Single Center, Randomized Prospective Comparative Effectiveness Study of Dorsal Column Spinal Cord Stimulation to Dorsal Root Ganglion Stimulation in the Treatment of Complex Regional Pain Syndrome
Conditions: Complex Regional Pain Syndrome
Sponsor: The Cleveland Clinic

Single Center, Randomized Prospective Comparative 
Effectiveness Study of Dorsal Column Spinal Cord 
Stimulation to Dorsal Root Ganglion Stimulation in the 
Treatment of Complex Regional Pain Syndrome 
 
Version: 1.5 
 
September 19, 2018 
 
 
Department of Evidence Based Pain Research 
Cleveland Clinic 
9500 Euclid Ave / C25 
Cleveland, Ohio 44195 
 
 
 
 
 
 

 
 
 
Protocol Version 1: “CRPS Neuromodulation”, Department of Evidence Based Pain Research, Cleveland Clinic 
 
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Protocol Synopsis 
Title: 
Single Center, Randomized Prospective Comparative Effectiveness Study 
of Dorsal Column Spinal Cord Stimulation to Dorsal Root Ganglion 
Stimulation in the Treatment of Complex Regional Pain Syndrome of the 
Lower Extremity 
Investigational 
Products 
1. Nuvectra Algovita Dorsal Column Spinal Cord Stimulation System 
2. Abbot Proclaim Dorsal Root Ganglion Spinal Cord Stimulation 
System 
Regulatory Status 
Post-market evaluation. The indications for both dorsal column and dorsal 
root ganglion neurostimulation utilized in this study are cleared by the 
FDA.   
Study Objective: 
To compare the outcomes of dorsal column stimulation with Dorsal Root 
Ganglion stimulation in patients with Complex Regional Pain Syndrome 
that persist despite a course of conservative management including 
physical therapy and analgesic pharmacotherapy. 
Study Design: 
Prospective, randomized single center study. Patients will be randomized 
in a 1:1 ratio to Dorsal Column or Dorsal Root Ganglion stimulation after 
they have failed conservative treatment.   
Patient Population: 
Patients with Budapest criteria (research diagnostic definition) of Complex 
Regional Pain Syndrome occurring below the umbilicus who have not had 
an adequate response to conservative management including analgesic and 
physical therapies. 
Enrollment Size and 
Number of Sites: 
A total of 62 patients will be recruited from a single center  
Primary Outcome: 
50% change in index pain using a Numerical Rating Scale (NRS) at 6 
months 
Secondary Outcome: 
30% change in function based on Oswestry Disability Index (ODI)  
Additional 
Assessments: 
 Change in Quality of Life as measured by EQ-5D 
 Change in Health Status measured by Short Form-36 (SF-36) 
 Pre and Post Procedure Pain medication usage  
 Global Improvement Impression of Change (PGIC) 
 Satisfaction with the pain relief, therapy in general, and likelihood 
of undergoing the therapy again for a similar outcome 
 Neurological assessment 
 Additional intervention(s)  

 
 
 
Protocol Version 1: “CRPS Neuromodulation”, Department of Evidence Based Pain Research, Cleveland Clinic 
 
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 Safety defined as adverse events related to the procedure or devices 
Inclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
All patients must meet all of the following Inclusion Criteria to be eligible 
to be enrolled into the study: 
 Patient is greater than18 years of age 
 An infraumbilical location of the index pain 
 Symptoms have been present for greater than 6 months 
 Continuing pain which is disproportionate to any inciting event 
 Report hyperesthesia and/or allodynia 
 Report vasomotor changes including temperature asymmetry and/or 
skin color changes and/or skin color asymmetry 
 Report edema and/or sweating changes and/or sweating asymmetry 
 Report decreased range of motion and/or motor dysfunction 
(weakness, tremor, dystonia) and/or trophic changes (hair, nail, 
skin) 
 Display at least one sign in two or more of the following categories: 
o Sensory: Evidence of hyperalgesia (to pinprick) and/or 
allodynia (to light touch and/or temperature sensation 
and/or deep somatic pressure and/or joint movement) 
o Vasomotor: Evidence of temperature asymmetry (>1°C) 
and/or skin color changes and/or asymmetry 
o Sudomotor/Edema: Evidence of edema and/or sweating 
changes and/or sweating asymmetry 
o Motor/Trophic: Evidence of decreased range of motion 
and/or motor dysfunction (weakness, tremor, dystonia) 
and/or trophic changes (hair, nail, skin) 
 Patient failed to have resolution of symptoms despite at least 4 
weeks of conservative management including analgesic 
pharmacotherapy and physical therapy 
 Patient has index site pain > spine pain  
 The subject is physically and mentally able to participate in the 
study 
 Patient is willing and able to provide informed consent 
 Patient is willing and able to comply with the study protocol 
Exclusion Criteria 
 
