A Post-Market, Multicenter, Prospective, Randomized Clinical Trial Comparing 10 kHz Spinal Cord Stimulation (HF10™ Therapy) Combined With Conventional Medical Management to Conventional Medical Management Alone in the Treatment of Chronic, Intractable, Neuropathic Limb Pain
Phase: NA
Conditions: Painful Diabetic Neuropathy
Sponsor: Nevro Corp

 
 
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INVESTIGATIONAL PLAN 
A Post-Market, Multicenter, Prospective, Randomized Clinical Trial Comparing 10 kHz Spinal 
Cord Stimulation (HF10™ Therapy) Combined with Conventional Medical Management to 
Conventional Medical Management Alone in the Treatment of Chronic, Intractable, Neuropathic 
Limb Pain 
                 
Protocol Number: 
 
 
CA2016-5 US 
 
Study Reference: 
 
 
SENZA-PDN-1 
 
Sponsor: 
 
 
 
Nevro Corp. 
1800 Bridge Parkway 
Redwood City, CA 94065 
 
Study Responsibility:  
 
Brad Gliner, MS 
Vice President, Clinical and Regulatory Affairs  
 
 
 
 
 
Nevro Corp. 
 
Date of Issue:  
 
 
19MAR2019 
 
Revision: 
 
 
 
D 
 
Revision History: 
 
 
  
 
 
  
 
 
 
 
 
Revision 
Description 
Date 
A 
Initial Release of Investigational Plan 
26MAY2017 
B 
Protocol enhancements and clarifications 
14MAR2018 
C 
Protocol clarifications 
28MAR2018 
D 
Protocol clarifications, revision of enrollment 
estimate 
19MAR2019 

 
 
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Table of Contents 
A. Purpose............................................................................................................................................. 6 
A.1. 
Name and Intended Use of the Study Interventions ............................................................. 6 
A.2. 
Purpose of the Investigation.................................................................................................. 6 
A.3. 
Study Size ............................................................................................................................. 6 
A.4. 
Duration of the Investigation ................................................................................................ 6 
B. Protocol ............................................................................................................................................ 7 
B.1. 
Rationale for Study ............................................................................................................... 7 
B.2. 
Study Objectives ................................................................................................................... 8 
B.3. 
Subject Population ................................................................................................................ 8 
B.3.1. 
Indications for Use .............................................................................................. 8 
B.3.2. 
Inclusion Criteria ................................................................................................ 9 
B.3.3. 
Exclusion Criteria ............................................................................................... 9 
B.4. 
Study Design ....................................................................................................................... 11 
B.4.1. 
Overall Design .................................................................................................. 11 
B.4.2. 
Bias ................................................................................................................... 11 
B.4.3. 
Randomization/Comparison Groups ................................................................. 11 
B.4.4. 
Crossover .......................................................................................................... 11 
B.4.5. 
Blinding............................................................................................................. 12 
B.4.6. 
Sample Size ....................................................................................................... 12 
B.4.6.1. 
Sample Size Rationale .......................................................................... 12 
B.4.7. 
Study Duration .................................................................................................. 12 
B.4.8. 
Interim Analysis ................................................................................................ 12 
B.5. 
Enrollment, Assessments, and Clinical Procedure ............................................................. 13 
B.5.1. 
Summary of Study Protocol .............................................................................. 13 
B.5.2. 
Consent/Enrollment .......................................................................................... 16 
B.5.3. 
Criteria Evaluation ............................................................................................ 16 
B.5.4. 
Baseline ............................................................................................................. 16 
B.5.5. 
Randomization .................................................................................................. 17 
B.5.6. 
Trial Phase (SCS group only) ........................................................................... 17 
B.5.7. 
End of Trial Assessment (SCS group only) ...................................................... 17 
B.5.8. 
Permanent Device Implant (SCS group only, 0-60 days from end of Trial 
Phase) 
18 
B.5.9. 
Device Activation (SCS group only, 0-14 days following Permanent Implant)
 
18 
B.5.10. 
Unscheduled Visits ........................................................................................... 19 
B.5.11. 
Telephone Calls ................................................................................................ 19 
B.5.12. 
1 (± 7 days), 3 (± 14 days), 6 (± 30 days), 9 (± 30 days), 12 (± 30 days), 18 (± 
30 days),  and 24 (± 30 days) Months Post-Device Activation (SCS) or Baseline (CMM 
only) 
19 
B.5.13. 
Other Assessments and Information ................................................................. 20 
B.5.14. 
Device Explant .................................................................................................. 20 
B.5.15. 
Early Subject Withdrawal ................................................................................. 21 
B.5.16. 
Study Completion ............................................................................................. 21 
B.5.17. 
Study Suspension and Termination .................................................................. 21 

 
 
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B.6. 
Study Endpoints .................................................................................................................. 22 
B.6.1. 
Outcome Measures............................................................................................ 22 
B.6.2. 
Definition of Success ........................................................................................ 24 
B.6.3. 
Safety ................................................................................................................ 24 
B.7. 
Data Collection and Analysis.............................................................................................. 27 
B.7.1. 
Data Collection ................................................................................................. 27 
B.7.2. 
Data Handling ................................................................................................... 27 
B.7.3. 
Record Keeping ................................................................................................ 27 
B.8. 
Outcome Measurements...................................................................................................... 30 
B.8.1. 
Effectiveness Measurements ............................................................................. 30 
B.8.2. 
Safety Measurements ........................................................................................ 31 
B.8.3. 
Statistical Analysis ............................................................................................ 32 
C. Risk Analysis ................................................................................................................................. 33 
C.1. 
Description and Analysis of All Increased Risks to Subjects ............................................. 33 
C.2. 
Potential Benefits to the Subject ......................................................................................... 41 
C.3. 
Minimization of Risks......................................................................................................... 41 
C.4. 
Justification for the Investigation........................................................................................ 41 
C.5. 
Description of the Subject Population ................................................................................ 41 
D. Description of the Study Interventions ....................................................................................... 43 
D.1. 
Each Important Component, Ingredient, and Property of the Device ................................. 43 
D.1.1. 
Device System Overview .................................................................................. 43 
D.1.2. 
Device System Details ...................................................................................... 43 
D.1.2.1. 
Major Components................................................................................ 43 
D.1.2.2. 
Surgical Accessories ............................................................................. 48 
D.2. 
Principle of Operation of the Device .................................................................................. 49 
D.3. 
Description of Conventional Medical Management (CMM).............................................. 49 
D.4. 
Labeling, Supply and Storage of Device ............................................................................ 50 
D.5. 
Any Anticipated Changes in the Device ............................................................................. 50 
D.6. 
Device Accountability ........................................................................................................ 50 
E. Administrative Procedures .......................................................................................................... 51 
E.1. 
Monitoring .......................................................................................................................... 51 
E.1.1. 
Study Monitor ................................................................................................... 51 
E.1.2. 
Monitoring Procedures...................................................................................... 51 
E.2. 
Data Quality Assurance ...................................................................................................... 51 
E.3. 
Study Conduct ..................................................................................................................... 52 
E.4. 
Informed Consent Materials ............................................................................................... 52 
E.5. 
IRB Information .................................................................................................................. 52 
E.6. 
Investigators and Institutions .............................................................................................. 52 
E.7. 
Amendments and Deviations .............................................................................................. 52 
E.8. 
Additional Record and Reports ........................................................................................... 53 
F. References ...................................................................................................................................... 54 
 
 

 
 
