29], which has been provided to well over one hundred thousand patients worldwide. Patients 
can greatly reduce or eliminate their intake of L-dopa or other drugs (anticholinergics, dopamine 
antagonists, etc.).  DBS, because it is targeted to a particular brain region, considerably reduces the 
possibility of adverse neural and systemic effects compared to most pharmacological approaches. Since the 
choice of DBS targets has a good basis in scientific investigation, the treatment is not merely empirical. 
Another key advantage is that the dose can be instantaneously modulated in various ways (e.g., voltage, 
pulse width, pulse frequency), including immediate stopping. Initial high cost seems to be the main 
disadvantage. Discounted over the predicted lifespan of the average patient, however, costs may compare 
favorably with drugs, especially if the lower probability of adverse effects is taken into account. 
Extensive experience with DBS in motor disorder patients has led to various technical improvements. 
Failures due to equipment breakdown, infection or improper targeting, for example, are becoming rare. 
This success has led to consideration of DBS for other chronic neurologic maladies, such as obsessive-
compulsive disorder, depression and epilepsy [30]. It has also prompted a reconsideration of DBS as a 
treatment for chronic, drug-refractory pain of various sorts, which was used for many years prior to the 
advent of DBS for motor disorders [31]. DBS for pain control can target several different brain regions. 
One main target is the midbrain periaqueductal gray (PAG) together with the nearby periventricular gray 
(PVG); another is the sensory thalamus (ST).  Reported long-term pain alleviation rates have been higher 
with PAG/PVG stimulation (79%) than with ST stimulation (58%) [31]. Cortical sites are also sometimes 
targeted for pain (Nguyen et al.), but these have apparently not worked well for SCI pain [32] and are not 
considered further here. 
7.2 
Conduct and Monitoring of Study: 
This study will be conducted in compliance with the protocol, and monitored according to Good Clinical 
Practices as outlined in 21 CFR 312 Subpart D and E6 ICH: Good Clinical Practice Guidance and other 
applicable regulatory requirements. 
7.3 
Overview of Target Patient Population: 
Veterans or non-veterans will be recruited, for a total of 12 participants. They will be men or women, fluent 
in English, of average literacy, 22-60 years of age, with an incomplete or complete SCI and neuropathic 
pain at or below the level of injury. We anticipate few or no females, because females are about 20% of the 
general injured population in the US [5] and because females are under 20% in most military branches and 
were fewer in previous years. The data obtained from this study may provide additional data to warrant 
extension of similar, future studies to additional populations. 
8 LITERATURE REVIEW 
8.1 
Animal Studies 
Traumatic spinal cord and brain injury are prime examples of neurological syndromes in which the key to 
permanently enhanced recovery lies in accentuating beneficial trophic effects. The present proposal stems 
in part from the preclinical studies of Dr. Ian Hentall, one of the co-investigators.  These animal studies 
were based on the hypothesis that brainstem raphe nuclei function to promote repair [33]. Raphe nuclei 
release serotonin nearly ubiquitously in brain and spinal cord. Serotonin is a neurotrophic molecule as a 
well as a classical neurotransmitter [34]. Along with 5-HT, many raphe neurons co-release peptides with 
neurotrophic effects, e.g., thyrotropin releasing hormone, galanin [35,36]. Some raphe neurons are known 
to be excited by diverse sensory and chemical correlates of trauma, e.g., pain, hypotension, circulating 
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with ascending divergent projections. After experimental fluid-percussion brain injury, it was found that 
one week of stimulation in the median or dorsal raphe nucleus boosted behavioral recovery (forelimb 
reaching, water-maze learning) and anatomical recovery (forebrain white matter, hippocampal neuron 
density) [33]. Molecular mechanisms for these effects are currently under investigation. For example, spinal 
cord concentrations of the key restorative molecule cyclic adenosine monophosphate (cAMP), which are 
greatly reduced by SCI, were returned to normal by 2 hours of NRM stimulation given 3 days post-injury, 
as were various downstream protein signaling targets of cAMP (unpublished). 
The earlier SCI work of this laboratory focused on acute thoracic (T8) injuries, testing both the PAG and 
the nucleus raphe magnus (NRM), which is the PAG’s main hindbrain relay to the spinal cord. Several days 
of stimulation in either region partially restored motor performance and normalized mechanical allodynia 
in forelimbs [38,39]. In histological analysis, myelination of white matter around the injury zone was seen 
to have recovered significantly when either site was stimulated. The NRM also significantly increased 
serotonin-containing terminals in gray matter.  
In recent unpublished studies with PAG stimulation, PAG stimulation was tested in rats with an acute 
cervical (C5) injury. One week of intermittent stimulation yielded long-term improvement in AD 7 weeks 
later, as measured by mean carotid pressure during colon distension (Figure 1). 
 
Figure 1. Cervical (C5) contusional incomplete SCI was made by a controlled force impactor in rats. The PAG was stimulated for 
1 week, starting 2 hours after SCI, applied for 12 hours daily through a tungsten microelectrode. Stimulus trains were 30 µA, 1 
ms, 8 Hz cathodal pulses, given in 5-minute periods alternated with 5 minutes of rest. A carotid artery cannula measured blood 
pressure responses during colon distension (3 cc, with a balloon catheter) or pinching of a hindpaw or forepaw. Autonomic 
dysreflexia evoked by colon distension 7 weeks after the SCI was clearly lower after the PAG stimulation. Data points for colon 
distension are averages of 3 trials of pressure applied for 100 s at 10-minute intervals, as illustrated by the traces on the right.  
Blood pressure changes during noxious pinch were reduced by PAG stimulation. However, hind paw responses were higher in 
normal rats than in injured rats, suggesting a complex interaction between sensory and autonomic recovery. 
 
In additional studies with PAG stimulation, 3 weeks of stimulation applied 6 weeks after C5 contusion 
improved recovery in motor tests of grip strength and angle of postural stability on an inclined plane (Figure 
2). More weeks of stimulation appear to be needed for older injuries.   
 

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Figure 2. PAG stimulation, with parameters as in Figure 1, was applied for 3 weeks, starting either 7 weeks (“early”) or 12 weeks 
(“late”) after C5 contusional SCI. Significant differences occurred in repeated measures analysis between the two interventions in 
the inclined plane test (left) and grip strength (right).  
 
Both the chronic and the acute treatments in these studies had the histochemical effect of reducing 
immunostaining to calcitonin-gene related peptide (CGRP) near the injury. Since CGRP is a key pain 
transmitter in the spinal cord, and is increased by SCI [40], this potentially important pain-reducing 
mechanism.  
 
Figure 3. Staining for CGRP 1 cm caudal to a C5 SCI in rats treated with PAG stimulation after acute or chronic SCI. 
 
Other recent work has focused on breathing. The C5 moderate contusion in rats was treated with 3 weeks 
of NRM stimulation with standard parameters as above. Breathing was monitored by whole body 
plethysmography in unrestrained rats. Minute volume was improved both during and after treatment weeks 
(Figure 4). 
 
Figure 4. The minute volume after C5 injury. All data has been normalized from baseline. There were significant differences 
between treatment groups (both n=6, p=.017, SPSS v19 repeated measures ANOVA).   
Change in minute volume
-40
-20
0
20
40
60
80
100
3
10
17
24
31
38
45
days after injury
D Minute Volume (ml/min)
NRM Stimulation
Non-treated SCI
stimulation

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Conclusion 
DBS in the midbrain PAG/PVG reverses ongoing pain in man. However, the data are too few to judge 
safety or efficacy for SCI pain.  Because current drug or cognitive therapies fail to control SCI pain in a 
significant proportion of cases, a renewed assessment of DBS in the PAG/PVG is justified. The assessment 
should involve a detailed characterization of pathology, treatment and outcome. Pain alleviation could also 
reduce ongoing autonomic dysreflexia [41], while preclinical findings suggest that permanent partial 
improvements in pain, autonomic deficits and motor performance could occur after prolonged stimulation. 
In man, spontaneous partial recovery has been noted many months after SCI, perhaps due to patterned 
neural activity [42]. DBS in the PAG/PVG could accentuate this restorative activity.  
Comparative advantages expected of DBS for treating SCI are as follows: 
 
Permanently improve symptoms, not merely relieve them. 
 
Every type of deficit recovers, not just, for example, limb movement or sensation 
 
No untoward effects of prolonged stimulation, based on by animal research 
 
Dose can be immediately reduced or discontinued if adverse effects appear 
 
Existing technology can be translated without modification to the treatment of SCI 
 
Trophic DBS has a strong scientific support basis and theoretical basis in repair models 
 
Can readily be combined in a non-interfering way with drug or cell implant therapy 
8.2 
Efficacy and Safety Data for DBS in Humans 
The total numbers of patients that have received DBS for any type of pain is relatively small, around a few 
hundred have been reported.  Only a small fraction of these had SCI pain. Based on two reviews, confirmed 
by a Medline search, we have created the following inclusive list of published primary reports of DBS for 
SCI pain.  One review contains a meta-analysis of all published studies of DBS for pain that met adequate 
criteria for patient selection, pain evaluation and follow-up duration, which included cases of SCI pain. The 
other review focuses on DBS for SCI pain [32].  Details on the age and injury level, the method of pain 
assessment and basic surgical details, such as the stimulation site, are sometimes unclear or absent, 
especially in the earlier reports  
Technical neurosurgical terms in DBS. (1) “Internalization” is the technical neurosurgical term for 
completing the acute implantation surgery by leaving the electrode in the brain and connecting it to a 
subcutaneously implanted electronic controller. (2) This controller is also referred to as a “generator”.  (3) 
“Leads” is another name for electrodes. 
1. 12 SCI patients, 5 internalized [43]. Two leads were implanted, one in PVG and one in ST, 
specifically in the ventral posterior lateral nucleus of thalamus (VPL). Cases were classified as 
Brown-Sequard (n=1), myelopathy (n=2), tetraplegia (n=1), post-dorsal root entry zone lesion 
(n=1), paraplegia (n=5), conus syndrome (n=1); syringomyelia (n=1); plexus avulsion (n=1). 
Patients were studied for 7 days before internalization of electronics and connector cables, which 
proceeded when a 50% or more pain reduction on a visual analog pain scale was achieved by a 
voltage that was 50% of the threshold for aversive responses. Reported aversive responses were 
paresthesias from ST stimulation and floating, and dizzy or warm feelings from the PVG.  Five 
patients met the criterion for internalization of electronic stimulators and connecting cables. Long-
term pain relief was seen in the following cases, all n=1; percentages shown are relief relative to 
pre-operative pain levels: myelopathy (25-50%), tetraplegia (0-25%), post-DREZ lesion (75-
100%), plexus avulsion (0-25%), paraplegia, (0-25%). Most patients received stimulation at both 
sites; the plexus avulsion case received only PVG stimulation. 