 
 
All patients who meet any of the following Exclusion Criteria should not 
be enrolled into the study: 
 Previous surgery to the spine which could compromise placement 
of the study device 

 
 
 
Protocol Version 1: “CRPS Neuromodulation”, Department of Evidence Based Pain Research, Cleveland Clinic 
 
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 Anatomical spinal abnormality including severe central canal 
stenosis or bony foraminal impingement which could preclude 
device placement 
 Foreseen need for MRI to monitor or evaluate another chronic 
condition 
 Previous experience with an implanted or trial neuromodulation 
system (spinal cord stimulation, peripheral nerve stimulation) for 
the treatment of pain at the index location 
 Active local or systemic infection 
 Actively in litigation for pain symptoms 
 Currently on Workman’s Compensation 
 Women who are pregnant or intend to become pregnant during the 
study duration 
Study Duration / 
Follow-up Period 
Patients will be followed for an additional 6 months after device implant, 
with visits at 10 and 30 days, and 3 and 6 months post-procedure. Interim 
visits for device programming visits will be considered routine.  
Baseline Visit 
• 
Demographics:  gender, age, height, weight 
• 
History 
• 
Characterization of the inciting event including duration of pain 
symptoms 
• 
Previous treatments including conservative management and 
physical therapy 
• 
Diagnosis and review of the inclusion and exclusion criteria 
• 
Neurological assessment 
• 
NRS for the index pain location 
• 
Pain medication usage (dosage and frequency) 
Psychological 
Assessment 
Psychological assessment will consider appropriateness for a 
neuromodulation system and for participation in a clinical device study. 
Pre Trial Visit 
• 
Neurological assessment 
• 
NRS for the index pain location 
• 
ODI 
• 
EQ-5D 
• 
SF-36 
• 
Satisfaction with baseline management strategy 
• 
Pain medication usage (dosage and frequency) 

 
 
 
Protocol Version 1: “CRPS Neuromodulation”, Department of Evidence Based Pain Research, Cleveland Clinic 
 
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• 
Presurgical trial evaluation as stratified by the investigator 
including advanced imaging if necessary 
• 
Randomization 
Trial Procedure  
• 
Neurological assessment 
• 
NRS for the index pain location 
• 
Pain medication usage (dosage and frequency) 
• 
Trial of the study device 
Trial Device Removal 
(7 days postop +/- 3 
days) 
 Wound check, trial device removal 
 NRS for index site pain 
 Neurological assessment 
 Additional intervention(s) 
 Complications / Adverse events 
Pre Implant Visit 
• 
Neurological assessment 
• 
NRS for the index pain location 
• 
ODI 
• 
EQ-5D 
• 
SF-36 
• 
Satisfaction with present management strategy 
• 
Pain medication usage (dosage and frequency) 
• 
Presurgical medical evaluation, history and physical 
examination, and additional special tests as stratified by the 
investigator including laboratory analysis, EKG, infectious 
screening, and/or advanced imaging  
Implant Procedure  
• 
Neurological assessment 
• 
NRS for the index pain location 
• 
Pain medication usage (dosage and frequency) 
• 
Implantation of the study device 
Post-Operative Follow-
up Visit (10 days postop 
+/- 3 days) 
 Wound check, suture removal 
 NRS for index site pain 
 Neurological assessment 
 Additional intervention(s) 
 Complications / Adverse events 
Follow-up Visit (30 days 
+/- 7 days) 
 NRS for index site pain 
 Neurological assessment 
 ODI 
 EQ-5D 

 
 
 
Protocol Version 1: “CRPS Neuromodulation”, Department of Evidence Based Pain Research, Cleveland Clinic 
 
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 SF-36 
 Pain medication usage (dosage and frequency) 
 PGIC 
 Additional intervention(s) 
 Complications / Adverse events 
 Radiograph to evaluate lead(s) position 
Follow-up Visit (3 
month +/- 14 days) 
 NRS for index site pain 
 Neurological assessment 
 ODI 
 EQ-5D 
 SF-36 
 Pain medication usage (dosage and frequency) 
 PGIC 
 Satisfaction questionnaire 
 Additional intervention(s) 
 Complications / Adverse events 
Follow-up Visit (6 
month +/- 14 days) 
 NRS for index site pain 
 Neurological assessment 
 ODI 
 EQ-5D 
 SF-36 
 Pain medication usage (dosage and frequency) 
 PGIC 
 Satisfaction questionnaire 
 Additional intervention(s) 
 Complications / Adverse events 
Anticipated 
Unscheduled Visits 
1. Radiograph to evaluate device positioning 
2. Ad hoc programming of the study device 
Site 
Department of Evidence Based Pain Research 
Cleveland Clinic 
9500 Euclid Ave / C25 
Cleveland, Ohio 44195 
 