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List of Abbreviations  
 
 
Abbreviation 
Definition 
6MWT 
6-Minute Walk Test 
AE 
Adverse Event 
BPI-DPN 
Brief Pain Inventory for Diabetic Peripheral Neuropathy 
CE 
Conformité Européene (European Conformity) 
cGCP 
Current Good Clinical Practice 
CGIC 
Clinician Global Impression of Change 
cm 
Centimeter 
CMM 
Conventional Medical Management 
CT 
Computed Tomography 
d 
Day 
DA 
Device Activation 
DN4 
Douleur Neuropathique 4 
DQOL 
Diabetes Quality of Life Measure 
DRG 
Dorsal Root Ganglion 
eCRF 
Electronic Case Report Form 
EMI 
Electromagnetic Interference 
EoT 
End of Trial 
EQ-5D-5L 
EuroQol Five Dimensions Questionnaire 
FDA 
Food and Drug Administration 
GABA 
Gamma-aminobutyric Acid 
GAF 
Global Assessment of Functioning 
GCP  
Good Clinical Practice 
GIC 
Global Impression of Change 
HbA1c 
Hemoglobin A1c 
HF10™ therapy Nevro Senza® 10 kHz Spinal Cord Stimulation 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IPG 
Implantable Pulse Generator 
IRB 
Institutional Review Board 
kHz 
Kilohertz 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MHz 
Megahertz 
min 
Minute 
mL 
Milliliter 
mm 
Millimeter 
MRI 
Magnetic Resonance Imaging 
NNH 
Numbers Needed to Harm 
NNT 
Numbers Needed to Treat 
NSS 
Modified Neuropathy Symptom Score 
OR 
Operating Room 

 
 
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PDN 
Painful Diabetic Neuropathy 
PGIC 
Patient Global Impression of Change 
PMA 
Premarket Approval 
PNS 
Peripheral Nerve Stimulation 
PSQ-3 
Pain and Sleep Questionnaire Three-Item Index 
SAE 
Serious Adverse Event 
SCS 
Spinal Cord Stimulation 
SF-12 
12-Item Short Form Survey 
SF-MPQ-2 
Short Form McGill Pain Questionnaire 
TGA 
Therapeutic Goods Administration 
TSM 
Trial Stimulator 
UADE 
Unanticipated Adverse Device Effect 
VAS 
10 cm Visual Analog Scale 
wks 
Weeks 

 
 
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A. Purpose 
A.1. Name and Intended Use of the Study Interventions 
The Senza® Spinal Cord Stimulation (SCS) system (manufactured by Nevro Corp., Redwood City, 
CA) is a Food and Drug Administration (FDA) approved device system (PMA P130022) 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 system is designed to deliver electrical stimulation to the spinal cord using 
electrodes (also referred to as leads) and implantable pulse generators (IPGs) as described in this 
investigational plan. Conventional medical management (CMM) may include a variety of non-
invasive or minimally invasive treatments that comprise the standard of care for neuropathic limb 
pain. The study interventions are to be used in accordance with Institutional Review Board (IRB) 
approval and require informed consent from study subjects. 
A.2. Purpose of the Investigation 
The purpose of this post-market study is to document comparative safety, clinical effectiveness, 
and cost-effectiveness of the addition of HF10™ therapy to CMM compared with CMM alone in 
subjects with chronic, intractable, neuropathic lower limb pain due to diabetic neuropathy (Painful 
Diabetic Neuropathy or PDN). This study is a multi-center, prospective, randomized comparison 
of the two treatments. 
A.3. Study Size 
Up to 432 subjects will be enrolled at multiple sites in the United States in order to obtain an 
estimated total of 216 randomized subjects (108 HF10 therapy plus CMM and 108 CMM alone) in 
the study. 
A.4. Duration of the Investigation 
The expected duration of this study is approximately 52 months. Enrollment is expected to last 20 
months, with subjects followed up to a 24 month period following permanent implant [HF10 
therapy plus CMM] or baseline visit [CMM alone], with safety and effectiveness assessments at 3 
months post-intervention. Due to the crossover option included in the study design, the time 
commitment for an individual subject to complete the study will vary from approximately 26 
months to 32 months, consisting of Baseline assessments, up to 14 days of HF10 therapy trial 
stimulation followed by permanent device implant for subjects randomized to the device, and last 
follow-up at 24 months post-intervention.   

 
 
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B. Protocol 
B.1. Rationale for Study 
Peripheral neuropathy is caused by damage to peripheral nerves, thereby causing pain, numbness, 
and/or weakness. Damage may affect small (myelinated A and unmyelinated C) fibers along with 
injury to large myelinated fibers. One of the classifications is based on whether the damage is to a 
single nerve (mononeuropathy) or multiple nerves (polyneuropathy). Some of the causes include 
metabolic or endocrine disorders (e.g., painful diabetic neuropathy or PDN), treatment induced 
toxicity (radiation or chemo-therapy induced neuropathy), alcohol (alcoholic neuropathy), infection 
(post-herpetic neuralgia caused by Herpes Zoster virus, Lyme disease), autoimmune disorders 
(Guillain-Barre’ syndrome, Charcot-Marie-Tooth neuropathy), stress (carpal tunnel syndrome, 
ulnar neuropathy, radial neuropathy, peroneal neuropathy) and trauma (trauma-induced 
neuropathy). Nearly half of these patients are diagnosed as idiopathic (Hsieh, 2010). 
The American Chronic Pain Association estimates that more than 15 million people in the U.S. and 
Europe have some degree of neuropathic pain. More than two out of every 100 persons are 
estimated to have peripheral neuropathy; the incidence rises to eight in every 100 for people aged 
55 or older (Azhary, Farooq, Bhanushali, Majid, & Kassab, 2010). In Europe, the prevalence of 
PDN ranged from 5.8–34% (Alleman, et al., 2015). The incidence rate of PDN was reported to be 
0.72 per 1000 persons per year for the Netherlands (Dieleman, Kerklaan, Huygen, Bouma, & 
Sturkenboom, 2008), and 0.64–0.69 per 1000 persons per year in the UK (Hall, Carroll, & McQuay, 
2008). Patients with PDN result in significant workforce and healthcare costs (Cole, 2007) (daCosta 
DiBonaventura, 2011). In addition, patients with PDN suffer diminished quality of life and 
increased disability (Dulipsingh, 2013) (Deli, 2013). 
Anticonvulsants, including gabapentin and pregabalin, are among the most commonly prescribed 
medications for neuropathic pain due to PDN (Yang, 2015). Pregabalin, or (S)-3-(aminomethyl)-5-
methylhexanoic acid, is an analog of the inhibitory neurotransmitter gamma-aminobutyric acid 
(GABA). It is a compound with analgesic, anticonvulsant, and anxiolytic properties active in the 
central nervous system (CNS). The drug binds potently to the 2- subunit of voltage-gated calcium 
channels, thereby reducing calcium influx at nerve terminals (Gee, et al., 1996). This in turn reduces 
the release of neurotransmitters like glutamate, noradrenaline, and substance P (Dooley, Mieske, & 
Borosky, 2000) (Dooley, Donovan, & Pugsley, 2000) (Fink, et al., 2002) (Maneuf, Hughes, & 
McKnight, 2001). Clinical studies have demonstrated the effectiveness of this drug in treating 
intractable limb pain from PDN resulting from both type 1 and 2 diabetes (Rosenstock, Tuchman, 
LaMoreaux, & Sharma, 2004) (Boyle, et al., 2012) (Arezzo, Rosenstock, LaMoreaux, & Pauer, 
2008). A review of 7 randomized controlled trials comparing pregabalin with placebo summarized 
the following average changes in pain scores: 1.47 cm (placebo), 1.98 cm (150 mg pregabalin), 
2.44 cm (300 mg pregabalin) and 2.75 cm (600 mg pregabalin) (Freeman, Durso-DeCruz, & Emir, 
2008). Mean follow-up was 4-12 weeks. Responder rates, representing the percent of subjects with 
at least 50% improvement from baseline, varied from 40-49% (placebo responder rates: 14.5-
23.0%). Adverse events reported include dizziness, peripheral edema, somnolence, infection and 
weight gain. Approximately 77% of patients prescribed pregabalin for PDN will discontinue the 
treatment within one year due to intolerable side effects or lack of efficacy (Yang, 2015). In 
addition, a recent meta-analysis of RCTs with pregabalin treatment of neuropathic pain calculated 
the Numbers Needed to Treat (NNT) to achieve 50% pain reduction is 7.7; however, the safety 
profile for this medication is poor as the Number Needed to Harm (NNH) is 13.9 (Finnerup, 2015). 