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2. 4 SCI patients, 3 internalized [44]. Pain in individual patients was distributed: in both lower 
extremities below T10, in all extremities below C5, in both lower extremities below T9, in the right 
lower limb (n=1). The first three cases were implanted bilaterally in the ventrocaudalis thalamic 
nucleus; the fourth received one lead in ventrocaudalis and one in the PAG/PVG. The first, third 
and fourth patients were internalized and experienced benefits lasting from 2 months to 5 years. 
3. 3 SCI patients, 1 internalized [45]. All sites were ST.  “One case of lower limb pain after excision 
of a neurofibroma of the lumbar region and two cases of gunshot wounds causing partial 
paraplegia.”  They “…experienced two early failures and one late failure because of tolerance 
development during the course of 2 years”. 
4. 8 SCI cases, 3 internalized [46]. There were 2 long-term successes, characterized as “almost 
complete pain relief” and “the patient's ability to resume a normal pain-free life”. All sites appear 
to have been in ST (VPL).   
5. SCI patients, 3 or 4 internalized [47]. The authors summarize their results as follows. “Fourteen 
electrodes, 7 sensory thalamic and 7 PAG/PVG, were implanted in 11 patients with pain secondary 
to spinal cord injury. Two of each class of electrodes were internalized (36%). No patient obtained 
long term pain relief with DBS”.  
6. 6 SCI patients, 5 internalized [48]. One patient had excellent relief and two had partial relief. 
Injuries are not described. Sites were ST (VPL) with or without PVG or PAG stimulation.  
This choice of sites reflected the view that ST should be targeted for neuropathic pain and PAG/PVG for 
nociceptive pain, since SCI pain is typically a mixture of nociceptive and neuropathic pain [49]. However, 
the neuropathic pain of SCI is mechanistically distinct from other central neuropathic pains (e.g. post-stroke 
or thalamic pain syndrome) [50]. 
Insertion of electrodes in the PAG/PVG is reported to cause short-term analgesia [44]. Yet insertion could 
quite likely produce the opposite effect in some participants, temporarily blocking the stimulation-produced 
analgesia, which would have been excluded by the selection criteria typically used, leading to 
underestimates of potential success rate.  
In summary, the total number of reported cases involving DBS surgery for SCI pain was 44. Only 21 were 
internalized, that is, involved applying DBS beyond the neurosurgical operation. The majority of SCI pain 
cases were given stimulation in either the ST or the ST combined with the PAG/PVG.  There are 3-4 cases 
of PAG/PVG stimulation without concomitant ST stimulation. Some of these were not typical spinal cord 
trauma. Thus existing data are too few to assess whether or not PAG/PVG stimulation is effective against 
SCI pain. Changes in other SCI symptoms were not described. A beneficial effect on autonomic dysreflexia 
is possible, since PAG/PVG stimulation inhibits the types of nociceptive pain that elicit it. 
 

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9    STUDY DEVICE 
9.1 
Device Description 
The Activa PC Deep Brain System as shown in Figure 1 below consists of the neurostimulator, leads, 
extensions, and clinician and patient programmers.  The Activa PC primary cell neurostimulator (model 
37601) is a multi-programmable device that can deliver electrical stimulation through one or two leads 
implanted in the brain. Stimulation is provided by controlled delivery of current from a battery in an 
implantable neurostimulator (INS) to metal leads (electrodes) surgically implanted in the brain. The INS is 
typically placed in the pectoral location or near the collarbone. Current is conducted to the electrodes via 
electrical conduits, including extensions (Models 37085 and 37086) and leads (model 3387), which are 
tunneled subdermally through the neck, travel through the skull, and terminate in a neural structure 
appropriate to the neurological disease being treated. The Activa PC system is capable of providing 
stimulation to 2 leads, each with 4 electrode contacts. Stimulation parameters are adjusted to optimize 
therapy for the patient. They can be independently controlled and include the following: active electrode(s), 
electrode polarity, pulse width, amplitude, and frequency. The stimulation settings are stored in programs. 
A program is a specific combination of pulse width, rate, and amplitude settings acting on a specific 
electrode combination on a lead, or on a lead and the INS, in unipolar mode. Up to four programs can be 
combined into a group. Pulse width, amplitude, and electrode polarity are independently programmed for 
each program within a group.  Rate, rate limits and cycling for each program within a group must have the 
same values. Stimulation is delivered to a maximum of two implanted leads (one lead per hemisphere), 
with a maximum of 4 electrodes per lead. Rate is limited to 250 Hz, pulse width is limited to 450 μsec, 
amplitude is limited to 10.5 V (or 25.5 mA) and the charge density warning threshold is 30 µC/cm2/phase. 
Stimulation programs are controlled by the clinician via the N’Vision Clinician Programmer.  A patient 
programmer (model 37642) will enable the patient to deactivate the device and can output an event log. 
 
 
 
 
 
Figure 5: Activa PC System 
 
 
 
 
 
 
 
 
 
 
 

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The Activa PC+S DBS Implantable System will have therapy equivalent to Activa PC. This equivalence 
includes stimulation capabilities (pulse width, rate amplitude, modes) and the use of the same model 8840 
Clinician Programmer and software, model 37642 patient programmer, and leads as the Activa PC 
system. In addition, sensing capability is included in the Activa PC+S implantable neurostimulator (INS), 
which is the same from factor as Activa PC. Sensing is controlled and its data managed with a User-
intuitive research interface, a Clinician Sensing Programmer. This tablet programmer interfaces to the 
INS via telemetry and to a personal computer via USB. The Clinician Sensing Programmer will not adjust 
or control therapy. Likewise, the 8840 Clinician Programmer and the two Patient Programmer models 
will not adjust or control Sensing. In addition, the Medtronic Activa PC+S 8180 Sensing Software will be 
used. Medtronic Activa PC+S 8180 Sensing Software is part of a neurostimulation system for deep brain 
stimulation used to exclusively program the Medtronic Activa PC+S Model 37604 Implantable 
Neurostimulator for sensing of brain electric field potential. The Activa PC+S Sensing Software system 
components consist of:  the Activa PC+S 8180 Sensing Software, the 8181 Sensing Tablet, and the SMTP 
(Sensing Programmer Telemetry Module). The Medtronic Activa PC+S 8180 Sensing Software, along 
with the Sensing Tablet and the SPTM, uses telemetry, a radio-frequency (RF) communication, to 
configure, record, and retrieve sensing information obtained from the Medtronic Activa PC+S 37604 
Implantable Neurostimulator. 
 
 
Figure 6. Activa PC+S Sensing Software System 

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10    RISK ANALYSIS 
The rationale for unilateral or bilateral DBS implants is based on the potential benefits that may be 
produced. For participants with chronic SCI, the benefits anticipated from DBS include reduction or 
alleviation of neuropathic pain. A beneficial effect on autonomic dysreflexia is also possible, since 
PAG/PVG stimulation inhibits the types of nociceptive pain that elicit it. 
The risks of the device implant surgery (to the participants) in this study are identical and no more than 
those associated with current DBS surgery for Parkinson’s treatment. The risks include, but are not limited 
to, bleeding, transfusion, infection, sensory impairment, paralysis, speech arrest, stroke, seizure, 
intracerebral hemorrhage, coma, and/or death. The participants will be made aware of the risks in writing 
and in person. These participants will all be consented prior to entering the study. 
To minimize surgical risks, exposure to general anesthetic, and additional stereotactic frame placement in 
one cranial procedure (as opposed to two separate) will be used to implant bilateral devices. This approach 
falls under the standard of care for DBS neurosurgery. 
There is potential throughout the study of adverse events occurring related to the implant itself.  These 
include but are not limited to, erosion of the device through the skin, migration or movement of the hardware 
in the brain, delayed infection of the device, battery failure, and/or mechanical failure of the device. These 
complications may necessitate further surgery to correct. However, it is important to note that the safety 
profile of this device and the surgical procedure is well established, and investigator(s) are well trained and 
have previously conducted several hundred identical implant procedures. 
10.1  Risk minimization 
The study protocol contains several measures to minimize risk, many adopted based on the experience in 
standard DBS surgery (Parkinson’s trial or other experiences that are relevant to the risk minimization 
measures that will be used). These include the design that the therapy is completely reversible (it can be 
fully explanted without damaging neuronal or muscular tissue). The user also has the ability to 
instantaneously turn off the device with the Patient Controller.  Additionally, participants will have 24 hour 
access  for contacting study personnel. 
If subjects have an implanted programmable pump, such as an intrathecal baclofen (ITB) pump, risk will 
be minimized as follows. The neurostimulator (generator) will be placed at least 8 inches from the pump 
and/or on the opposite side of the body. Whenever the pump or neurostimulator is reprogrammed, each 
device will be checked before the patient leaves a programming session to ensure that the other device was 
not inadvertently affected. Patients will be told to contact their physician immediately if they experience 
symptoms (such as spasms) that could be related to either device or to the medical condition treated by 
either device. Subjects with implantable pump systems will be evaluated for MR compatibility 
(susceptibility to magnetic fields) prior to MR imaging. 

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11    STUDY OBJECTIVES AND PURPOSE 
11.1  Purpose/Objective 
We propose an investigation of the safety of deep brain stimulation (DBS) for the alleviation of chronic 
neuropathic pain in patients with spinal cord injury (SCI). The stimulation will be applied bilaterally or 
unilaterally in the midbrain periaqueductal-periventricular gray region (PAG/PVG). Indications of efficacy 
will also be examined. Patients will receive bilateral implants in the case of complete SCI (ASIA-A).  
Patients with an incomplete SCI who can localize pain to one side of the body will receive unilateral 
stimulation of the PAG contralateral to the sites of pain. 
Although PAG/PVG stimulation has been used previously in SCI pain patients, the small numbers of 
patients studied and the lack of detail on their testing and injury status makes a phase I trial appropriate. 
Effective treatment of pain could also bring benefits to patients with autonomic dysreflexia (AD), which 
can be provoked by painful visceral and somatic stimuli below an incomplete lesion. Autonomic 
functioning will therefore be studied as a secondary outcome. Preclinical evidence from rats suggests that 
prolonged PAG stimulation may lead to enduring improvements in all deficits (sensory, motor, and 
autonomic). The proposed study will therefore examine if such improvements occur when PAG/PVG 
stimulation is applied over many weeks.  
Aim 1 is to determine whether DBS in the PAG/PVG at analgesic intensities produces any systemic or 
neurological adverse effects in patients with longstanding SCI (>1 year), either immediately or as a result 
of prolonged application for up 40 weeks.  
Aim 2 is to determine whether acute application of DBS in the PAG/PVG influences the severity of 
spontaneous ongoing pain caused by longstanding SCI.  
Aim 3 is to determine whether DBS in the PAG/PVG affects stimulus-evoked or persistent hypertension (a 
major sign of autonomic dysreflexia) in chronic SCI patients.  
Aim 4 is to determine whether prolonged PAG/PVG stimulation (for 10 months) leads to cumulative 
changes in chronic pain severity, motor or autonomic symptoms in chronic SCI patients. 
11.2  Core (null) Hypothesis:  
The null hypothesis is that, in humans, deep brain stimulation (DBS) applied bilaterally or unilaterally in 
the midbrain periaqueductal-periventricular gray region (PAG/PVG) will not alleviate chronic neuropathic 
pain in patients with spinal cord injury (SCI). 
11.3  Primary Objectives: 
To evaluate the safety and efficacy of deep brain stimulation (DBS) applied bilaterally or unilaterally in the 
midbrain periaqueductal-periventricular gray region (PAG/PVG) for alleviation of chronic neuropathic pain 
in patients with spinal cord injury (SCI). 
11.4  Secondary Objectives: 
To assess the clinical effects of DBS on autonomic functioning when PAG/PVG stimulation is applied over 
many weeks (44 weeks); to determine with Activa PC+S whether local field portentials in the PAG/PVG 
can be used to predict the efficacy of DBS in this region.  