 

 
 
 
Protocol Version 1: “CRPS Neuromodulation”, Department of Evidence Based Pain Research, Cleveland Clinic 
 
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Protocol Version 1: “CRPS Neuromodulation”, Department of Evidence Based Pain Research, Cleveland Clinic 
 
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Table of Contents 
1 INTRODUCTION ................................................................................................................ 9 
1.1 Background and Rationale ............................................................................................9 
2 DEVICE DESCRIPTION ..................................................................................................... 9 
2.1 Device Indications for Use ............................................................................................9 
3 STUDY PURPOSE AND OBJECTIVE ............................................................................. 10 
4 STUDY ENDPOINTS ........................................................................................................ 10 
4.1 Primary Endpoint ........................................................................................................10 
4.2 Additional Assessments ..............................................................................................10 
5 STUDY DESIGN................................................................................................................ 10 
5.1 Overview .....................................................................................................................10 
5.2 Sample Size and Number of Centers ..........................................................................11 
5.3 Study Duration ............................................................................................................11 
6 STUDY PROCEDURES .................................................................................................... 12 
6.1 Patient Eligibility, Pre-Screening and Exclusions ......................................................12 
6.2 Enrollment and Written Informed Consent.................................................................13 
6.3 Randomization ............................................................................................................14 
6.4 Baseline Evaluation ....................................................................................................14 
6.5 Procedure / Hospital Discharge ..................................................................................15 
6.6 Post-Operative Procedures and Outcomes ..................................................................16 
6.7 Patient Early Discontinuation / Withdrawal and Replacement of Patients .................18 
6.8 Lost to Follow-up Patients ..........................................................................................18 
7 Risk / Benefit Analysis ....................................................................................................... 18 
7.1 Benefits .......................................................................................................................18 
7.2 Risks ............................................................................................................................18 
8 STATISTICAL SECTION ................................................................................................. 19 
8.1 Statistical Considerations ............................................................................................19 
8.2 Statistical Software .....................................................................................................19 

 
 
 
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9 DATA MANAGEMENT.................................................................................................... 20 
9.1 Data Collection ...........................................................................................................20 
10 ADVERSE EVENTS ........................................................................................................ 20 
10.1 Definitions.................................................................................................................20 
10.2 Adverse Event Reporting ..........................................................................................21 
11 STUDY ADMINISTRATION .......................................................................................... 22 
11.1 Statement of Compliance ..........................................................................................22 
11.2 Investigational Review Board Approval (IRB) ........................................................22 
11.3 Informed Consent......................................................................................................22 
11.4 Amending the Protocol .............................................................................................23 
11.5 Protocol Deviations/Violations and Medical Emergencies ......................................23 
11.6 Criteria for Terminating Study..................................................................................24 
 

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1 INTRODUCTION 
1.1 
Background and Rationale 
Complex Regional Pain Syndrome (CRPS) is a constellation of pain symptoms which are 
associated with impairment in mood, social and physical function (Harden, et al. 2007) 
(Deer, Levy and Kramer 2017) (Banks and Kerns 1996) (Modovan, et al. 2009).  Spinal 
Cord Stimulation (SCS), a technique of placing electrodes into the epidural space is a 
validated treatment for Complex Regional Pain Syndrome (Deer, et al. 2014).  Treatment of 
CRPS with SCS, in combination with physical therapy, reduced pain to a greater degree 
than physical therapy alone (Kemler, et al. 2000). 40%-50% of CRPS patients achieve 
>50% pain relief with SCS using dorsal column stimulation (Kemler, et al. 2000) (Geurts, et 
al. 2013).  Dorsal Root Ganglion (DRG) SCS has also recently demonstrated clinical 
efficacy in patients with CRPS and peripheral causalgia (Deer, Levy and Kramer 2017) 
(Van Buyten, et al. 2015).  We hypothesize that DRG stimulation is non-inferior to dorsal 
column SCS in patients with CRPS who have failed to respond to a course of analgesics and 
physical therapy.  Additionally, we aim to assess functional, quality of life, patient 
satisfaction and medication requirements in subjects treated with neuromodulation for CRPS 
and contrast outcomes amongst subjects treated with DRG SCS and dorsal column SCS. 
 
2 Device Indications for Use 
DEVICE DESCRIPTIONS 
See the manufacturer’s Instructions for Use and Surgical Technique Manual for more 
detailed information. 
 