 
 
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Low-frequency, paresthesia-based spinal cord stimulation (SCS) has also been shown to be 
effective in treating intractable pain associated with many peripheral neuropathies, including 
several studies on PDN (Kumar, Toth, & Nath, 1996) (Kumar, Toth, Nath, & Laing, 1998) (Pluijms, 
et al., 2012) (Slangen, et al., 2013) (Tesfaye, et al., 1996). In a single center, observational study, 
Pluijms et al. reported that the median pain score of subjects treated with SCS decreased from 6 cm 
at baseline to 1.8 cm at 3 months on the visual analog scale (VAS, range: 0-10 cm). However, at 12 
months the median pain score increased up to 2.9 cm with slightly over half the subjects (8/15 or 
53%) still responding to the therapy with at least 50% improvement in pain. In another study 
comparing SCS with best medical treatment, pain scores measured with the numerical rating scale 
(NRS, range: 0-10) decreased from 7.3 and 6.7 (day and night, respectively) at baseline to 4 and 
3.5 at 24 months (van Beek, et al., 2015). Responder rates (subjects with ≥ 50% pain reduction) 
ranged from 47% (8/17, day) to 35% (6/17, night). Changes in pain scores in these studies were 
deemed both clinically and statistically significant. 
Unlike traditional low-frequency, paresthesia-based SCS that seeks to induce paresthesias in the 
affected distribution, HF10 therapy delivers paresthesia-independent, high frequency (10 kHz) 
stimulation, by use of a unique waveform and uniform pulse width. The therapy has demonstrated 
safety and superior effectiveness for the treatment of back and leg pain (Kapural L. , et al., 2016) 
(Kapural L. , et al., 2015) (Al-Kaisy, et al., 2014). HF10 therapy has also been studied for the 
treatment of migraine headaches (Arcioni, et al., 2015) and upper and lower limb neuropathic pain 
(Al-Kaisy, Palmisani, Smith, Harris, & Pang, 2015). In a prospective, multicenter study treating 
chronic intractable pain of the limbs from peripheral polyneuropathy using HF10 therapy, subjects 
reported a decrease in mean pain score from 7.6 cm (±0.3, standard error of the mean [SEM]) at 
baseline (N=26) to 2.1 cm (±0.5, SEM) at 1 month post-implant (N=16), with 81% of subjects 
deemed responders (presented at NANS 2017, data on file). While these results are preliminary, 
they are nonetheless promising. 
The current treatments for neuropathic pain secondary to PDN are suboptimal with substantial room 
for improvement. In the proposed post-market study, HF10 therapy plus CMM will be compared 
with CMM alone for safety, clinical effectiveness, and cost-effectiveness in treating subjects 
diagnosed with chronic, neuropathic limb pain resulting from diabetic neuropathy. 
B.2. Study Objectives 
The primary objective of this post-market study is: 
To compare the safety, clinical effectiveness, and cost-effectiveness of HF10 therapy plus 
CMM to CMM alone for the treatment of chronic, intractable, neuropathic lower limb pain 
resulting from diabetic neuropathy. 
B.3. Subject Population 
B.3.1. Indications for Use 
HF10 therapy (Senza System PMA P130022) has been approved by the FDA with Indications 
for Use including the management of neuropathic pain of the limbs as described in this 
Investigational Plan. Treatment of subjects with peripheral neuropathies that result in limb pain 
is therefore an on-label use of the Senza System. CMM will follow the Investigators’ standard 
of care and/or published clinical guidelines (Dworkin, 2010). Treatments include, but are not 

 
 
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limited to, pharmacological agents, physical therapy, cognitive therapy, chiropractic care, nerve 
blocks, and other non-invasive or minimally invasive therapies. 
B.3.2. Inclusion Criteria 
To participate in the study, subjects must meet all of the following inclusion criteria: 
 
1. Have been clinically diagnosed with diabetes, according to the American Diabetes 
Association guidelines, as well as painful diabetic neuropathy (PDN) of the lower limbs, 
and: 
a. are symptomatic despite conservative therapy for a minimum of 12 
months 
b. have tried pregabalin (Lyrica®) OR gabapentin (Neurontin®, Gralise®, 
etc.) administered at an adequate dose and for an appropriate duration, in 
the Investigator’s judgement 
c. have tried at least one other class of analgesic medication in addition to 
pregabalin/gabapentin 
d. are on a stable dosage of analgesic medications for at least 30 days 
2. Average pain intensity of ≥ 5 out of 10 cm on the VAS in the lower extremities at 
enrollment. 
3. Have stable neurological status measured by motor, sensory and reflex function as 
determined by the investigator. 
4. Be on a stable analgesic regimen, as determined by the Investigator, for at least 30 days 
prior to assessing pain intensity as described in inclusion criterion #2, and be willing to 
stay on those medications with no dose adjustments until activation of the permanently 
implanted SCS device (HF10 therapy group) or baseline assessment (CMM only group). 
5. Be 22 years of age or older at the time of enrollment. 
6. Be an appropriate candidate for the surgical procedures required in this study based on 
the clinical judgment of the implanting physician. 
7. Be capable of subjective evaluation, able to read and understand English-written 
questionnaires, and able to read, understand and sign the written informed consent in 
English. 
8. Be willing and capable of giving informed consent. 
9. Be willing and able to comply with study-related requirements, procedures, and 
scheduled visits. 
10. Have adequate cognitive ability to use a patient programmer and recharger as 
determined by the Investigator. 
B.3.3. Exclusion Criteria 
To participate in the study, subjects must not meet any of the following exclusion criteria: 
 

 
 