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12    STUDY DESIGN 
12.1  Type of Study 
Phase 1, open label study. 
12.2  Expected Number of Participants 
Twelve (12) participants with SCI for >1 year and show chronic persistent pain that has not fully responded 
to drug treatment. 
12.3  Treatment Groups 
One (1) Treatment group. All participants will receive the same treatment (long-term DBS in PAG/PVG) 
and undergo the same procedural protocol.  Ethical considerations forbid a control group that receives 
implant surgery without stimulation. Hence participants must serve as their own controls. 
After internalization of the pulse generator (electronic stimulator) and subcutaneous tunneling of 
connecting cables to the electrode and 12-48 hours for recovery from this internalization procedure, 
stimulation will be applied to the patient. The patient will be asked to report their ongoing pain level, on a 
0-10 numerical rating scale (NRS) with the stimulation turned off and, for each electrode contact, in small 
voltage steps up to the threshold for any aversive effects (if not seen in the first step). Floating, dizzy or 
warm feelings can be expected, based on literature reports. If there is no ongoing pain, cutaneous brushing 
to cause allodynia below the injury, at sensitive sites determined in the pre-surgical testing sessions, will 
be used. Blood pressure will also be measured by cuff before and during electrical stimulation. This will be 
repeated on week 12 The optimal level will be 67% of threshold for aversive or other unwanted effects (e.g. 
motor) or device maximum (10 V) if such effects are not observed. We expect the optimal voltage to be 4-
10V. A frequency range of 10-20 Hz and pulse width range of 250-450 µs is anticipated, but these 
parameters will be set according to the subject’s responses. The subject returns home with the optimal 
stimulation settings after each programming session. 
Subjects will receive monthly adjustment of stimulation levels to optimize analgesia on the NRS. They will 
be given the option of remaining in the study if any level becomes unpleasant in later months. 
The subject will be given up to 4 different program groups after  study week 16, differing in contacts, 
voltages, frequencies  and pulse widths, all determined to be without adverse effect by the clinician 
programmer in the in-person office session. The subject is asked to switch program groups using their 
patient programmer.  They switch immediately if relief is unsatisfactory, and stay with the best program 
for pain relief, or with any adequate program if the best is not determined, keeping a pain diary (score 0-
10) at intervals of 24 hours or less to help determine the best program group.    
If the subject reports effects of DBS on sleep, the stimulation will be cycled in appropriate 12-hour on and 
off periods in a 4 week trial period and maintained if superior. Also, if the subject does not tolerate 
continuous stimulation for many hours, cycling at shorter intervals (e.g., one-hour on and off periods) will 
be tested.  
Although all subjects receive the same DBS treatment, a subset will receive the PC+S device for additional 
sensing of brain signals. After regulatory permissions have been obtained, the next subject to reach surgical 
consent (stage 3 consent) will receive this device. Subsequent enrollees will also receive the Activa PC+S 
DBS system. 
12.4 Schematic diagram ("Study Flow Charts") of trial design, and procedures 
A. Table 1 lists the major procedures relevant to this study.  
B. Table 2 contains the flow sheet which shows the frequency and timing of all visits. 

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12.5  Description of the Measures Taken to Minimize/Avoid Bias 
As this is an open label safety study without a control group, no specific measures will be taken (e.g., 
randomization, blinding, etc.) to minimize /avoid bias.  Subjects will not be randomized, and all will receive 
the same pattern. The subject and the primary evaluator will not be blinded to the stimulation level. Long-
term changes over the course of the treatment will be analyzed by time-series analysis of the adjusted 
stimulation levels. Placebo effects from surgery, as well as the safety and stability of the DBS implant, will 
be analyzed when the stimulator is inactivated during programming adjustment sessions by investigators. 
 
12.6  Duration of Subject Participation  
 
Participants will be monitored throughout a one year evaluation period for occurrence of AEs (acute, 
delayed, and/or cumulative), as well as for changes in clinical status, neurological status. 
 
Safety and efficacy assessments will be performed at week 1 and 2 post-intervention and at 4-week 
intervals post-intervention from study week 8 until study week 24, and at 8-week intervals thereafter 
until study week 48 . The last one of these assessments will take place on study week 52. The week 
52 assessment will include a qualitative exit interview with audio recording. The subject and 
investigators will be given the opportunity for open comments and questions concerning elements of 
the study. 
 
After the initial 52-week study period subjects can choose to remain in the study for an extended period 
lasting approximately 104 weeks. The details of this extension period are covered next in section 12.6.1. 
12.6.1  Extension of study 
Introduction. The study will be extended for approximately 2 more years, precisely 104 weeks.  The purpose 
is to obtain long-term follow-up information on safety and efficacy, in subjects that have opted to receive 
continuing brain stimulation. We label weeks in terms of original enrollment. Thus the surgery occurs in 
weeks 7 and 8 and the original study finishes in week 52, with the extension lasting from week 53 to week 
156. 
Aims: 
1. To evaluate any changes in pain relief in the 2nd and 3rd year of deep brain stimulation (DBS) in 
the midbrain periaqueductal/periventricular gray (PAG/PVG). 
2. To assess needs for changes in stimulation parameters (contact selection, voltage, frequency, 
pulse width) to continue optimal relief. 
3. To determine changes in injury status revealed by the ASIA score.  
4. To uncover later-occurring adverse effects. 
 
Enrollment. Subjects will preferably continue without a gap at the end of the original 52 week study. 
However, they may be enrolled at any time during the extension to accommodate the time needed to obtain 
regulatory approval for the extension or subjects who wish to take a break. An additional informed consent 
form will be used for enrollment.  
Procedures. Subjects will receive continuous DBS in the PAG/PVG from the previously implanted system. 
They will return every 12 weeks to the study site to optimize the stimulation parameters for pain control. 
The optimum may drift or may not have been determined previously from the very large range of possible 
settings. Subjects will leave the visits with a blinded choice of settings (2 to 4, labeled A, B, C D), which 
they can explore at home. Preliminary findings suggest that pain changes over several days when settings 
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at other times for stimulation adjustment or other study related issues. Some later subjects may have a PC+S 
generator device implanted, which allows recording from the stimulating leads. Subjects with this device 
will also undergo brief recording sessions during visits, following the protocol of the first year.  
Tests and questionnaires. The study extension will use only questionnaires and study forms from the 
original study. It will omit autonomic system testing and quantitative sensory testing. On-site assessment 
will be done in clinical exam rooms and offices of the Miami Project to Cure Paralysis of the University of 
Miami Miller School of Medicine, including ASIA assessment. If the stimulator settings are producing 
consistent adequate pain relief, visits may be omitted at the subject’s discretion, except for weeks 104 and 
156, and assessments will be made by telephone questionnaire.   
The following will be assessed every 12 weeks.   
International Spinal Cord Injury pain basic data set (ISCI) 
Neuropathic Pain Symptom Inventory (NPSI) 
Beck depression inventory (BDI) 
Guy-Farrar patient global impression of change (PGIC) 
Medication usage 
 
In addition, subjects will be asked to keep a pain diary with a morning and evening pain score rated from 0 
(no pain) to 10 (worst ever pain). The pain diary will be retrieved at the visits or by telephone.  
At weeks 104 and 156, we will determine the ASIA score (American Spinal Injury Association neurological 
examination, sensory and motor). On week 156, an open ended qualitative exit interview will be conducted 
with audiovisual recording, including questions on the overall experience, effects on daily life, etc. 
Adverse events (AEs) will be recorded immediately after telephone contact by the subject (subject-reported 
AEs) and during visits to the study site (clinician-reported AEs).  
 

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 
Table 1:  List of Procedures for planned study 
 
Screening: 
1 
Urine pregnancy test  
 
2 
HIV, HBV, HCV testing 
 
3 
Laboratory tests (CBC, CMP, BSCP, prothrombin time test) 
 
4 
Medical history, Brief neurological and medical examination   
 
5 
Autonomic dysreflexia assessment 
 
6 
Spinal Cord Injury history 
 
7 
ASIA motor / sensory scores 
 
8 
Functional and pain assessments 
 
9 
Psychological Assessment (MMSE, BDI) 
 
10 
Drug abuse screening test 
 
 
Baseline Procedures (at 2- weeks): 
1 
Autonomic dysreflexia assessment 
 
2 
Functional and pain assessments 
 
3 
Psychological Assessment (MMSE, BDI) 
 
4 
ASIA motor / sensory scores 
 
5 
Medical history, Brief neurological and medical examination   
 
6 
Patient diary on medications 
 
 
DBS Device Implantation Surgical  Procedure: 
1 
Initial MRI / CT scan of the spine 
 
2 
Chest X-ray; Electro-cardiogram 
 
3 
1-Targeting & Lead placement: at 7-week 
 
3 
2-DBS  & Lead connection: at 8-week 
 
 
ICU Monitoring/Medical Treatment: 
1 
Blood Pressure Monitoring 
 
2 
Oxygenation 
 
3 
Additional physiological monitoring specific to subject (displayed on telemetry monitor) 
 
4 
Laboratory tests (CBC, CMP, BSCP, prothrombin time test) 
 
5 
Post op medications (antibiotics, DVT prophylaxis, etc.) 
 
 
Follow-Up Procedures: 
1 
Long-term DBS in PAG/PVG starting on week 8 
 
2 
Telephone interview: weekly, except  on-site visit weeks, from week 3   
 
3 
Pain assessments: on even weeks, starting on week 10 
 
4 
Autonomic Standards Assessments: on on-site visit weeks 
 
5 
Tilt table response exam: at 20-week, 32-week, and 52-week 
 
6 
Beck Depression Inventory:  on visit weeks 
 
7 
Folstein Mini-Mental State exam: at 20-week, 32-week, and 52-week 
 
8 
Patient Global Impression of Change: weekly, starting on week 9 
 
9 
ASIA motor and sensory assessments: at 20-week, 32-week and 52-week.   
 
10 
Qualitative exit interview at 52 weeks 
 

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Table 2.  Flow sheet of Visits/Assessments 
Study Visit Schedule for the initial 52-week study period: 
 

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12.7  Description of the "Stopping Rules" or "Discontinuation Criteria" for Individual 
Participants, Parts of Trial, and Entire Trial.  
A. Termination by the Participants 
Participants may withdraw consent to participate in this study at any time by informing the Principal 
Investigator. No further procedures will be performed or information will be collected from participants 
that withdraw consent. Previously collected data and samples will be used for the study analysis.  
B. Termination by the Sponsor  
The Sponsor may terminate the study at any time for any of the following reasons: 
 
Failure to enroll patients. 
 