The Nuvectra Algovita Dorsal Column Spinal Cord Stimulator is indicated as an aid in the 
management of chronic intractable pain of the trunk and/or limbs, including unilateral or 
bilateral pain associated with failed back surgery syndrome, intractable low back pain and 
leg pain.   
The Axium Neurostimulator System is indicated for spinal column stimulation via epidural 
and intra-spinal lead access to the dorsal root ganglion as an aid in the management of 
moderate to severe chronic intractable pain of the lower limbs in adult patients with 
Complex Regional Pain Syndrome Types I and II 
Systems that will be utilized in this study are indicated for use in this condition and have 
already been cleared for marketing by the FDA. 

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
3 STUDY PURPOSE AND OBJECTIVE 
The purpose of this study is to compare outcomes between dorsal column spinal cord 
stimulation and dorsal root ganglion spinal cord stimulation in patients with Complex 
Regional Pain Syndrome at an infraumbilical location who have failed a course of 
conservative management including analgesic pharmacotherapy and physical therapy.  
4 STUDY ENDPOINTS 
The following endpoints will be evaluated in all patients enrolled in the study. 
4.1 
Primary Endpoint 
 The primary endpoint in this study is 50% change in index pain using a Numerical 
Rating Scale (NRS) at 6 months 
4.2 
Additional Assessments 
 Change in function based on Oswestry Disability Index (ODI)  
 Global Improvement Impression of Change (PGIC) 
 Change in Quality of Life as measured by EQ-5D 
 Pre and Post Procedure Pain medication usage (dosage and frequency) 
 Patient Satisfaction 
 Procedure time 
 Neurological assessment 
 Additional intervention(s)  
 Safety defined as adverse events related to the procedure or device 
5 STUDY DESIGN 
5.1 
Overview 
This is a prospective randomized post-marketing clinical study. Patients will be 
randomized in a 1:1 ratio to Dorsal Column or Dorsal Root Ganglion Spinal Cord 
Stimulation if they have failed a course of conservative management including analgesics 
and physical therapy.  All patients are expected to undergo clinical, neurological, and 
imaging assessments, if appropriate, at selected follow-up visits.   
 
 

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
Figure 1. Study Design Flow Chart 
 
 
5.2 
Sample Size and Number of Centers 
The study will be conducted a single center with a target maximum of 62 patients (31 
randomized to each group).  
5.3 
Study Duration 
Enrollment of subjects in this study is anticipated to take 24 months.  Clinical follow-up 
evaluations will be conducted at 10 days, 1, 3 and 6 months post-implant.  The total study 
duration is expected to be at least 30 months. 

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
6 STUDY PROCEDURES 
6.1 
Patient Eligibility, Pre-Screening and Exclusions 
All patients presenting to the Investigators with Budapest criteria, research subset1, for the 
diagnosis of Complex Regional Pain Syndrome at an infraumbilical location who have not 
had an adequate response to a course of conservative management including analgesics and 
physical therapy will be screened for eligibility.  A Screening/Enrollment Log will be 
utilized in order to maintain a cumulative tracking of all screened patients.  
Patients must meet all inclusion/exclusion criteria for enrollment in the clinical study.  
Reasons for screening failure(s) will be documented.    
6.1.1 Inclusion Criteria  
Patients must meet ALL of the following criteria to be eligible for participation in the 
study:    
 Patient is greater than 18 years of age 
 An infraumbilical location of the index pain 
 Symptoms have been present for greater than 6 months 
 Continuing pain which is disproportionate to any inciting event 
 Report hyperesthesia and/or allodynia 
 Report vasomotor changes including temperature asymmetry and/or skin color 
changes and/or skin color asymmetry 
 Report edema and/or sweating changes and/or sweating asymmetry 
 Report decreased range of motion and/or motor dysfunction (weakness, tremor, 
dystonia) and/or trophic changes (hair, nail, skin) 
                                                 
 
1 To make the clinical diagnosis of CRPS using the “research subset” patients must have at least one symptom in all four symptom categories and 
at least one sign (observed at evaluation) in two or more sign categories. 
1. Continuing pain, which is disproportionate to any inciting event 
2. Must report at least one symptom in three of the four following categories: 
 
Sensory: Reports of hyperesthesia and/or allodynia 
 
Vasomotor: Reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry 
 
Sudomotor/Edema: Reports of edema and/or sweating changes and/or sweating asymmetry 
 
Motor/Trophic: Reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes 
(hair, nail, skin) 
3. Must display at least one sign at time of evaluation in two or more of the following categories: 
 
Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic 
 
pressure and/or joint movement) 
 
Vasomotor: Evidence of temperature asymmetry (>1°C) and/or skin color changes and/or asymmetry 
 
Sudomotor/Edema: Evidence of edema and/or sweating changes and/or sweating asymmetry 
 
Motor/Trophic: Evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes 
 
(hair, nail, skin) 
4. There is no other diagnosis that better explains the signs and symptoms (Harden, et al. 2007) 
 

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
 Display at least one sign in two or more of the following categories: 
o Sensory: Evidence of hyperalgesia (to pinprick) and/or allodynia (to 
light touch and/or temperature sensation and/or deep somatic pressure 
and/or joint movement) 
o Vasomotor: Evidence of temperature asymmetry (>1°C) and/or skin 
color changes and/or asymmetry 
o Sudomotor/Edema: Evidence of edema and/or sweating changes 
and/or sweating asymmetry 
o Motor/Trophic: Evidence of decreased range of motion and/or motor 
dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, 
nail, skin) 
 Patient failed to have resolution of symptoms despite at least 4 weeks of 
conservative management including analgesic pharmacotherapy and physical 
therapy 
 Patient has index site pain > spine pain  
 The subject is physically and mentally able and willing to participate in the study 
 Patient is willing and able to provide informed consent 
 
6.1.2 Exclusion Criteria 
All patients who meet any of the following Exclusion Criteria should not be enrolled into 
the study: 
 Previous surgery to the spine which could compromise placement of the study 
device 
 Anatomical abnormality including severe central canal stenosis or bony foraminal 
impingement which could preclude device placement 
 Foreseen need for MRI to monitor or evaluate another chronic condition 
 Previous experience with neuromodulation (spinal cord stimulation, peripheral 
nerve stimulation) for the treatment of pain at the index location 
 Active local or systemic infection 
 Actively in litigation for pain symptoms 
 Currently on Workman’s Compensation for a pain complaint at the index site 
 Women who are pregnant or intend to become pregnant during the study duration 
 
6.2 Enrollment and Written Informed Consent 
Patients who pass the initial pre-screening will be asked to sign the study-specific IRB -
approved Informed Consent form before any study-specific tests or procedures are 
performed.  The investigator will inform the potential subject of the elements of the clinical 

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
study including, risks, potential benefits and required follow-up procedures prior to 
obtaining the potential subject’s informed consent.  
6.3 
Randomization  
After informed consent has been obtained, patients will be randomized in a 1:1 ratio to one 
of two treatment groups: Dorsal Column Stimulation or Dorsal Root Ganglion Spinal Cord 
Stimulation. The investigator will be given numbered, sealed envelopes with a slip inside 
that discloses the patient assignment.  
If a patient randomized to either group refuses the proposed treatment plan, they will be 
removed as a study participant. Patients withdrawing from the study due to randomization 
assignment will receive standard care with a new randomization code being assigned to the 
next enrolled study patient. 
Investigators, their study staff, as well as study subjects will not be masked to the assigned 
study device. Observers will record sensory deficits to touch, pain, temperature, motor 
strength of major muscle groups, patient reflexes (0-4 scale), analgesics doses and 
frequency, and radiographic assessments if necessary.  Subjects will complete the patient 
questionnaires at each follow-up visit. 
6.4 
Baseline Evaluation 
The following evaluations are required at the time of patient screening/baseline. 
 Demographic Information: gender, age, weight, height, and smoking status. 
 Medical / Surgical History / Previous conservative treatment(s) 
 Physical/Neurological Exam  
o Sensory Function/Deficit - Evaluated by the subject’s response to light touch 
and/ or pinprick at infraumbilical dermatome areas. 
o Motor Strength - Evaluated by the subject’s ability to contract various muscle 
groups.  Strength will be measured pre-operatively and at each follow-up visit 
as either:   
0 - absent, total paralysis 
1 - trace, palpable or visible contraction 
2 - poor, active movement through full range of motion (ROM) with 
gravity eliminated 
3 - fair, active movement through full ROM against gravity 
4 - good, active movement through full ROM against resistance 
5 - normal 
 
 Local tissue temperature asymmetry in the index pain location compared to the 
contralateral side. 

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
 Pain Assessment: intensity of index pain using a Numerical Rating Scale (NRS)   
 Functional Assessment: Oswestry Disability Index (ODI) 
 Quality of Life Assessment:  EQ-5D 
 Health Status Assessment: SF-36 
 Pain medication usage (dosage and frequency) 
 Patient satisfaction with present treatment strategy 
6.5 Procedure  
The appropriate procedure will be performed based on the randomization assignment for 
each patient.  Patients randomized to either group will have the device trialed, then 
implanted according to the standard procedures and practices at our institution.  
 