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1. Have a diagnosis of a lower limb mononeuropathy (e.g., causalgia and tibial or peroneal 
neuropathies), have had a lower limb amputation other than toes due to diabetes, or have 
large (≥3 cm) and/or gangrenous ulcers of the lower limbs. 
2. Have an average pain intensity of ≥ 3 out of 10 cm on the VAS in the upper extremities 
due to diabetic neuropathy at enrollment. 
3. Currently have a hemoglobin A1c (HbA1c) > 10%. 
4. Have a BMI > 45. 
5. Currently prescribed a daily opioid dosage > 120 mg morphine equivalents. 
6. Have a medical condition or pain in other area(s), not intended to be treated in this study, 
that could interfere with study procedures, accurate pain reporting, and/or confound 
evaluation of study endpoints, as determined by the Investigator (such as primary 
headache, fibromyalgia, post-herpetic neuralgia, osteoarthritis, peripheral vascular 
disease, or small vessel disease). 
7. Have a current diagnosis of a progressive neurological disease such a multiple sclerosis, 
chronic inflammatory demyelinating polyneuropathy, rapidly progressive arachnoiditis, 
brain or spinal cord tumor, central deafferentation syndrome, Complex Regional Pain 
Syndrome, acute herniating disc, severe spinal stenosis and brachial plexus injury, as 
determined by the Investigator.  
8. Have a current diagnosis or condition such as a coagulation disorder, bleeding diathesis, 
platelet dysfunction, low platelet count, severely diminished functional capacity due to 
underlying cardiac/pulmonary disease, symptomatic uncontrolled hypertension, 
progressive peripheral vascular disease or uncontrolled diabetes mellitus that presents 
excess risk for performing the procedure, as determined clinically by the Investigator. 
9. Have prior experience with SCS, dorsal root ganglion (DRG) stimulation, peripheral 
nerve field stimulation (PNfS), or peripheral nerve stimulation (PNS) for chronic 
intractable pain. 
10. Have significant spinal stenosis, objective evidence of epidural scarring and/or any signs 
or symptoms of myelopathy as determined by the Investigator based on MRI conducted 
within the past 12 months. 
11. Any previous history of surgery on the posterior elements (laminectomy, posterior 
fusion) resulting in a compromised epidural space, as determined by the Investigator. 
12. Be benefitting from an interventional procedure and/or surgery to treat lower limb pain 
(Subjects should be enrolled at least 30 days from last benefit). 
13. Have an existing drug pump and/or another active implantable device such as a 
pacemaker. 
14. Have a condition currently requiring or likely to require the use of diathermy or MRI 
that is inconsistent with Senza system guidelines in the Physician’s Manual. 
15. Have either a metastatic malignant neoplasm or untreated local malignant neoplasm.  
16. Have a life expectancy of less than one year. 

 
 
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17. Have a local infection at the anticipated surgical entry site or an active systemic 
infection. 
18. Be pregnant or plan to become pregnant during the study. Women of childbearing 
potential who are sexually active must use a reliable form of birth control, be surgically 
sterile, or be at least 2 years post-menopausal. 
19. Have within 6 months of enrollment a significant untreated addiction to dependency 
producing medications, alcohol or illicit drugs. 
20. Be concomitantly participating in another clinical study. 
21. Be involved in an injury claim under current litigation. 
22. Be a recipient of temporary Social Security Disability Insurance (SSDI) benefits due to 
chronic pain. 
23. Have a pending or approved worker’s compensation claim. 
24. Have evidence of an active disruptive psychological or psychiatric disorder or other 
known condition significant enough to impact perception of pain, compliance with 
intervention and/or ability to evaluate treatment outcome, as determined by a 
psychologist in the last 12 months.  
B.4. Study Design 
B.4.1. Overall Design 
This is a post-market, multi-center, prospective, randomized clinical study to document the 
comparative safety, clinical effectiveness, and cost-effectiveness of the addition of HF10 
therapy to CMM compared with CMM alone in subjects with chronic, intractable, neuropathic 
lower limb pain. Data from follow-up visits will be compared to baseline data for each treatment 
group. Comparisons will also be made between the treatment groups. 
B.4.2. Bias 
In preparing the investigational plan and associated documentation, an attempt has been made 
to anticipate and minimize potential sources of bias. The qualifications of each Investigator and 
his/her ability to appropriately screen and treat subjects from his/her caseloads and to comply 
with investigational plan requirements will be reviewed before their participation in the trial.   
B.4.3. Randomization/Comparison Groups 
Subjects meeting inclusion and exclusion criteria will be randomized 1:1 to HF10 therapy 
delivered by the Senza System plus CMM or to CMM alone. 
B.4.4. Crossover 
Subjects randomized to either treatment group will have the potential to crossover to the 
alternative treatment arm at the 6-month visit if they meet all of the following criteria: 
• < 50% lower limb pain relief from baseline. For pain relief calculations, a subject’s right 
and left lower limb VAS scores collected during a single visit will be averaged together 
to generate a lower limb pain score. 

 
 
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• Documented subject dissatisfaction with the treatment (“dissatisfied” or “very 
dissatisfied” on subject satisfaction measure). 
• Investigator agreement with crossover. 
B.4.5. Blinding 
This study is not blinded. Due to the nature of the treatments, specifically an implanted medical 
device compared with CMM, it is not feasible to blind either the subjects or the clinical site 
personnel to the treatment group assignments. This factor aside, there is little reason to believe 
that responses provided by subjects or Investigators/clinical staff will be influenced by the 
knowledge of which treatment is received. 
B.4.6. Sample Size 
Up to 432 subjects will be enrolled at multiple sites in the United States in order to obtain an 
estimated total of 108 subjects randomized to HF10 plus CMM and 108 subjects randomized to 
CMM alone. 
B.4.6.1. 
Sample Size Rationale 
Up to 432 subjects will be provisionally enrolled at multiple clinical sites in the United 
States. Assuming a 50% screen failure rate,1 an estimated total of 216 subjects will be 
randomized, resulting in 108 subjects assigned to each treatment group. The subjects will 
continue with their respective treatments through the 3 month primary endpoint with an 
expected 10% attrition rate, resulting in approximately 97 subjects in each group at the 
primary endpoint. This is the sample size required based on the following assumptions: a 
60% responder rate for the HF10 therapy group (80% trial success rate and 75% responders 
at 3 months among permanent implant subjects), a 36% responder rate for the CMM only 
group, 90% power, and two-sided type I error of 0.05. 
B.4.7. Study Duration 
The expected duration of this study is approximately 52 months.  Enrollment is expected to last 
20 months, with subjects followed up to a 24 month period following permanent implant (HF10 
therapy plus CMM group) or baseline assessment (CMM only group), with a composite of 
effectiveness and safety assessed at 3 months post-intervention. Due to the crossover option 
included in the study design, the time commitment for an individual subject to complete the 
study will vary from approximately 26 months to 32 months, consisting of Baseline 
assessments, up to 14 days of trial stimulation followed by permanent device implant for 
subjects randomized to the device arm, and last follow-up at 24 months post-intervention.   
B.4.8. Interim Analysis 
Interim analysis will be performed to reassess sample size assumptions when 25% of the 
subjects reach the 3 month primary endpoint. 
 
1 This study includes an exclusion criterion for HbA1c in excess of 10% at enrollment. This threshold is approximately one 
standard deviation above the average HbA1c values found in prior studies in this population. Assuming a normal 
distribution, this criterion may result in excluding approximately 16% of enrolled subjects. An additional 34% of enrolled 
subjects may screen fail due to failure to meet other inclusion/exclusion criteria. 