Protocol violations. 
 
Inaccurate or incomplete data. 
 
Unsafe or unethical practices. 
 
Questionable safety of the study device. 
 
Administrative decision. 
C. Termination by the Principal Investigator: 
The Principal Investigator may remove a subject from the study at any time for any of the following 
reasons (Note:  If the PI removes a subject prematurely, the PI shall promptly provide the IRB/IEC and 
the Sponsor with a written statement describing why the study subject was removed prematurely).   
 
Onset of confounding neurological problems such as severe dysesthesia, severe neuropathic pain, 
or changing neurological level.  
 
Serious adverse event: discontinuation due to a serious adverse event. 
 
Lost to follow-up: the subject fails to return to the study site for scheduled visits and does not 
respond to attempts to contact. 
 
Withdrew consent: the subject decides to stop his participation for any other reason than an adverse 
event, or is unable to complete the study as described in the study protocol. 
 
Administrative: the Sponsor decides to terminate an individual subject or decides to discontinue 
the study due to general safety concerns. 
 
Protocol violation: anything that is a direct and significant violation of the clinical study protocol.  
D. Partial Termination  
If the treatment appears at any point to be clearly successful in any patient, the choice of constant 
stimulation at the best amplitude will be offered. Regardless of whether the stimulation is stopped 
permanently or left at a constant level, the patient will be followed according to the study plan for as 
long as they remain willing. The patient may also elect to receive no further stimulation but to stay in 
the full study to assess pain and other variables.  
E. Futility and Enrichment: 
Gradual benefits may be seen from prolonged treatment. Therefore the study will not be stopped early 
in the absence of interim benefits, nor will the stimulation intensity be increased. 

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13    SELECTION OF PARTICIPANTS 
13.1  Recruitment Procedure 
Some recruitment will be done through the newsletter of the Paralyzed Veterans of America (South Florida 
Chapter). This is a congressionally chartered Veterans service organization, whose members are veterans 
of the armed forces who have experienced SCI. In addition, participants will be solicited through the 
newsletter of the Miami VAMC.  Other potential subjects will be identified from a database maintained by 
The Miami Project to Cure Paralysis. Potential study participants will be asked to contact Dr. Martinez-
Arizala, Chief of the Spinal Cord Injury Service of the Miami VA Medical Center, if they are interested in 
learning more about the study. Dr. Martinez-Arizala will also conduct a medical record review to identify 
potential participants among the patients who in the past or currently are visiting his clinic. These patients 
will be contacted by Ms. Fisher  (Study Coordinator) who will inform them about the study over the phone 
or by sending them a copy of the recruitment material in the mail. 
Compensation will be provided for each visit (n=10), as a fixed amount ($100.00 per visit) to cover expected 
average travel and incidental costs. An extra payment will be given for participation in the entire study 
($400.00). If a patient does not have a telephone, an inexpensive pay-as-you go cellular telephone will be 
provided (from additional internal funding sources).  
13.2  Consent Procedures 
Informed consent will be obtained in 3 steps: (1) for clinical and psychological screening, (2) for the main 
functional testing, (3) for DBS surgery. The Study Coordinator and Dr. Martinez-Arizala will address 
questions during steps 1 and 2 (to be done in the 1st week at the Miami VA Hospital). This will be done in 
a private examination room, with the patient offered the possibility of reviewing the informed consent form 
and asking questions for up to 2 weeks before deciding (they would need to make a 2nd visit for this); Drs. 
Jagid and Luca will be present for step 3 (to be done in the 7th week at the University of Miami Hospital). 
The step 2 consent process will include showing the patient the surgical (step 3) consent form, and 
explaining the surgery, in order for the potential participants to have 6 weeks to review the surgery consent 
and ask any question they might have about the procedure. The step 3 consent will explain that the subject 
may receive the Activa PC+S DBS device system or the Activa PC. 
Participants will be screened before the step 2 consent discussion for drug abuse or major psychiatric 
problems. Literacy is an inclusion criterion. Participants can request a meeting or telephone conversation 
at any time during the study with the PI or relevant Co-investigator, as well as with the Study Coordinator. 
The Study Coordinator will be the primary contact for this. Her email address and telephone numbers will 
be provided to participants for this purpose. 
A pregnancy screen will be performed on all females of potential child bearing age.  All SCI patients 
excluded following the screening will be recorded to identify potential factors impeding patient enrollment 
which can be addressed by the study Executive Committee.  Patients unable to provide informed consent 
will be denied entry into the study.  The fully executed informed consents will be placed in the chart, with 
copies given to the patient and maintained in the site’s study binder.   
13.3  Inclusion Criteria 
a) Age: 22 - 60 years old at last birthday; 
b) Diagnosis of traumatic SCI at or above the 12th thoracic segment (T12) that occurred >365 days;  
c) Neuropathic pain below the level of injury, as determined based on pain in an area with neurological 
deficit and described as burning, shooting, electric, stinging etc. 

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d) The injury must have occurred at least 1 year prior to entering the study and participants must have 
experienced chronic pain for a minimum of six months. 
e) The disability must have a grade on the American Spinal Injury Association Impairment Scale 
(AIS) of ASIA-A, ASIA-B, ASIA-C or ASIA-D as determined by qualified examiners. 
f) Pain (neuropathic) of moderate severity or greater is present, when the patient is taking their routine 
pain medication,  with a score of at least 4 on a numerical rating scale (range of 0 to 10). 
g) Participants who are on medications for other conditions, such as diabetes, will be considered as 
candidates for this study. The dose will be monitored throughout the trial. (They will be excluded 
if the drug is being used to treat epilepsy, Parkinson’s diseases, or other brain degenerative 
diseases.) 
h) Participants will be allowed to utilize over-the-counter drugs such as NSAIDs, acetaminophen and 
aspirin. Their use will be documented in the weekly pain assessments. A list of “allowed” 
medications will be provided to study participants. After the surgery, patients will be allowed to 
take stay on the protocol if they take Tramadol (50-100 mg, 2 times a day for up to 2 weeks) as a 
rescue drug in addition to their stable medication. 
i) The patient must be taking pain medication to maintain a stable level of medication from 4 weeks 
before surgery to 12 weeks after (the primary endpoint), except on the day of surgery. On the day 
of the surgery, in the presence of a physician who can provide immediate backup pain control if 
needed, medications will be stopped until the acute effects of DBS on analgesia have been 
evaluated. 
j) The participant must be willing to comply with the protocol including all scheduled visits. 
k) Autonomic dysreflexia can be present but is not a necessary requirement. Autonomic dysreflexia 
will be defined as rise of systolic pressure by more than 30 mm Hg during noxious skin stimulation 
or when the bladder or bowel are full, or apparently spontaneously over a period of minutes 
l) Literate at 8th grade level or above. 
m) Treatment with at least two of the following drug classes must have failed to give satisfactory pain 
relief within the last two years: anticonvulsants (e.g., pregabalin, gabapentin); antidepressants (e.g., 
trazodone, amitriptyline); NSAIDS (e.g., ibuprofen). In addition, at least one of the following must 
have proved ineffective: exercise-based rehabilitation, massage therapy using a variety of methods, 
acupuncture using pressure, needles, heat, or electrical stimulation on specific points on the body 
and psychological interventions such as cognitive therapy. 
n) The subject must provide a letter of clearance for the DBS surgery from their primary physician. 
13.4  Exclusion Criteria 
a) Any failure to meet above criteria; 
b) Pregnant women or women who are contemplating pregnancy. 
c) Prior history of abusing non-prescribed drugs. 
d) A recent (one-year) history of alcohol abuse. 
e) Renal disease, heart disease or uncontrolled hypertension, liver disease or hepatic cirrhosis. 
f) Active major medical or psychiatric illness; a score of less than 25 on the MMSE. 
g) Significant post-traumatic encephalopathy from head trauma sustained at SCI. 
h) Pain is only nociceptive, due to muscle spasm 
 

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Additional Surgical Exclusion Criteria: 
1) Coagulopathy 
2) Thrombocytopenia or platelet dysfunction 
3) Inability to cooperate 
4) Any clinically significant abnormality, not expected on the basis of age (age-related), that is 
seen in magnetic resonance imaging (MRI). 
5) Peripheral vascular disease. 
6) Depression, as defined by a Beck Depression Inventory (BDI-1a), score 30 or above. 
7) Existing implantable cardiac pacemaker, defibrillator or neurostimulator. 
8) Diathermy treatment during the course of the study (unless limited to brain and cervical spine 
and using a head send-receive coil 
9) Adverse reaction to stimulation (such as inability to stimulate at analgesic levels without 
causing clinical hypertension or hypotension) or allergy or hypersensitivity to any materials of 
the neurostimulation system 
10) Comorbid neurological diseases or disorders, including a history of seizures 
13.5  Withdrawal Criteria: 
a) Participants may withdraw consent to participate in this study at any time by informing the Principal 
Investigator. No further procedures will be performed or information will be collected from 
participants that withdraw consent. Previously collected data and samples will be used for the study 
analysis;  
b) The only anticipated circumstance under which the Principal Investigator would terminate a 
subject’s participation is if information was obtained which made the subject ineligible for the 
study. The primary reason for this premature termination is to be indicated by selecting one of the 
following definitions: 
 
Gradual deterioration in neurological status from incomplete to complete SCI, or change in 
ASIA grade to a more severe level: B to A, C to A or B, D to A or B or C; 
 
Unresolved post-surgical wound infection; 
 
Onset of confounding neurological problems such as severe dysesthesia, severe neuropathic 
pain or changing neurological level;  
 
Serious adverse event: discontinuation due to a serious adverse event; 
 
Lost to follow-up: the subject fails to return to the study site for scheduled visits and does not 
respond to attempts to contact; 
 
Withdrew consent: the subject decides to stop his participation for any other reason than an 
adverse event, or is unable to complete the study as described in the study protocol; 
 
Administrative: the Sponsor decides to terminate an individual subject or decides to discontinue 
the study due to general safety concerns; 
 
Protocol violation: anything that is a direct and significant violation of the clinical study 
protocol.  

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14    TREATMENT OF PARTICIPANTS 
14.1  Recruitment and Screening Procedures and Assessments: 
Screening and recruitment of participants will take place at the Veterans Hospital and at The Miami Project 
to Cure Paralysis. Participants will be inpatients or outpatients at Veterans Hospital or University of Miami 
Hospital (UMH). After admission, the PI or designated representative will be informed of the patient and 
their history will be carefully screened for relevant selection criteria (as outlined in Table 1, and Table 2 in 
section 13.6) and the patient’s MRI of the spine will be reviewed. Patients with spinal cord transection and 
contusive signal change exceeding 3 cm in length will not be eligible for the study. Eligible patients will 
be informed of the study, counseled regarding its key steps, and procedures, and asked to provide Informed 
Consent. 
14.2  Method of Assigning Participants to Treatment Groups: 
Not applicable. This study will employ an open label, non-randomized, and non-placebo controlled design. 
There will be only one treatment group. 
14.3  Participant Procedures and Assessments 
14.3.1 Baseline Assessments 
Participants who remain eligible after all the screening procedures are complete will undergo the following 
baseline assessments at 2- week, prior to surgical procedures. 
 