Those who fail to respond to a trial of the randomized device will have the opportunity to 
cross over, and retrial the alternative device.  Should they have favorable response to the 
second device, they will proceed to implant of the alternative system.   
 
Any female patient of child bearing age who does not have a documented history of 
surgical sterilization will have a urine pregnancy test performed within two hours before 
the device is trialed or implanted. 
 
Pain medications may be administered at the investigator’s or prescriber’s discretion.  A 
pain medication log will be given to the patient.  Continuous pain medication usage will be 
documented.  The treating physician may continue to pharmaceutically manage the 
patient’s pain through the length of the study as clinically indicated. Use of pain 
medications after either intervention, when compared to pre-intervention dosing, will be 
considered. The investigator or research coordinator will review the study requirements 
with the patient in order to maximize compliance with the follow-up schedule and the 
concomitant medical regimen. 
The following parameters for both groups will be noted on the case report forms:  
 Index pain location 
 Procedure time 
 Physical/Neurological Exam 
 Complications / Adverse events 
 Radiographic Assessment confirming appropriate device placement 
 Pain medications 

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
6.6 Post Procedures and Outcomes 
Follow-up visits are scheduled for appointed times after the date of the procedure.  It is 
important that this schedule is adhered to as closely as possible for all subjects.  Study 
visits not completed within these time periods will be regarded as deviations.  A study visit 
should be scheduled as closely as possible to the earlier part of the time period to allow for 
possible re-scheduling, thereby preventing a deviation. All subjects will be asked to return 
to the clinic at intervals described in Table 1. Device programming and radiographic lead 
positioning confirmation visits are anticipated unscheduled visits and do not represent 
protocol deviations, and may occur ad hoc.     
The following post-operative data will be collected:    
 NRS for the index site pain 
 ODI 
 EQ-5D 
 Global Improvement Impression of Change (PGIC) 
 SF-36 
 Pain medication usage (dosage and frequency) 
 Neurological assessment 
 Patient Satisfaction 
 Additional intervention(s)  
 Complications / Adverse events 

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Table 1:  Schedule of Assessments 
Assessment 
 
 
 
Pre-op 
Trial 
Procedure 
Trial 
Removal 
Follow-up 
7 (+/- 3 
days) 
Implant 
Procedure 
Post-
Operative 
Follow-up 
10 (+/- 3 
days) 
Follow-up 
Visit (30 
days +/- 7 
days) 
Follow-up 
Visit (3 
months +/- 
14 days) 
Follow-up 
Visit (6 
months +/- 
14 days) 
 
Unscheduled 
Visit 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical & Interval 
History 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Physical Exam / 
Neurological 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pain Scales (NRS) & 
Pain Medication Usage 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Oswestry Disability 
Index (ODI) 
X 
 
 
 
 
X 
X 
X 
 
 
EQ-5D 
X 
 
 
 
 
X 
X 
X 
 
 
Global Improvement 
Impression of Change 
(PGIC) 
 
 
X 
 
X 
X 
X 
X 
 
 
SF-36 
 
 
 
 
 
X 
X 
X 
 
 
Patient Satisfaction 
X 
 
X 
 
X 
X 
X 
X 
 
 
Adverse Events* 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Other Interventions 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
*Adverse events should be recorded at any time during the course of the study 

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6.7 Patient Early Discontinuation / Withdrawal and Replacement of Patients  
All subjects are informed of their right to withdraw from the clinical study at any time.  
Additionally, the investigator may prematurely discontinue any patient’s participation in 
the study if the investigator feels that the patient can no longer fully comply with the 
requirements of the study or if any of the study procedures are deemed potentially harmful 
to the patient. However, it is anticipated that such withdrawals will be infrequent to ensure 
the integrity of the study.  The reason for early discontinuation will be documented in the 
source documents and case report forms. 
6.8 Lost to Follow-up Patients 
Every attempt will be made to have all subjects complete the follow-up visit schedule. A 
subject will not be considered lost to follow-up unless efforts to obtain compliance are 
unsuccessful. At a minimum, the effort to obtain follow-up information will include three 
attempts to make contact via telephone and if unsuccessful, then a certified letter from the 
investigator will be sent to the subject’s last known address. In general, the study site 
coordinator should attempt to contact the subject after each missed visit to re-schedule the 
visit or collect patient-reported outcomes via phone interview. 
7   Risk / Benefit Analysis 
7.1 Benefits 
Possible benefits of neuromodulation with either device may include the reduction of 
pain.  
7.2 Risks  
Possible risks associated with neuromodulation in either arm include: 
 Failure to relieve pain 
 Unable to place the device due to anatomical abnormality 
 Infection 
 Dural tear / CSF leak 
 Nerve root irritation or nerve root injury with or without neurological deficit 
 Seroma / Hematoma 
 Vascular injury 
 Bowel / bladder incontinence 
 Bleeding 
 Epidural fibrosis 

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
Mean radiation exposure with spinal cord stimulation has been estimated at 13.9mGy, 
range: 1.8mGy-43.7mGy (Wininger, Deshpande and Deshpande 2010).  
 