 
 
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B.5. Enrollment, Assessments, and Clinical Procedure 
Enrollment of subjects will occur at the clinical sites only after IRB approval and written informed 
consent from subjects have been obtained. Subjects who have been determined to be candidates for 
SCS therapy will be approached by Investigators/clinical site staff about potential participation in 
the study. Following consent, subjects will be selected to participate in the study based upon 
inclusion and exclusion criteria defined in this investigational plan. Inclusion and exclusion criteria 
will be assessed based on pain assessments, MRI, pregnancy test (if needed), psychological 
evaluation, laboratory tests, including measure of HbA1c, subject medical records and history, 
assessment tools, subject interviews, and the Investigator’s clinical judgment.  
B.5.1. Summary of Study Protocol 
Study subjects will be identified from the pool of candidates for SCS therapy affiliated with, or 
referred to, the clinical sites. Advertisements may be distributed, as approved by local IRBs. 
Subjects will participate in this investigational plan that includes entry criteria evaluation, 
baseline assessments, trial stimulation (HF10 therapy subjects), and post-trial assessments 
(HF10 therapy subjects). Subjects randomized to the HF10 therapy plus CMM arm with a 
successful trial phase will be eligible to receive a permanent implant of an IPG and leads. 
Subjects randomized to the CMM only arm will be optimized according to the Investigator’s 
standard of care and/or clinical treatment guidelines (Dworkin, 2010). Subjects will receive 
their assigned treatment for 24 months with assessments at 1, 3, 6, 9, 12, 18, and 24 months 
Post-Intervention. 
Subjects who sign the informed consent will undergo evaluations to determine eligibility for 
the study based on the inclusion and exclusion criteria. Baseline assessments will include 
measures for pain, disability, functioning, neurological function, work status, weight, healthcare 
utilization (including medication usage for pain and diabetes management, as well as office and 
hospital visits), health-related quality of life, sleep, assessment of adverse events and collection 
of third-party payer data. The presence of any lower limb wounds will be documented by 
measuring the greatest diameter and taking a photograph. 
Implantation and use of the Senza System will follow the Nevro Physician's Implant Manual 
and other supporting manuals. It is recommended that subjects maintain blood glucose levels 
less than 200 mg/dL during the perioperative period. Subjects will undergo a Trial Phase lasting 
up to 14 days to determine his/her response to SCS therapy. Following the Trial Phase with 
external device stimulation, subjects will be assessed for their pain. Those who have an 
“unsuccessful” trial with less than 50% lower limb pain reduction from baseline will be 
followed on CMM for 6 months prior to study completion. Those who have a "successful” Trial 
Phase (defined as a 50% or greater pain reduction in lower limb pain from Baseline) will be 
eligible to proceed to permanent implantation of a Senza system. Following permanent device 
implant, the IPG will be activated and stimulation will be delivered on an ongoing basis for the 
entirety of the patient’s participation in the study, up to 24 months. At the 6 month assessment, 
subjects may opt to crossover to the CMM only treatment arm if they meet the criteria for 
crossover. Subjects who crossover will complete the remainder of the scheduled 24 months of 
follow-up. 
Administration of CMM will follow the Investigator’s standard of care and/or published clinical 
guidelines (Dworkin, 2010) in order to maximize pain relief with minimal side effects. 
Treatments include, but are not limited to, pharmacological agents, physical therapy, cognitive 

 
 
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therapy, chiropractic care, nerve blocks, and other non-invasive or minimally invasive 
therapies. The follow-up schedule for the CMM only group starts at the baseline assessment 
and will continue up to 24 months. Subjects may opt to crossover to the HF10 therapy plus 
CMM group at the 6 month assessment if they meet the criteria for crossover. These subjects 
will undergo trial stimulation with HF10 therapy with those who achieve at least 50% lower 
limb pain reduction from baseline eligible for a permanent device implant. Permanent implant 
subjects will receive 24 months of stimulation delivery with regularly scheduled assessments. 
Subjects who crossover to the HF10 therapy arm but fail trial stimulation with less than 50% 
lower limb pain reduction from baseline will be monitored for adverse events for 2 weeks before 
exiting the study.  
At 1, 9, and 18 months Post-Intervention, subjects will be assessed for pain and adverse events 
as well as disability, functioning, healthcare utilization (including medication usage for pain 
and diabetes management, as well as office and hospital visits), weight, health-related quality 
of life, and sleep. The presence of any lower limb wounds will be documented by measuring 
the greatest diameter and taking a photograph. At 3, 6, 12,  and 24 months Post-Intervention, 
subjects will be assessed for pain intensity, distribution of pain and other symptoms (HF10 
therapy group only), adverse events, disability, functioning, health-related quality of life, 
healthcare utilization (including medication usage for pain and diabetes management, as well 
as office and hospital visits), neurological function, weight, sleep, clinician global impression 
of change, patient global impression of change, and subject satisfaction. The presence of any 
lower limb wounds will be documented by measuring the greatest diameter and taking a 
photograph. Subject HbA1c levels will be measured at 3, 6, 12, 18, and 24 months. At the 6, 
12, and 24 month visits subjects will also be asked about their work status. Subjects in the HF10 
therapy group will be assessed for pain intensity at the End of Trial as well as the distribution 
of pain at Trial and possibly the End of Trial and Permanent Implant visits. HF10 therapy 
subjects may be assessed for the distribution of additional symptoms (such as numbness, cold, 
tingling, or burning) at the Trial and Permanent Implant visits. HF10 therapy subjects will have 
paresthesia assessments with low frequency stimulation at 3 and 24 months and may have 
paresthesia assessments with low frequency stimulation at the Trial, End of Trial, Permanent 
Implant, Permanent Device Activation visit and at 1, 6, 9, 12, and 18 months Post-Permanent 
Device Activation. In addition, AP, lateral and/or oblique x-rays may be performed at follow-
up to assess lead location in the stimulation group. 
 
 

 
 
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Figure 1. Summary of the sequence of study-related assessments, procedures, and activities. 
 
 
 
 
†Primary endpoint analysis 
*Option to cross-over to other therapy arm 

 
 