Functional Pain Assessments  
o ISCI basic pain dataset and Neuropathic Pain Symptom Inventory (NPSI) 
o West Haven-Yale Multidimensional Pain Inventory for persons with SCI (MPI-SCI) 
o Allodynia testing  
o Quantitative sensory testing (QST) 
 
Quality of Life assessments 
o Beck Depression Inventory (BDI, version 1a) 
 
Autonomic Assessment:  
o Autonomic Standards Assessment (BP, HR, sympathetic skin response) 
o Tilt table exam response. 
14.3.2 Surgical Procedures and Assessments.  
The surgical procedure for implantation of a PAG/PVG deep brain stimulator is described here.  The 
procedure technique is no different than FDA approved deep brain stimulator procedures for movement 
disorder.  All patients undergo MRI imaging of the brain prior to surgery. Particular imaging sequences 
consist of thin cut (1-2mm) T1 and T2 weighted images.  On the morning of surgery, in the pre-anesthesia 
holding area, a Cosbid, Robert, Wells (CRW) frame is rigidly affixed to the skull with four point fixation.  
This is done with local anesthetic injections consisting of .5% Marcaine with epinephrine 1:200,000, a total 
of 20-30cc is usually used.   
Once the frame is in place, the patient will undergo a CT scan of the brain without contrast agent.  This CT 
scan has the localizer rods in place, which create a stereotactic field for precise localization of target.  The 
imaging studies including the CT scan and the prior obtained MRI are uploaded into a Medtronic planning 
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then outputs an X, Y, and Z coordinate for the chosen target. More than one MRI scan may be necessary if 
determined by the neurosurgeon, in order to obtain optimal image resolution and fusing with the CT scan 
by the planning station software.  
The patient is then placed on the operating room table in the supine position with the head elevated 
approximately 45o.  The patients head is fixed in this position with the use of the frame.  The entire head is 
then shaved and the right frontal area of the scalp approximately 11cm back from the nasion and 3.5cm off 
the midline on the right side is injected with approximately 20cc of 0.5% Marcaine with 1:200,000 
epinephrine. The CRW arc with the X,Y, and Z coordinate for the target is then applied to the CRW frame.  
A small curvilinear incision is then made and a 14mm burr hole is made using a Midas Rex drill.  A burr 
hole cap is applied to the circumference of the burr hole.  The dura is then opened using electrocautery 
exposing the underlying cortical surface.  An 11-blade scalpel is then used to score the pia.  At this point, 
a Ben-Gunn Stage is applied to the CRW arc and a cannula is inserted down the center channel of the Ben-
Gunn through the burr hole, traversing the right frontal lobe to end at a depth of 25mm above the desired 
target.   
With the use of neurophysiologic monitoring the target is optimized for lead placement.  Neurophysiologic 
monitoring for this target, the periaqueductal grey, is not well defined.  Therefore, targeting will be 
primarily based on image guidance.  The lead (model # 3387) itself is then inserted to a pre-defined depth 
of 237mm.  This will place the tip at the chosen target.   
Test stimulation will be performed to determine the adequacy of targeting.  The patient will report feelings 
evoked by various stimulation parameters to be sure that appropriate stimulatory effects are felt and that no 
adverse stimulatory effects are induced at normal programming thresholds (see 14.7). 
After confirmation of target accuracy the lead is secured in place.  A lead protector is placed over the distal 
end of the lead which is tunneled into a subgaleal pocket over the right parietal boss. The frontal scalp 
incision is closed with a combination of 2-0 vicryl and staples.  The CRW frame is then removed from the 
patients head.  An additional CT scan may be performed after the lead implantation procedure to confirm 
target and ensure no trauma has occurred.  
General anesthesia is induced, and the patient is endotracheally intubated.  The operating room table is 
turned 90o and the patients head turned 70o to the left, placed on a donut head holder with a roll under the 
shoulder blades to put the neck in slight extension.  
The surgical sites are then prepped and draped sterilely.  Local anesthetic is injected using 0.5% Marcaine 
with 1:200,000 epinephrine.  A three finger-breadth linear incision is made two finger-breadths below the 
right clavicle and a subcutaneous pocket is made just over the pectoralis fascia.  A counter-incision is made 
over the distal lead at the parietal boss and the lead is exposed at the parietal boss.  The distal lead protector 
is removed.  A subcutaneous passer is used to make a subcutaneous tract from the parietal boss counter-
incision to the subclavicular incision.  An extension cable is tunneled down the passer and brought out of 
the subclavicular incision.  The passer is then withdrawn and the proximal portion of the extension is 
connected to the distal portion of the lead.  The distal portion of the extension is connected to the superficial 
channel of the neurostimulator.  The neurostimulator and excess extension cable are then inserted into the 
chest wall pocket and anchored to the pectoralis fascia using a 3-0 prolene stitch.  In subjects with 
implantable programmable pumps, the neurostimulator must be placed at least 8 inches from the implanted 
pump. The chest incision is re-approximated using 3-0 vicryl stitch in an interrupted, inverted subcuticular 
manner.  Steri-strips are applied to the skin.  The parietal boss incision is re-approximated by using 2-0 
vicryl for the galea and staples for the skin.  
14.3.3 Targeting & Lead Placement 
Targeting is accomplished by combining high resolution 3T MRI images with thin cut CT scan images and 
the use of computerized targeting software. Images are uploaded into the targeting software.  The computer 
then fuses both MRI and CT scans together.  The operator of the computer is then able to identify certain 

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landmarks including the anterior commissure (AC) and posterior commissure (PC).  The intercommisural 
length is then calculated.  The actual target is then identified by using offsets from these structures.  In the 
case of the periaqueductal grey, the X coordinate is 10mm posterior to the mid-commisural point, the Y 
coordinate is 2-3mm lateral to the wall of the IIIrd ventricle, and the Z coordinate is in the plane of the 
intercommisural line.  T2 weighted images can then be used to further refine the target based on direct 
visualization of the periaqueductal grey.   
Once the final target is identified, the computer yields an X,Y,Z coordinate for the stereotactic field.  This 
is set on the CRW arc and used to deliver the lead. 
14.3.4 Macrostimulation and Sensing 
Once the lead is at target, test stimulation will begin with an external neurostimulator (model # 37022).  
Macrostimulation will be performed by a Neurologist who specializes in neurophysiologic monitoring for 
deep brain stimulation.  He has been involved in well over 700 similar procedures.  The macrostimulation 
procedure involves an algorithm that tests all combinations of contacts in a bipolar fashion.  Both pulse-
width and frequency will be set at fixed values and amplitude will be gradually increased in steps while 
recording clinical effects.  The goal will be to determine optimal settings for therapeutic effects as well as 
suboptimal settings that induce side effects.  It should be noted that all effects from stimulation are fully 
reversible by cessation of stimulation or revision of programming parameters.  Upon successful 
intraoperative macrostimulation, the implantable neurostimulator (model 37601) will be connected. 
Therapeutic effect can be elicited by the patient reporting a warm feeling in various areas of the body.  No 
such feeling, however, does not preclude optimal targeting.  Chronic stimulation may be needed to induce 
a beneficial effect.  
Likewise, changes in vital signs will also be assessed as these changes are indicative of autonomic effects.  
Examples would be change in heart rate, systolic blood pressure, etc.   
Neurologic changes would also be assessed as the periaqueductal grey is close to the superior colliculus 
and thus various eye findings might be induced. 
If the subject reports effects of DBS on sleep, the stimulation will be cycled in appropriate 12-hour on and 
off periods in a 4 week trial period and maintained if superior. Also, if the subject does not tolerate 
continuous stimulation for many hours, cycling at faster on and off periods will be tested. 
In subjects with an implanted PC+S device, the visits at weeks 12, 16, 20, 24, 32, 40, 48 and 52 will include 
recording of local field potentials. Recording will be done from all contacts during DBS at optimal setting 
for pain relief, over a period of one minute. 
14.3.5 Monitoring Participant for Comfort 
All participants will be arousable during surgery and thus able to vocalize any discomfort.  Our institution 
has a specially trained anesthesia team adept at deep brain stimulation surgery and its particular nuances as 
it pertains to awake procedures.  Patients will all be on a Precedex drip for sedation with intermittent dosing 
of remifentanyl for comfort. 
The second surgery for generator internalization involves general anesthesia, skin incision and 
subcutaneous manipulation. Due to these factors (superficial post-operative pain, incomplete recovery from 
anesthesia), the subject may not be in a satisfactory state to be discharged on the surgery day, especially if 
scheduling factors cause a late surgery.  Physician judgement will be used to decide whether an additional 
1-2 days of in-hospital observation is appropriate.  
Subjects or investigator-clinicians can request and carry out an additional unscheduled in-person visit to 
study sites at any time. This will be done if the subject has any perceived safety issues, or requests a change 
in stimulation parameters to improve pain control. 

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14.4  Lead and or DBS Removal 
These devices have been designed and tested, with FDA approval for certain disorders, to be permanent 
implants.  However, there are occasions in which the device or a portion of the system might need to be 
removed.  If necessary, this requires additional surgery with risk.   
The most common reason for removal is infection.  At our institution, deep brain stimulation carries a 1.5% 
risk of infection necessitating removal.  The majority of the time, the implantable neurostimulator and 
extension cables need to be removed with preservation of the intracranial lead.  This is a result of the fact 
that most infections start at the neurostimulator implant site.   
Alternative reasons for removal of the system would be patient request in the event that the device does not 
produce its intended results.  However, in this instance, it is rare for patients to request removal as it requires 
additional surgery and there is no significant risk to keeping the device.  Devices may also malfunction or 
break necessitating removal or revision surgery to fix.   
Generators have a lifespan which ends at the time of battery failure. On average generator batteries fail after 
3-5 years depending on stimulation parameters. Battery longevity depends also on sensing features. Thus it 
is expected that the battery of the Activa PC+S 37604 Neurostimulator will last less than that of the Activa 
PC 37601 (which does not allow for sensing). When considering the stimulation parameters currently being 
used in the study, the Medtronic reference manual for battery longevity of the Activa PC+S 
neurostimulation system for DBS estimates the longevity at roughly over 4.5 years. This number only 
represents an estimate, considering battery longevity depends on several factors: programmed parameters, 
system impedance, hours per day of stimulation, degree of patient control over programmable stimulation 
parameters, and the use of sensing features (in the case of the Activa PC+S system). This figure is based on 
stimulation frequencies >100 Hz as used in  movement disorders; it is expected that pain treatment will use 
lower frequencies (<25 Hz) which will give at least 1-2 years more lifetime according to calculations based 
on manufacturer’s confidential data (M949908A001, System eligibility and battery longevity manual for 
Activa PC+S). In the event that battery replacement would be needed, routine, same day, surgery is 
performed to remove and replace the generator.   
14.5  Post Implantation Procedures & Follow-up 
Procedures performed to evaluate the safety of the investigational procedures and to evaluate subject 
outcome for this study include: 
A. Beginning one week after surgery, participants will undergo follow-up assessments post-implantation: 
i. 
Pain assessments every 2 weeks (ISCI basic pain data set, NPSI,), starting on week 10, will 
assess for development of, or changes in neuropathic pain; more comprehensive pain testing 
(MPI quantitative sensory testing/allodynia) will take place on comprehensive testing visit 
weeks (20-week, 32-week, and 52-week). 
ii. 
Autonomic Standards Assessment: on on-site visit weeks (BP, HR, sympathetic skin response) 
and on week 20, week 32, and week 52 (Tilt table response exam). Patient Self-assessment of 
Autonomic Responses occurs weekly starting on week 3, except on on-site visit weeks.  
iii. 
QoL assessments: on on-site visit weeks, starting on week 12 (Beck Depression Inventory 
(BDI-1a)) and weekly, starting on week 9 (Guy/Farrar Patient Global Impression of Change 
(PGIC)); 
iv. 
ASIA motor and sensory assessments:  on weeks 20, 32 and 52 to assess any improvement or 
deterioration in neurological function; 
v. 
a qualitative exit interview with audio recording at 52 weeks, giving subject and investigators 
will be given the opportunity for open comments and questions concerning elements of the 
study. 