8 STATISTICAL SECTION 
8.1  Statistical Considerations 
A binary responder rate for spinal cord stimulation is defined as those subjects who 
achieved ≥50% diminution in pain intensity.  Historical responder rates with legacy spinal 
cord stimulation arrays were nearly 50% (North, et al. 2005). Contemporary responder 
rates utilizing novel programming algorithms and targeted placement now exceed 80% 
(Kapural, et al. 2015) (Deer, Levy and Kramer 2017) (Russo, et al. 2018).   
8.2 Statistical Software 
All statistical analysis will be performed using R Statistical Software Version 3.4.1. 
8.3 Determination of the Sample Size 
Sample size was determined based on the planned noninferiority test for effectiveness to 
primary end point of treatment success and contemporary responder rates. Treatment 
success was defined as ≥50% reduction in the Numerical Rating Scale (NRS) score in the 
index  area of pain. Previous data indicated that the success rate of DRG, defined as a 50% 
reduction in pain intensity, was 81%, and 56% for SCS (Deer, Levy and Kramer 2017). 
Assuming 15% attrition, an estimated 62 subjects (31 subjects in each arm) would provide 
greater than 70% power to test the primary end point hypothesis with a noninferiority 
margin of 5% at the 95% confidence interval. 
8.4 Analysis of the Primary Endpoint 
Descriptive statistics for all continuous variables will be presented as number of subjects, 
mean with SD and  median with  range and for the categorical variables, number and 
percentage of subjects will be used.  DRG stimulation and SCS will be compared using a 2-
sample t test (or Wilcoxon rank-sum test) for continuous outcomes and Pearson χ2 test (or 
Fisher exact test) for categorical outcomes. Choice of parametric or alternative tests will be 
determined based on the data distributions for each measure. Two-sided confidence intervals 
will be also provided for certain outcome measures of interest to assess differences between 
the two different treatment arms. The primary end point analyzes the success rate between 
the two treatment arms using Blackwelder method for testing noninferiority between 2 
proportions at a one-sided significance of 0.05 with setting the noninferiority margin at 5 %.  

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
 
9 DATA MANAGEMENT 
9.1 Data Collection 
Data will be collected on paper case report forms (CRF).  A unique study number will be 
assigned to each patient. All information recorded on the CRF about the patient will be 
recorded with the study number on it. The main database will contain only the study 
number to identify the patient. The code with patient name and study number will be 
maintained in a locked file cabinet in the secured designated location at the site.  Any 
computerized data is password protected. 
10 ADVERSE EVENTS 
10.1 Definitions 
10.1.1 Adverse Events 
Adverse events (AE) are any untoward medical occurrence, unintended disease or injury, 
or untoward clinical signs (including abnormal laboratory findings) in which subjects, 
users or other persons, whether or not related to the investigational medical device. 
All adverse events, regardless of relationship to the device, must be recorded, as 
applicable, on the case report forms provided. Adverse events that occur during this study 
should be treated by established standards of care, which will protect the life and safety 
of the patients. 
Adverse events shall be assessed and documented at the time of the procedure and at all 
study follow-up visits. 

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
10.1.2 Serious Adverse Events 
An adverse event is considered a Serious Adverse Event (SAE) that 
a) led to death 
b) led to a serious deterioration in the health of the subject, that either resulted in 
 
1) a life-threatening illness or injury, or  
2) a permanent impairment of a body structure or a body function, or  
3) in-patient hospitalization or prolongation of existing hospitalization, or  
4) a medical or surgical intervention to prevent permanent life-threatening 
illness or injury or permanent impairment to body structure or a body 
function.  
c) led to fetal distress, fetal death or a congenital abnormality  
10.1.3 Unanticipated Serious Adverse Device Effect 
An Unanticipated Serious Adverse Device Effect (USADE) is defined as any serious 
adverse effect on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death were not previously identified 
in nature, severity, or degree of incidence in the investigational plan, or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects.  
10.2 Adverse Event Reporting 
Any adverse event that occurs during the course of the study must be reported using the 
appropriate forms.  The Investigator must determine whether the adverse event is serious or 
unanticipated, its intensity, and the relationship of each adverse event to the study device 
and/or procedure.  
For any adverse event that is ongoing at the time of the initial report, periodic follow-up 
information is required until the adverse event is resolved or is judged to be chronically 
stable.   
The Investigator will report all serious adverse events, including unanticipated adverse 
device effects, to the IRB according to the IRB requirements.  