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B.5.2. Consent/Enrollment 
Subjects will be consented for the study prior to the initiation of any study-related assessments, 
including those that might determine any remaining eligibility criteria, procedures, and/or 
activities. Subjects will be assigned a unique study identification number following consent.  
B.5.3. Criteria Evaluation  
Subjects will be assessed against the study inclusion and exclusion criteria. Subjects determined 
to be on stable pain medications (no change to analgesic medications for ≥ 30 days) will be 
initially assessed for pain using a 10 cm VAS. To be eligible to participate, the subject must 
mark an average pain score ≥ 5 cm on the VAS for the lower limbs. Subjects who mark an 
average pain score ≥ 3 cm on the VAS for the upper limbs due to diabetic neuropathy will be 
excluded. Subjects with upper limb pain unrelated to diabetic neuropathy may be enrolled even 
if the upper limb pain VAS exceeds 3 cm if, in the Investigator’s clinical judgement, the pain 
will not confound the subject’s ability to accurately report lower limb pain. Throughout the 
study, appropriateness for advancement to the next stage of the study will be evaluated by a 
study site Investigator. Pregnancy tests will be conducted for participants of child bearing 
potential; pregnant women will not be allowed to participate. A psychological evaluation will 
be conducted by a site psychologist for subjects who did not have an evaluation conducted 
within 12 months prior to enrollment, or sooner, at the discretion of the Investigator. Subjects 
will be assessed for adverse events at all follow-up visits. Study subjects must meet all of the 
study inclusion criteria and none of the study exclusion criteria to be eligible for study 
participation. Inclusion and exclusion criteria will be evaluated with pain assessments, a 
pregnancy test, if necessary, psychological evaluation, subject medical records and history, 
MRI performed within the past 12 months, labwork for measure of HbA1c, subject interviews, 
recording dosages for all current medications, including those for pain relief as well as diabetes 
management, and the Investigator’s clinical judgment. Those subjects who meet the entry 
criteria will proceed to Baseline assessment, and subjects who do not will be discontinued from 
the study. With the exception of lab measures of HbA1c, results of assessments from Entry 
Criteria Evaluation will not be included as a Baseline assessment; however, if entry criteria 
evaluation and baseline assessment occur on the same date, the subject will complete a single 
worksheet for lower limb pain VAS scores to satisfy the requirement for both visits. In this case, 
the site would document that a single VAS score worksheet was collected for both entry 
evaluation and baseline.  
B.5.4. Baseline 
At the Baseline visit, assessments will be performed and subjects will be asked to fill out 
standard questionnaires to assess their baseline pain severity and stability, pain experience, 
functioning, disability, healthcare utilization (including medication usage for pain [opioid 
intake expressed as morphine sulfate equivalents per day and any other analgesic medications], 
and diabetes management, as well as recent office and hospital visits), health-related quality of 
life, and sleep. The presence of any lower limb wounds will be documented by measuring the 
greatest diameter and taking a photograph. Medical and surgical histories will be collected. A 
walking assessment will be performed. A neurological assessment will be conducted. It is 
preferable that the healthcare provider who conducts the baseline neurological assessment 
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Pre-operative assessments will follow the standard of care for SCS therapy and be determined 
by the site Investigator. Third party payer coverage data and work status will also be collected. 
In addition, subjects will be assessed for adverse events. 
B.5.5. Randomization 
Following completion of the Baseline procedures, eligible subjects will be randomized by the 
sites using a block technique in a 1:1 ratio to either the HF10 therapy plus CMM group or CMM 
alone. Those randomized to the stimulation group will receive HF10 therapy with the Senza 
System in addition to CMM. Implantation and use of the Senza System will follow the Nevro 
Physician’s Implant Manual and other supporting Manuals. Those randomized to CMM only 
will be optimized according to the Investigator’s standard of care and/or published clinical 
guidelines (Dworkin, 2010) in order to maximize pain relief with minimal side effects. CMM 
treatments include, but are not limited to, pharmacological agents, physical therapy, cognitive 
therapy, chiropractic care, nerve blocks, and other non-invasive or minimally invasive 
therapies. 
B.5.6. Trial Phase (SCS group only) 
Subjects randomized to the stimulation group will undergo a Trial Phase which may last up to 
14 days.  It is recommended that subjects maintain blood glucose levels less than 200 mg/dL 
during the perioperative period. Before the Trial begins, subjects will record the distribution of 
pain on a map and may also be asked to record additional symptoms, such as numbness, cold, 
tingling, or burning, on a map. Percutaneous leads will be placed in the epidural space at a 
vertebral level based on the subject’s pain condition and pain pattern as described in the 
Physician Implant Manual. Subjects will be assessed for possible adverse events. Radiographic 
images of anterior-posterior, lateral and/or oblique views of the leads will be captured to ensure 
appropriate placement. Additional images may be captured as necessary. Any changes in 
medication intake, including medications for pain and diabetes management, will be recorded. 
Stimulation will be delivered from an external pulse generator.   
Standard SCS practice will be followed to determine when stimulation parameters should be 
modified; however, it is recommended that stimulation parameters be trialed by a subject for at 
least 2 days prior to making programming changes in stimulation. The primary factor for 
determining stimulation parameters is subject self-reported pain relief. The stimulation 
parameters will be modified until at least 50% self-reported pain reduction from baseline is 
achieved or until conclusion of the trial phase. Paresthesia assessment (low-frequency SCS) 
may be performed to assess lead location. Programming adjustments for optimal pain relief may 
be made based on patient feedback.  
 
B.5.7. End of Trial Assessment (SCS group only) 
At the end of the Trial Phase, subjects will be assessed for pain and changes in medication 
intake, including medications for pain and diabetes management. At this visit, subjects will also 
be assessed for possible adverse events, neuropathic symptoms, and neurological function. 
Subjects may be asked to record the distribution of pain on a map. Radiographic images of 
anterior-posterior, lateral and/or oblique views of the leads will be captured. In the case of a 
permanent, buried lead trial, radiographic images of the leads will instead be captured after the 

 
 
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Permanent Implant procedure. Additional images may be captured as necessary for this 
treatment group. 
The purpose of the Trial Phase is to determine whether subjects respond favorably to HF10 
therapy and should be candidates to proceed to permanent implant of the device system.  A 30% 
reduction in pain has been documented as being clinically meaningful (Farrar, Young Jr, 
LaMoreaux, Werth, & Poole, 2001) (Oakley, Krames, Stamatos, & Foster, 2008). A successful 
trial is defined as the subject experiencing 50% or greater pain reduction in the primary area of 
pain as compared to Baseline pain levels. A threshold of 50% for the Trial Phase exceeds the 
minimum threshold for being clinically meaningful and therefore indicates that the subject is 
likely to respond longer term to the therapy, potentially achieving at least a 50% pain reduction 
during the permanent implant phase as defined in the Individual Subject Success criterion.   
Subjects who pass the Trial Phase will be scheduled for permanent implantation of the Senza 
System after the Investigator and subject agree that the subject should continue to the next 
phase. Subjects who have failed the Trial Phase will not receive a permanent SCS system as 
part of the study, but will receive CMM and continue to be followed for 6 months of data 
collection prior to exiting the study. 
B.5.8. Permanent Device Implant (SCS group only, 0-60 days from end of Trial 
Phase) 
As in the Trial Phase for stimulation group subjects, it is recommended that subjects maintain 
blood glucose levels less than 200 mg/dL during the perioperative period. Before the Permanent 
Implant procedure, subjects may record the distribution of pain and additional symptoms, such 
as numbness, cold, tingling, or burning, on a map. Percutaneous leads will be placed in the 
epidural space at a vertebral level based on the subject’s pain condition and pain pattern as 
described in the Physician Implant Manual (if permanent leads are placed for the Trial Phase, 
an IPG will be implanted and connected to the existing leads). It is suggested that the IPG be 
implanted approximately 1.5 cm below the surface of the skin in the buttock or abdomen. 
Radiographic images of anterior-posterior, lateral and/or oblique views of the leads will be 
captured as needed to insure appropriate placement. Additional images may be captured as 
necessary. The IPG will be programmed to provide adequate pain relief. The primary factor for 
determining stimulation parameters is the subject’s self-reported pain relief. The amplitude of 
the stimulation range will be kept at a tolerable range and parameters will be modified until at 
least 50% self-reported pain reduction from baseline is achieved. The subject will be provided 
with instructions on how to operate the charger and remote control at this visit. Paresthesia 
assessment with low-frequency SCS may be performed to assess lead location. Following 
programming, the IPG will be left in the off position until the device activation visit, which may 
occur on the same day as the implant or up to 14 days later, at the discretion of the Investigator. 
Subjects will be assessed for changes in medication intake, including medications for pain and 
diabetes management, and possible adverse events during the device placement procedure, if 
any. The clinical site’s standard practice for prophylactic pre-surgery antibiotics and post-
surgery analgesic medications will be followed.   
B.5.9. Device Activation (SCS group only, 0-14 days following Permanent Implant) 
The IPG will be activated at this visit and the subject will be provided with a device charger 
and remote control. Changes in medication usage, including medications for pain and diabetes 

 
 