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B.   Follow-up assessments will take place either at the Miami VA Hospital or at The Miami Project to Cure 
Paralysis, Department of Neurological Surgery, for regular follow-up visits for 44 weeks post-surgery.  
At each visit, information will be collected regarding the safety of the treatment, the presence or absence 
of adverse side effects, and the efficacy of the therapy with respect to recovery of neurological 
functioning or the development of adverse effects. 
14.6  Medication(s)/Treatment(s) Permitted (Concomitant Medications) and not Permitted 
Before and/or During the Trial:  
A. Permitted Treatment 
All medication taken by the participant during the study is to be recorded.  All medications required 
to treat the participant should be administered as recommended.  The following data will be recorded 
for all included participants up to the end of the study period:  name of drug or nature of treatment, 
start and end dates, hours of administration, and indication.  Fluid and blood replacement will be 
measured and documented on a daily basis.  Additionally, any therapeutic or surgical procedure 
performed during the study period should be recorded, including the date, description of the 
procedure, and clinical findings 
B. Prohibited Treatment 
Investigational drugs and any other intervention (not part of the guidelines for management of SCI) 
known to have a potential impact on outcome are prohibited. 
14.7  Procedures for Monitoring Participant Compliance 
(Please Refer to Section 20 QUALITY CONTROL and QUALITY ASSURANCE) 
15    SAFETY 
Participants will be continuously monitored throughout a one (1) year evaluation period.  Assessments will 
be performed as outlined in Table 1 and Table 2 in section 13.6. Assessments will also include monitoring 
of occurrence of AEs (acute, delayed, and/or cumulative), as well for changes in clinical status, neurological 
status and/or functional status.  Safety will be determined as follows: 
a) Adverse events or other safety concerns will be ascribed to one of two categories: (1) general known 
problems with all types of DBS (e.g. infection) or with untreated SCI (e.g., bladder control failure); 
(2) problems caused by the PAG/PVG site in particular (e.g., hypotension) or to a specific response 
of SCI symptoms to DBS (e.g., more pain). The first category will not lead to ejection of the 
method. The second category can be evaluated more by turning off the stimulation or examining 
correlations with the 4-week periods of (8-weeks after week 24) adjustment of stimulation 
amplitudes. Second-category events will be carefully assessed and will lead to discontinuation of 
the study treatment if they cannot be ascribed to special circumstances in a given patient. 
b) Comprehensive pain, motor and autonomic assessment will occur on screening and enrollment 
(baseline) and then on on-site visit weeks (weeks 12, 16, 20, 24, 32, 40, 48 and 52).  
c) The correct functioning of the DBS apparatus will be monitored every 4 weeks, after implantation, 
until week 24. Thereafter this assessment occurs every 8 weeks, and on the last visit (week 52). 
d) Pain Assessments using the ISCIPDS:B and neuropathic rating scale will evaluate development of 
neuropathic pain syndromes. 
The secondary hypothesis which concerns autonomic assessment will also take place during routine 
patient visits. Heart rate, blood pressure, sweating, body temperature and breathing will be classified as 
normal, abnormal, unknown, or unable to access. Within the abnormal category, sub-categories will be 

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specified: for heart rate, bradycardia, tachycardia or other dysrhythmias; for blood pressure, systolic blood 
pressure under 90 mm Hg, orthostatic hypotension, autonomic dysreflexia; for sweating, hyperhydrosis 
above lesion, hyperhydrosis below lesion, hyperhydrosis below lesion; for body temperature, 
hyperthermia, hypothermia; for breathing, requiring full ventilatory support, requiring partial ventilatory 
support, impaired not requiring ventilatory support. Lower urinary tract, bowel and sexual function will 
be scored on the following: awareness of need to empty bladder and ability to prevent urine leakage; 
sensation of need for bowel movement, ability to prevent stool leakage, voluntary anal sphincter 
contraction; genital arousal (psychogenic and reflex), orgasm, ejaculation (male), and sensation of menses 
(female). 
Comprehensive testing sessions will analyze vagal and sympathetic influences on the cardiovascular 
system, measuring blood pressure and heart rate variability (power spectrum analysis) during sit-up or 
tilt-table challenge. However, if a subject is not able to tolerate the tilt table response exam to completion, 
he/she will not be required to fulfill this test at subsequent visits. The neurologist will decide whether it is 
recommended for subjects to undergo this assessment thereafter. Additionally, the test will not be 
required for subjects not expected to show autonomic dysreflexia because of their lower level of injury, as 
determined by the neurologist.  
Assessment of motor and non-pain somatosensory function will be done during visits every 4 weeks. 
Clinical sensory testing will include Light Touch and Pin Prick tests defined in the ASIA standards [1]. The 
Beck Depression Inventory (BDI-1a) will also be used, to assess emotional function in neuropathic pain 
[4]. A score of 30 or above indicates severe depression. If BDI assessment suggests suicidal thoughts, the 
Columbia Suicide Severity Rating Scale will be used in consultation with a clinical psychologist. 
16    ASSESSMENT OF TREND-TOWARD-EFFICACY 
The trend towards efficacy of the intervention will be assessed from the following parameters: 
a. AIS upper and lower extremity motor and sensory scores. 
b. Pain Assessments: ISCI basic pain dataset, quantitative sensory testing and Self-report version of 
ISCI basic pain dataset. 
c. Autonomic Assessments: BP, HR, tilt table response, sympathetic skin responses,  
d. Quality of Life: Beck Depression Inventory (BDI-1a), Guy/Farrar Patient Global Impression of 
Change (PGIC). 
17    STATISTICAL CONSIDERATIONS 
17.1  Safety Analyses: 
The analyses for safety will be mainly descriptive, focusing on trends for within-subject differences and 
changes in reported pain intensity during routine patient visits for the duration of the study. The expected 
outcome is stable, long-lasting change in the Pain Assessment Scale score from baseline to 44 weeks 
post-implant   .All AEs and SAEs will be listed and their incidence compared to historical controls.  The 
primary safety analysis will be conducted on all patient data when all 12 participants have completed the 
study.   
Table 3: Surgical and equipment adverse events in DBS, based on 3 sources. The percentage per patient is 
given.  
Information source 
Reference 1 
(n=133) 
Reference 2 
(n=124) 
Reference 3  (n=468) 

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Lead fracture 
6% 
3% 
0.4% 
Intraoperative electrode migration 
1.5% 
 
Late postoperative electrode migration 
1.5% 
 
Implanted pulse generator migration 
1.5% 
4% 
 
Erosion 
2.3% 
3.2% 
0.4% 
Infection 
1.5% 
1.6% 
1.3% 
Erosion plus infection 
1.5% 
 
Frequent external interference 
1.5% 
 
 
Other 
 
8.9% 
0.02% 
TOTAL 
17.3% 
17.7% 
2.3% 
Reference 1. Blomstedt P, Hariz MI. (2005. Hardware-related complications of deep brain stimulation: a ten 
year experience. Acta Neurochir (Wien). 147:1061-4.  
Reference 2. Schuepbach WM,  et al. (2013) Neurostimulation for Parkinson's disease with early motor 
complications. N Engl J Med. 368: 610-22. 
Reference 3. Experience of functional neurosurgery group (J. Jagid, B. Gallo, C. Luca) at the University of 
Miami (unpublished) 
Safety will not primarily be evaluated statistically. 
In addition to the continual monitoring of adverse events, safety analyses will use generalized linear 
models. The main dependent variable of interest is the Numeric Rating Scale (NRS) score for pain. 
Additionally there will be a fairly large number of dependent variables derived from assessments of other 
symptoms. Distributions will be modeled as binomial (yes=1 or no=0) or multinomial (e.g., score =1, 2, 
or 0) or normal (e.g., heart rate peak power after tilt, quantitative sensory thresholds). Less frequently, a 
Poisson distribution will be appropriate (e.g., number of times the patient reports autonomic dysreflexia in 
a given period). An appropriate link function will be chosen for each assumed distribution. Covariates to 
be considered are injury level, injury completeness and electrode configuration. The hypotheses to be 
tested for any variable (using the above factor coding) is that B<>A, C<>B, D<>B and D<>C. Marginal 
means can be used for this (except in multinomial examples, when main effects must suffice).  Some 
participants may lack data from one condition (if they immediately opted for continuous high-level 
stimulation after the initial untreated period). If the continuous treatment is stopped soon after it starts, 
only the placebo effect (A<>B) will be available. Representative independent variables from each type of 
symptom will be further explored by discriminant analysis, which can confirm that one or more treatment 
condition represents a distinct state in the multivariate outcome space. 
17.2    Efficacy Analyses: 
To test the core hypothesis and secondary outcome measures, the analysis (descriptive) for efficacy trends 
will be conducted on the baseline through 52 weeks of data collection for all twelve (12) participants 
enrolled. 
The one-minute recordings of local fields potentials from the bilateral or unilateral contacts PAG/PVG by 
the PC+S device will be analyzed in the time domain (autocorrelations and inter-lead cross-correlations)  
and the frequency domain (power in alpha, beta, gamma and delta EEG bands). Peaks in spectra or in 
auto- or cross-correlations  will be examined for correlations with pain level (analgesia obtained) for each 
contact or pair of contacts.  The potential ability shown by these results for usefulness in electrode 
targeting of future subjects (with pain from SCI or other causes) will be evaluated. That is, their 

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predictions of efficacy will be evaluated. These preliminary findings will be considered in the planning of 
studies with larger subject populations with pain of adequate statistical power. 
17.3    Power Analyses: 
This study is to be conducted for a period of three (3) years, starting from when the first subject is enrolled.  
As this is an open label safety study without a control group, no statistical analyses (other than descriptive) 
are proposed.  
While a formal power analysis is not warranted, analysis of statistical power could be based on ASIA motor 
scores, whose variability has been most thoroughly detailed in the literature. This score ranges between 0 
and 100. Data from a large-scale drug study on SCI showed that a 10-point change will reach a significance 
level of 0.05 if the number of patients with chronic cervical or thoracic injuries classified as ASIA A or B 
is ≈8 [51]. Recovery of sensory scores is typically more than 10%. Thus, the population size (n=12) should 
therefore have sufficient power for many planned statistical tests, especially since participants will serve as 
their own controls. 
17.4    Missing Data 
Although every attempt will be made to avoid missing outcome data, missing data is anticipated with any 
longitudinal study. The missing data can be defined as intermittent or dropout. Although every effort will 
be made to prevent participants from missing visits or dropping out of this study, it is possible that some of 
the measurements planned over the 52 weeks will be missing. The impact of missing data will be examined 
by comparing means and standard deviations for participants that have and do not have the relevant missed 
visit data. The reason for missing data will be fully examined to confirm this assumption.  
Missing data will be imputed using regression methods. 
17.5    Participant Attrition 
Because of the lengthy 44-week follow-up, efforts will be made to minimize the number of participants lost 
to follow-up by developing good rapport, making the participant feel comfortable with the research staff 
and having regular correspondence between assessments. To maintain contact and continued willingness 
for study participation at each visit participants will provide their current address and phone number, pager 
numbers, and e-mail address as well as contact information for at least two individuals who live outside of 
their household yet are likely to know their whereabouts. Contact information and contact history will be 
entered into an electronic database allowing regular review and update. 
 