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
11 STUDY ADMINISTRATION 
11.1 Statement of Compliance 
The clinical investigations will be in accordance with the ethical principles of the 
Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil October 2013), 
ISO 14155:2011 and ICH-GCP Guidelines. 
The clinical investigation shall not commence until approval by the IRB.   
Any additional requirements imposed by the IRB or regulatory authority shall be followed. 
11.2 Investigational Review Board Approval (IRB) 
The study protocol shall be reviewed and approved by the IRB prior to patient enrollment. 
Significant changes to the investigational plan must be approved in writing by the IRB 
prior to implementation.  A significant change is one which may increase the risk or 
present a new risk to a patient, or which may adversely affect the scientific validity of the 
study. 
11.3 Informed Consent 
Informed consent must be obtained from all subjects as per regulations, prior to 
participation in the study.  
It is the responsibility of the Investigator to ensure written informed consent from each 
subject, or the legally authorized representative of the subject, is obtained prior to the 
initiation of any study-related procedures.   
Patients who agree to participate in this study will do so voluntarily.  They will be treated 
on an equal basis with all other patients. Choosing not to participate will not affect their 
care in any way.   
Study personnel fully knowledgeable in the purposes and procedures of the study will 
approach all prospective study participants. The facilities and settings in which prospective 
participants will be presented with the opportunity to learn about and consent to 
participation in the study will provide them sufficient quiet and unhurried time to be 
informed of the study, to ask questions, and between consent being given and the initiation 
of study procedures. Study personnel will, after presenting the study to prospective 
participants, assess the subject’s understanding and autonomy by asking the subject to 
explain the study in his/her own words.  

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
Once that step is completed, consent will be able to be given by the subject’s signing the 
consent form. A copy of the consent form will be given to all consented participants.   
Signed subject consent forms must be retained in the study files by the Investigator, and 
available for review by the IRB and/or regulatory agencies, as applicable.  
The informed consent form and any other written information provided to subjects will be 
revised whenever important new information becomes available, or if there is an 
amendment to the protocol which necessitates a change to the content of subject 
information and/or to the consent form.  The Investigator will inform the subject of 
changes in a timely manner, and will ask the subject/patient to confirm his/her continuation 
in the study by signing a revised consent form.   
Any revised informed consent form and other written information provided to subjects 
must receive IRB approval, as applicable 
11.4 Amending the Protocol 
This protocol is to be followed exactly, and will only be altered by written amendments. 
Amendments must be approved by all parties responsible for approving the Protocol 
including the IRB prior to implementation. However, in situations where the amendment is 
regarding safety issues and there is an immediate hazard to patients, the amendment will be 
submitted as an urgent amendment and can be implemented in the study prior to approval.  
The Informed Consent and CRFs will be reviewed to ensure these are amended if 
necessary.  
Administrative changes that do not affect the patient benefit/risk ratio (e.g., editorial 
changes for clarity) may be made without any further approvals.  
11.5 Protocol Deviations/Violations and Medical Emergencies 
A protocol deviation or violation is a failure to comply with the requirements of the clinical 
study as specified in the protocol.  Examples of protocol deviations include late visits, 
missed visits, required follow-up testing not completed.  An example of a protocol 
violation includes enrollment of a study subject who fails to meet inclusion/exclusion 
criteria as specified in the protocol.  Each investigator shall conduct this clinical study in 
accordance with the study protocol and any conditions required by the IRB. 

 
 
 
 
 
 
 
 
 
 
 
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Protocol # CRPS Neuromodulation, Version 1.4 
11.6 Criteria for Terminating Study 
The investigator reserves the right to terminate the study but intends only to exercise this 
right for valid scientific or administrative reasons and reasons related to protection of 
patients. The IRB will be notified in writing in the event of termination.  
Possible reasons for study termination include: 
 
The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study. 
In the event that the study is discontinued, study patients will be contacted by phone and 
registered mail. Study patients contacted will be asked to come into to clinic, to have their 
questions and concerns addressed, as well as discuss a continued plan of care. 
 
12 References 
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Deer, TR, RM Levy, and J Kramer. 2017. "Dorsal root ganglion stimulation yielded higher 
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Geurts, JA, H Smits, MA Kemler, F Brunner, AG kessles, and M van Kleef. 2013. "Spinal cord 
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