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management, will be assessed. Subjects will also be assessed for possible adverse events. The 
presence of any lower limb wounds will be documented by measuring the greatest diameter and 
taking a photograph. 
B.5.10. Unscheduled Visits 
Unscheduled visits may occur at any time during the study for the assessment of possible 
adverse events, medication changes and programming adjustments. Each unscheduled visit 
must be documented on the unscheduled visit electronic Case Report Form (eCRF). 
B.5.11. Telephone Calls 
The study site staff may contact subjects by telephone, per the site’s standard of care, to check 
on the well-being of the subject, remind the subject of an upcoming scheduled visit, remind the 
subject to keep analgesic medication usage unchanged for two weeks prior to the scheduled 
visit, remind the subject to maintain normal activity levels prior to scheduled study visits, and 
to contact the Investigator/study staff with any questions or concerns. Participants with HF10 
therapy may also be contacted by a Nevro representative to see if they are having problems with 
the equipment and answer questions related to the use of the device. 
B.5.12. 1 (± 7 days), 3 (± 14 days), 6 (± 30 days), 9 (± 30 days), 12 (± 30 days), 18 (± 
30 days),  and 24 (± 30 days) Months Post-Device Activation (SCS) or Baseline 
(CMM only) 
Subjects will be assessed for pain, adverse events, disability, functioning, healthcare utilization 
(including medication usage for pain and diabetes management, as well as office and hospital 
visits), weight, and sleep at follow-up visits at 1, 3, 6, 9, 12, 18, and 24 months Post-
Intervention. The presence of any lower limb wounds will be documented by measuring the 
greatest diameter and taking a photograph. HF10 therapy subjects may undergo device 
programming or have additional radiographic images taken at these visits, if necessary. Health-
related quality of life, Patient Global Impression of Change, Clinician Global Impression of 
Change, subject satisfaction, and neurological assessment will be performed only at 3, 6, 12, 
and 24 months Post-Intervention. HF10 therapy subjects will be asked to record the distribution 
of pain and additional symptoms, such as numbness, cold, tingling, or burning, on a map at 3, 
6, 12, and 24 months Post-Permanent Device Activation. Hemoglobin A1c measurements will 
be collected at 3, 6, 12, 18, and 24 months. In addition, information regarding work status will 
be collected at the 6, 12, and 24 month visits. A walking assessment will be performed at 3, 12, 
and 24 months. Paresthesia mapping in the stimulation group subjects will be performed at low 
frequency at 3 and 24 months Post-Permanent Device Activation. Paresthesia assessment with 
low-frequency SCS may be performed to assess lead location at 1, 6, 9, 12, and 18 months Post-
Permanent Device Activation.  
At the 6 Month Post-Intervention visit, the continued effect of treatment on achieving pain relief 
will be assessed. Each subject and the Investigator will evaluate whether or not there has been 
sufficient pain relief to continue treatment. If the subject and Investigator agree that pain relief 
has been sufficient to continue therapy, the SCS system will be left in place for the stimulation 
subjects or conventional therapies will continue to be administered for the CMM only subjects. 
If the subject and Investigator believe that the treatment has not generated sufficient pain relief 
to warrant continued treatment, then the IPG and leads will be removed for the stimulation 

 
 
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subjects or conventional therapies may be discontinued for the CMM only subjects. Subjects 
have the option to crossover to the alternate treatment arm at the 6 month visit if they experience 
insufficient pain relief, are not satisfied with their therapy, and the Investigator agrees with the 
decision.  
A similar assessment will be performed at 24 Months Post-Intervention. Following this last 
study visit, subjects will be followed by the Investigator at regular intervals, as dictated by the 
standard of care at each site, in order to facilitate pain management, medication adjustments 
stimulation adjustments, and possible revisions and/or replacements of device components. 
These visits will occur until device explant or discontinuation of therapy. Any additional non-
study related monitoring of the subject will be the responsibility of the subject’s personal 
physician, as dictated by reasonable medical care. If the subject and/or Investigator believe that 
the treatment has not generated sufficient pain relief to warrant continuation, then the IPG and 
leads will be removed for the stimulation subjects or conventional therapies will be discontinued 
for the CMM only subjects. 
B.5.13. Other Assessments and Information 
For stimulation group subjects, paresthesia assessment (low-frequency SCS) may be performed. 
Programming adjustments may be made based on patient feedback following testing. At any 
time during the study, if lead migration is suspected, the subject may have additional 
radiographic images taken to determine lead positioning. In the event the subject’s lead 
locations are not adequate for pain relief, as determined by the Investigator, leads may be moved 
to a different vertebral location. 
Medication Usage: 
• All subjects will continue to take their stable, pre-study doses of analgesic medications 
until the device activation visit (HF10 plus CMM group) or baseline assessment (CMM 
only group), with the exception of procedure-related analgesics prescribed according to 
the Investigator’s standard of care. 
• Subjects will be required to maintain stable dosing of all analgesic medications for two 
weeks prior to scheduled follow-up visits. 
• Changes to non-study medications shall be permitted as directed by the treating 
physician. 
• Following SCS trials and permanent IPG implants, the clinical site’s standard practice 
for prophylactic pre-surgery antibiotics and post-surgery analgesic medications will be 
followed. Investigators will instruct subjects not to change usage of any other 
concomitant analgesic medications. 
• All prescription medications as well as over-the-counter analgesic medications taken by 
subjects will be recorded throughout the study. 
B.5.14. Device Explant 
At any time during the study, subjects in the stimulation group may elect to have the SCS system 
explanted. Additionally, an Investigator may elect to explant a device due to an adverse event. 

 
 
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If any serious adverse event(s) (e.g., subject injury) occurs that is believed to be related to the 
Senza device or there is a Senza device malfunction, it is requested that the device be explanted.  
When the Senza IPG and/or the lead(s) is/are explanted from a subject for any reason, the 
Investigator is to contact Nevro prior to the procedure to arrange shipping of the explanted 
device(s) to Nevro. The explanted device(s) and all accessories (i.e., Charger, Remote Control) 
are to be returned to Nevro for device analysis.   
B.5.15. Early Subject Withdrawal 
Subjects may be withdrawn early from the study for a number of reasons, including but not 
limited to: 
• Entry criteria failure (e.g., lower limb pain VAS score < 5 cm) 
• Trial stimulation failure 
• Subject request 
• Investigator request 
• Subject pregnancy 
• Subject lost to follow-up 
• Subject death 
• Adverse events (e.g., intolerable adverse event occurrence or treatment forces subject to 
stop participation in the study) 
• Lack of efficacy  
If a study subject is discontinued from the study early, a Termination eCRF will be completed 
describing the reason for discontinuation. Subjects will be asked about adverse events or 
device/medication-related issues. In situations where study withdrawal is due to an adverse 
event, subjects will be followed until resolution of that adverse event or determination that the 
subject’s condition is stable. If a subject has withdrawn consent for the study, the site should no 
longer collect any further data for that participant.   
B.5.16. Study Completion 
All subjects randomized in this study are expected to complete all scheduled visits through the 
24 Month Post-Intervention Visit. A Study Completion eCRF should be completed at the last 
study visit. In situations where there is an ongoing study-related adverse event, subjects will be 
followed until resolution of that adverse event or determination that the subject’s condition is 
stable, at which point the Study Completion eCRF should be completed. 
The study may be completed when all of the requirements of the investigational plan have been 
fulfilled. Subjects will be considered to have completed all study requirements following 
completion of the 24 Month Post-Intervention visit. The clinical site will be considered to have 
completed the study requirements at the end of the clinical site close out monitoring visit. The 
study will be considered completed when all close out visits have been completed and all 
Sponsor and Investigator reports have been issued. 
B.5.17. Study Suspension and Termination 
Nevro, the Investigators, or the IRB may suspend or terminate the study at any time. If the study 
is suspended or terminated prematurely, all currently randomized subjects will be withdrawn 
from the study and a Study Completion eCRF or Termination eCRF will be completed. If there 