18    DIRECT ACCESS TO SOURCE DATA/DOCUMENTS  
The Investigator agrees that qualified representatives of the Sponsor and regulatory agencies will have the 
right, both during and after this study, to conduct inspections and to audit and review medical records 
(CRFs, source data/documents, etc.) pertinent to the clinical study as permitted by the regulations.  Patients 
will not be identified by name, and confidentiality of information in medical records will be preserved.  The 
confidentiality of the patient will be maintained unless disclosure is required by regulations.  Accordingly, 
the following statement (or similar statement) will be included in the informed consent document: 
Representatives of regulatory agencies, IRB/IECs, the Sponsor, and your personal 
physician may review your medical records and all information related to this study 
as permitted by law.  Identifying information will not appear on any record received 
by the Sponsor.  Your identity will remain confidential unless disclosure is required 
by law.   

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19    QUALITY CONTROL AND QUALITY ASSURANCE 
19.1  Quality Control and Assurance Checks  
a. Before enrolling any patients in this study, the Study Monitor and the Investigator will review the 
protocol, the CRFs and instructions for their completion, the procedure for obtaining informed 
consent, and the procedure for reporting AEs and SAEs.  
b. The Medical Monitor(s) will review the data for safety information; the Study Coordinator will 
review the data for legibility, completeness, and logical consistency.   
c. Additionally, the Study Coordinator will identify missing data, selected protocol violations, out-
of-range data, and other data inconsistencies.  Queries for data clarification or correction are 
forwarded to the investigator for resolution.  A sample set of records will be fully audited against 
the corresponding CRFs. 
19.2    Study Conduct 
a. This study will be conducted in accordance with the IRB/FDA-approved protocol, and applicable 
regulations constituting Good Clinical Practices.   
19.3    Monitoring of the Study  
 Monitoring will be conducted by the University of Miami’s Clinical Research Operations and Regulatory 
Support Quality Control (CRORS QC) office. Site visits are made before the study begins, at regular 
intervals during the study, and at the study closeout.  Communication by telephone, mail and e-mail may 
be used as needed to supplement site visits.  The Investigator and study personnel will cooperate with the 
Sponsor, provide all appropriate documentation, and be available to discuss the study.  The purpose of the 
site visits is to verify the following:   
i. 
Adherence to the protocol.  (The Investigator will not deviate from the protocol without prior 
written approval of Sponsor, except in emergencies. For medical emergencies, approval of a 
protocol deviation is not required, but Sponsor must be notified as soon as possible.) 
ii. 
The completeness and accuracy of the CRFs and the device dispensing and inventory record.  
(Adequate time and space for these visits shall be allocated by the Investigator.)  
iii. 
Compliance with regulations.  The verification will require comparison of the source 
documents to the CRFs. 
19.4    Protocol Deviations 
Protocol deviations will be reported on the CRF, and will also be identified in data review by the 
Study Coordinator.  Any deviation to the protocol that may have an effect on the safety or rights of 
the participant or the integrity of the study will be reported to the University of Miami Human 
Subject Research Office (UM HSRO) and FDA as soon as the deviation is identified. 
All important deviations related to study inclusion or exclusion criteria, conduct of the trial, patient 
management or patient assessment will be documented and appropriately summarized. 
19.5   Progress Reports  
The PI will distribute bi-annual progress reports to the Funding Sponsor, the Miami Project to Cure 
Paralysis, communicating enrollment data, adverse events, and any outstanding issues or other 
relevant information.  At the time of the IRB renewal the PI will submit in writing the frequency of 
the data monitoring, a summary of adverse events, other external factors or relevant information 
that might have an impact on the safety or ethics of the study, final conclusions regarding changes 

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to the anticipated risk/benefit ratio to study participation, and final recommendations related to the 
continuation, alteration, or termination of the study.   
19.6   Audits and Inspections 
The conduct of the study (including the selected CRFs and corresponding patient source records) 
will be periodically audited for compliance with FDA's Good clinical Practices and ICH-E6.  Such 
audits will be conducted at least twice in the course of the Study, and will be conducted by the UM 
Office of Research Compliance & Quality Assurance (RCQA) auditors. 
The knowledge of any pending compliance inspection/visit by the FDA, OHRP, or other 
government agency concerning clinical investigation or research, the issuance of Inspection 
Reports, FDA Form 483, warning letters or actions taken by any Regulatory Agencies including 
legal or medical actions and any instances of serious or continuing noncompliance with the 
regulations or requirements will be reported immediately to the Sponsor and the IRB. 
20    ETHICS 
20.1   Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
The clinical protocol will be submitted to and approved by the University of Miami Human Subject 
Research Office (UM HSRO) and the FDA, and will not be initiated until written notification of 
approval of the research project is issued.  Accurate and complete study records will be maintained 
and made available to representatives of the UM HSRO and FDA as a part of their responsibility to 
protect human subjects in research. 
20.2   Informed Consent 
a. Participants with chronic spinal cord injury will be recruited from consecutive patients 
including men and women.  Only participants who can provide their own Informed Consent 
without proxy will be included in the study.   The discussions will take place in an area where 
privacy and confidentiality can be respected.  The participant will be given sufficient time to 
comprehend the research and discuss the study before making a decision.  The researcher will 
clearly explain the background/purpose, voluntary nature, commitment, risks, benefits, 
alternatives, and other elements, and will answer any questions.  If the participant agrees to 
participate, written Informed Consent will be obtained and study intervention/treatment 
protocol will ensue.   
b. The device implantation surgery informed consent will be obtained 2-3 days prior to 
scheduling the procedure. 
c. It will be explained to the patient that they have the right to refuse to take part and/or withdraw 
from this study at any time without penalty or loss of care.  Their ongoing medical care will not 
be affected by the decision to take part or not take part in this study.  Participants who take part 
in the study will receive the same level of care that is considered the community standard.  
Patients who do not to take part in the study will also receive community standard care.   
20.3   Declaration of Helsinki 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with good clinical practice (GCP) and the applicable 
regulatory requirements.   

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20.4   Participant Confidentiality 
To maintain participant confidentiality, all study documents and files will use an anonymous study 
identification number to identify participants and only the study coordinator will maintain linkages, 
and have access to, subject identities.  Local computer storage of data is password protected and 
located within a hospital- or institute-based firewall.  Study data will be stored in the clinical research 
office at the Lois Pope Life Center.   
The Data Safety Monitoring Plan to maintain confidentiality is as follows.   
a. The data will be stored for at least ten (10) years.   
b. All physiologic and neuropsychological data is coded with a unique identifying number, different 
from the subject’s medical record number or social security number, to maintain confidentiality, 
in order for these to be matched to the samples.  The study coordinator is responsible for 
maintaining this code.  The demographic information of the subject initially required to code 
with is password protected on his/her computer and is within a locked office.  
c. All signed consents and study data are stored within a locked filing cabinet in a locked office for 
which the PI will have oversight. Only personnel listed on study protocols will have access to 
study data.  However, pertinent study data will be shared with a subject in cases where the subject 
could possibly benefit medically or otherwise from the data, or upon their request.   
d. Any findings that increase risks to participants will also be shared with all study participants.   
e. Study data will also be made available to the Funding Sponsor, The Miami Project to Cure 
Paralysis and the FDA for audit.  
f. Study data may also be made available to consultants hired by the Miami Project to Cure 
Paralysis/Miller School of Medicine bound by written confidentiality for the specific purpose of 
providing oversight on the project.  
21     DATA HANDLING AND RECORDKEEPING 
21.1   Case Report Forms 
a. Where possible, data will be documented in source documents initially and then recorded on 
CRFs.  Dark indelible-ink pens (preferably black-ink ballpoint pens) shall be used.   
b. The originals of the CRFs plus one additional copy must be returned to the Sponsor; the PI must 
retain a copy of the CRFs for his/her file.   
c. CRFs and other pertinent records are to be submitted to the Sponsor during and/or at completion 
or termination of the study. 
d. The Investigator also must submit all incomplete CRFs that document patient experience with 
the study device, including retrievable data on patients who withdraw before completion of the 
study. 
e. Laboratory results and ECG results will be processed using electronic data provided from the 
centralized organizations and directly submitted to the data management group.  Any additional 
types of data that will be recorded directly into the CRF shall be listed in Section 10.3.8 of this 
protocol. 
21.2    The Study Coordinator 
The PI will monitor the progress of the research study with the assistance of a Study Coordinator.  
Data will be entered into Case Record Forms (CRF) at the study site within 5 days of the data time-

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point, and the Study Coordinator will review the accuracy of the entered data by comparison with 
participants’ medical records within thirty (30) days.  Potential discrepancies will be flagged and 
checked/corrected by study site personnel. 
21.3    Adverse Event Reporting 
The Investigator agrees to report all AEs to the Sponsor as described in the Adverse Events Reporting 
section, Appendix 1.  Furthermore, the Investigator is responsible for ensuring that any Co-
investigator or Sub investigator promptly brings AEs to the attention of the Investigator.  The 
Investigator also is responsible for informing the participating IRB/IEC of any SAEs.   
21.4    Protocol Amendments 
a) Any significant change in the study protocol will require an amendment.  In addition, major 
modifications to the research protocol and any modifications that could potentially increase risk to 
participants will be submitted to the FDA for approval prior to implementation.   
b) The Investigator and the Medical Monitor indicate their approval of significant changes to the 
protocol or CRFs by signing the approval page of the amendment.  Once the Sponsor has approved 
a protocol amendment, the Investigator shall submit it to the IRB/IEC for written approval.  The 
Sponsor submits a copy of the protocol amendment to the appropriate regulatory agency/agencies.  
A protocol amendment may be implemented after it has been approved by the IRB/IEC.   
c) A protocol change intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, but the change must then be documented in an amendment, reported to 
the IRB/IEC within five (5) working days, and submitted to the appropriate regulatory agency in 
the required time frame.   
d) Minor amendments (including minor changes to CRFs) will be submitted with the continuing 
review report to the UM HSRO for acceptance. 
21.5    Final Study Report  
a) The Investigator must complete a report notifying the IRB/IEC of the conclusion of the clinical 
study.  This report should be made within three (3) months of completion or termination of the 
study.   
b) The final report sent to the IRB/IEC must also be sent to the Sponsor and, along with the 
completed CRFs, constitutes the final summary to the Sponsor, thereby fulfilling the 
Investigator's regulatory responsibility. 
21.6    Records Retention  
a) The Investigator shall retain and preserve one copy of all data generated in the course of the study, 
specifically including but not limited to those documents defined by GCP as essential documents, 
for the longer of:  (a) 2 years after the last marketing authorization for the study drug has been 
approved or the Sponsor has discontinued its research with respect to such drug or (b) such longer 
period as required by applicable global regulatory requirements.   
b) At the end of such period, the Investigator shall notify the Sponsor of the intent to destroy all such 
material.   
c) The Sponsor shall have 30 days to respond to the Investigator’s notice, and the Sponsor shall have 
a further opportunity to retain such materials at the Sponsor’s expense. 

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22    FINANCING AND INSURANCE REGARDING PATIENT INJURY  
In general, if a patient is injured as a direct result of the study device, the Sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent the expenses are not covered by the patient’s 
medical insurance, a government program, or other responsible third party.  If laws or regulations of the 
locality in which the trial is taking place require additional payment of expenses, the Sponsor shall comply 
with such law or regulation.  Where applicable, the Sponsor will take specific national insurance. 
23    PUBLICATION POLICY 
All data will be summarized and analyzed. The Principal Investigators will prepare a clinical narrative. The 
Principal Investigators will prepare abstract submissions to an appropriate research meeting and a 
manuscript for submission to a peer-reviewed journal. The publication policies of The Miami Project to 
Cure Paralysis and Miller School of Medicine follow those recommended by the Association of American 
Medical colleges and the Institute of Medicine. The trial will be fully registered according to International 
Committee of Medical Journal Editors (ICMJE) standards within 21 days of its outset in 
http://clinicaltrials.gov/. 
24    APPENDICES 
24.1 
Appendix 1 - Description of Adverse Event Reporting (following page) 
24.2 
Appendix 2 – Protocol References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24.1  APPENDIX 1 -- ADVERSE EVENTS REPORTING 
1. Definitions 
1.1. An Adverse Event (AE) [a.k.a. "adverse experience"] is any untoward, undesired, unplanned 
clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations 

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occurring in a human being participating in a clinical study with a Sponsor study device, regardless 
of causal relationship.  This includes the following: 
 
Any clinically significant worsening of a preexisting condition. 
 
Any recurrence of a preexisting condition. 
 
An AE occurring from excessive output of a Sponsor study device whether accidental 
or intentional (i.e., an amplitude higher than that prescribed by a clinical 
neurophysiologist). 
 
An AE that has been associated with the discontinuation of the use of a Sponsor study 
device. 
Note:  A medical procedure is not an AE, but the reason for a procedure may be an AE. 
1.2. A Preexisting Condition is a clinical condition (including a condition being treated) that is 
diagnosed before the patient signs the informed consent form and that is documented as part of the 
patient’s medical history.  
The questions concerning whether the condition existed before the start of the active phase of the 
study and whether it has increased in severity and/or frequency are used to determine whether an 
event is a treatment-emergent AE (TEAE).  An AE is considered to be treatment emergent if: 
 
 it was not present when the active phase of the study began and is not a chronic 
condition that is part of the patient’s medical history, or  
 
it was present at the start of the active phase of the study or as part of the patient’s 
medical history, but the severity or frequency increased during the active phase.  The 
active phase of the study begins at the time of the first use of the study device. 
1.3. A Serious Adverse Event (SAE) is any AE occurring at any dose (voltage output) that results in 
one (1) or more of the following outcomes:  
 
Death. 
 
Life threatening situation (see below). 
 
Inpatient hospitalization or prolongation of an existing hospitalization (see below). 
 
Persistent or significant disability or incapacity (see below). 
 
Congenital anomaly or birth defect. 
Additionally, important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed above.  Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not require hospitalization.  If there is any doubt whether the information constitutes an AE or 
SAE, the information is treated as an AE or SAE. 
1.4. A Life Threatening Adverse Event is any AE that places the patient at immediate risk of death 
from the event as it occurred.  A life-threatening event does not include an event that might have 
caused death had it occurred in a more severe form but that did not create an immediate risk of 
death as it actually occurred.    
1.5. Hospitalization is to be considered only as an overnight admission.  Hospitalization or 
prolongation of a hospitalization is a criterion for considering an AE to be serious.  In the absence 
of an AE, the participating Investigator should not report hospitalization or prolongation of 
hospitalization on a CRF.  This is the case in the following situations:  

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 Hospitalization or prolongation of hospitalization is needed for a procedure required by 
the protocol.   
 Day or night survey visits for biopsy or surgery required by the protocol. 
 Hospitalization or prolongation of hospitalization as part of a routine procedure 
followed by the study center (e.g., stent removal after surgery). 
 
In addition, a hospitalization planned before the start of the study for a preexisting 
condition that has not worsened does not constitute an SAE (e.g., elective hospitalization 
for a total knee replacement due to a preexisting condition of osteoarthritis of the knee that 
has not worsened during the study). 
1.6. Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions.  
2. Timing for Reporting Serious Adverse Events 
2.1. Any SAE, regardless of causal relationship, must be reported to the Sponsor's Medical Monitor 
(or a designated affiliate) immediately (i.e., within 24 hrs).  A completed Serious Adverse Event 
Form must be faxed to the number indicated at the front of the clinical protocol no later than 24 
hours after the investigator becomes aware of the SAE.  A phone call should be made to confirm 
that the SAE fax was received.  Compliance with this time requirement is essential for the Sponsor 
to comply with regulatory obligations.  
2.2. Follow-up information relating to an SAE must be reported to a Sponsor Medical Monitor (or an 
affiliate or designee) within 24 hours of receipt by the Investigator by faxing a completed serious 
adverse event form to the number indicated in the front of this protocol and confirming by 
telephone that the fax was received.  The patient should be observed and monitored carefully until 
the condition resolves or stabilizes or its cause is identified.  
2.3. Any emergency must be reported to a Sponsor Medical Monitor (or an affiliate or designee) 
immediately (within 24 hours) by contacting a Medical Monitor listed in the front of this protocol.  
2.4. For all other inquiries and information about this study, contact Miami Project to Cure Paralysis 
at the phone number listed in the front of the clinical protocol.  
3. Reportable Events/Information 
3.1. An AE or SAE that occurs between the time that the patient signs the informed consent form 
through thirty (30) days from the patient’s last dose (voltage output), regardless of study device or 
protocol relationship should be reported.  This includes events that emerge during the screening 
and pre-treatment run-in periods.   
 
All AEs and SAEs will be recorded on source documents and recorded on CRFs.   
 
All AEs and SAEs that occur after the screening period will be recorded on the CRFs.   
 
The Sponsor Medical Monitor must instruct the investigator to follow up as is medically 
necessary on all AEs, SAEs, and other reportable events until the event has subsided or 
values have returned to baseline, or in case of permanent impairment, until the condition 
stabilizes.   
3.2. For SAEs:  The investigator will provide all documentation pertaining to the event (e.g., additional 
laboratory tests, consultation reports, discharge summaries, postmortem reports, etc.) to the 
Sponsor Medical Monitor in a timely manner.  Reports relative to the patient’s subsequent course 
must be submitted to the Sponsor until the event has subsided or, in case of permanent impairment, 
until the condition stabilizes.  

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4. Post-study SAEs related to device include any abnormal biological or vital signs values that are 
considered clinically relevant by the Investigator.  These must be reported in the same time frame and 
following the same process as for an AE or an SAE 
4.1. The Investigator managing the excessive voltage may order any additional test(s) he or she thinks 
is necessary to manage the patient properly. 
5. Recording and Reporting 
5.1. At each required study visit, all AEs that have occurred since the previous visit must be 
documented and recorded in the Adverse Event Record of the patient’s CRF.  The information 
recorded should be based on the signs or symptoms detected during the physical examination and 
clinical evaluation of the patient.  In addition to the information obtained from those sources, the 
patient should be asked the following nonspecific question:  "How have you been feeling since 
your last visit?"  Signs and symptoms should be recorded using standard medical terminology. 
5.2. The following AE information must be included (when applicable):   
 
the specific condition or event and direction of change;  
 
whether the condition was preexisting (i.e., an acute condition present at the start of the 
study or history of a chronic condition) and, if so, whether it has worsened (e.g., in severity 
and/or frequency);  
 
the dates and times of occurrence; severity; causal relationship to study device; action 
taken; and outcome.   
5.3. The causal relation between an AE and the study device will be determined by the investigator on 
the basis of his or her clinical judgment and the following definitions: 
 
Definitely related:  Event can be fully explained by use of the study device. 
 
Probably related:  Event is most likely to be explained by use of the study device rather 
than the patient’s clinical state or other agents/therapies. 
 
Possibly related:  Event may be explained by use of the study device or by the patient’s 
clinical state or other agents/therapies. 
 
Probably not related:  Event is most likely to be explained by the patient’s clinical state or 
other agents/therapies, rather than the study device. 
 
Definitely not related:  Event can be fully explained by the patient’s clinical state or other 
agents/therapies. 
5.4. When assessing the relationship between use of a study device and an AE, the following should 
be considered: 
 
Temporal relationship between use of the study device and the AE. 
 
Biological plausibility of relationship. 
 
Patient’s underlying clinical state or concomitant agents and/or therapies. 
5.5. SAEs that are not study device related may nevertheless be considered by the participating 
Investigator or the Medical Monitor (or designee) to be related to the conduct of the clinical study, 
i.e., to a patient's participation in the study.  For example, a protocol-related SAE may be related 
to a procedure required by the protocol. 
5.6. The following definitions should be used when determining the severity of an AE.  Please note 
that there are some cases in which removal of study device may be appropriate. 
 
Mild (grade 1):  The AE is noticeable to the patient but does not interfere with routine 
activity.  The AE does not require discontinuing use or reducing the voltage output of the 

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study device. 
 
Moderate (grade 2):  The AE interferes with routine activity but responds to symptomatic 
therapy or rest.  The AE may require reducing the voltage output but not discontinuing use 
of the study device. 
 
Severe (grade 3):  The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy.  In addition, the AE leads to discontinuing use or 
reducing the voltage output of the study device. 
 
Life Threatening (grade 4):  The AE requires discontinuing use of the study device.  The 
patient is at immediate risk of death. 
 

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