 
 
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is an ongoing adverse event related to the device or therapy, the subject will be followed until 
resolution of that adverse event or determination that the subject’s condition is stable.  
In the event of suspension or termination of the study, subjects in the stimulation group may be 
explanted according to Device Explant procedures. Subjects may also choose to retain the 
implant and receive ongoing stimulation. Subsequent follow-up of these subjects is the 
responsibility of the subject’s personal physician.   
Nevro reserves the right to terminate the study, but intends only to exercise this right for valid 
scientific or business reasons, or reasons related to the protections of subjects. Investigators and 
IRBs will be notified in writing in the event of study termination. Possible reasons for study 
termination include, but are not limited to: 
• The discovery of unexpected, significant, or unacceptable risk to subjects enrolled in the 
study. 
• A decision on the part of Nevro to suspend or discontinue development of the Senza 
device. 
This study will be in compliance with the requirements of the clinical trial registration and 
results submission described in Section 801 of the Food and Drug Administration Amendments 
Act, known as FDAAA 801 and will hasten the posting of the results if the study is terminated 
early.  
Nevro reserves the right to stop the enrollment of subjects at a clinical site at any time. Possible 
reasons for suspending or terminating a clinical site may include, but are not limited to:  
• Investigator non-compliance  
• Repeated failure to complete or submit eCRFs in a timely manner 
• Failure to obtain written informed consent 
• Failure to report SAEs or UADEs to the Sponsor and/or IRB within 48 hours of 
knowledge 
• Multiple or severe protocol deviations without justification 
• Failure to control or account for study products used 
• Lack of patient accrual/enrollment 
 
B.6. Study Endpoints 
B.6.1. Outcome Measures 
The primary endpoint of this study is a composite of safety and effectiveness, specifically the 
difference between treatment groups in responder rates at 3 month follow-up in subjects without 
a clinically meaningful neurological deficit compared with baseline. A responder is defined as 
a subject with ≥ 50% lower limb pain reduction from baseline. For each subject, the right and 
left lower limb VAS scores collected during a single visit will be averaged together to generate 
a lower limb pain score. 
In addition to the primary endpoint, several secondary endpoints will be evaluated. For all 
analyses, right and left lower limb VAS scores collected on a single visit will be averaged 
together to generate a lower limb pain score for each subject. The secondary endpoints will 
include: 

 
 
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• Difference between the treatment groups in proportion of remitters (remission is defined 
as having a lower limb pain VAS score ≤ 2.5 cm) at 3 months. 
• Difference between the treatment groups in crossover rates. 
• Within group evaluation of responder rates at 12 months. 
• Within group evaluation of proportion of remitters at 12 months. 
• Within group evaluation of changes in health-related quality of life as assessed by the 
EuroQol Five Dimensions questionnaire (EQ-5D-5L) at 12 months. 
• Difference between the treatment groups in proportion of subjects with improvement 
from baseline in neurological assessment (motor, sensory or reflex) at 3 months. 
• Within group evaluation of the proportion of subjects with improvement from baseline 
in neurological assessment (motor, sensory or reflex) at 12 months. 
• Within group evaluation of the average percentage change from baseline in HbA1c 
levels at 12 months. 
 
Tertiary endpoints: 
• Difference between the treatment groups in the average percentage change from 
baseline in lower limb pain VAS scores at 3 and 6 months. Within group evaluations 
will be done at 12 and 24 months. 
• Difference between the treatment groups in proportion of subjects with ≥ 30% 
improvement in lower limb pain VAS at 3 and 6 months. Within group evaluations will 
be done at 12 and 24 months. 
• Difference between the treatment groups in proportion of remitters at 6 months. Within 
group evaluation will be done at 24 months. 
• Difference between the treatment groups in responder rates at 6 months. Within group 
evaluation at 24 months. 
• Difference between the treatment groups in proportion of subjects with improvement 
from baseline in neurological assessment (motor, sensory or reflex) at 6 months. Within 
group evaluation will be done at 24 months. 
• Difference between the treatment groups in Numbers Needed to Treat (NNT) based on 
responder rates at 3 and 6 months. Within group evaluations will be done at 12 and 24 
months. 
• Difference between the treatment groups in average percentage change from baseline in 
opioid dosage at 3 and 6 months. Within group evaluations will be done at 12 and 24 
months. 
• Difference between the treatment groups in average percentage change from baseline in 
PDN-specific analgesic dosages at 3 and 6 months. Within group evaluations will be 
done at 12 and 24 months. 

 
 
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• Difference between the treatment groups in average percentage change from baseline in 
HbA1c,  levels at 3 and 6 months. Within group evaluation will be done at 24 months. 
• Difference between the treatment groups in average percentage change from baseline in 
diabetic control medication dosages at 3 and 6 months. Within group evaluations will 
be done at 12 and 24 months. 
• Difference between the treatment groups in average percentage change from baseline in 
BMI at 3 and 6 months. Within group evaluations will be done at 12 and 24 months. 
• Difference between the treatment groups in the average percentage change from 
baseline on distance covered during the 6MWT at 3 months. Within group evaluations 
will be done at 12 and 24 months. 
• Difference between the treatment groups in the change over time in size of lower limb 
wounds at 3 and 6 months. Within group evaluations will be done at 12 and 24 months. 
• Difference between the treatment groups at 3 and 6 months in health economic 
outcomes, including: 1) healthcare utilization [i.e. medications, office visits, ER visits, 
hospital admissions, medical tests, etc.]; 2) employment status; and 3) health-related 
quality of life as assessed by the EuroQol Five Dimensions questionnaire (EQ-5D-5L) 
and the Diabetes Quality of Life measure (DQOL). Within group evaluations will be 
done at 12 and 24 months. 
 
All other outcome measures will be quantified and reported as mean ± standard deviation 
(where applicable). Descriptive and non-descriptive statistics will also be reported. 
B.6.2. Definition of Success 
Individual subject success encompasses clinical effectiveness and safety at the 3 month follow-
up: 
• Effectiveness: A responder is defined as a subject with ≥ 50% improvement from 
baseline lower limb pain score, as measured by the 10 cm VAS. For each subject, the 
right and left lower limb VAS scores collected during a single visit will be averaged 
together to generate a lower limb pain score. 
• Safety: A subject without a clinically meaningful decrease from baseline in 
neurological status. 
Study success is assessed by comparing responder and safety rates between treatment groups at 
3 months. 
B.6.3. Safety 
Safety will be assessed by characterizing clinically meaningful deficits in neurological status 
(primary) and adverse events (secondary) at all study visits. 
Neurologic status includes motor, sensory and reflex functions, which will be characterized as 
improved, maintained, or a deficit as compared with baseline status as follows: 

 
 
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A clinically meaningful neurological improvement is defined as a significant persistent 
improvement in neurological function that impacts subject’s well-being and is attributable 
to a neurological finding; and is new or improved as compared with the baseline assessment. 
A clinically meaningful neurological deficit is defined as a treatment-related significant 
persistent abnormality in neurological function that impacts subject’s well-being and is 
attributable to a neurological finding; and is new or worsened as compared with the baseline 
assessment. 
If neither a clinically meaningful neurological improvement nor a clinically meaningful 
neurological deficit is observed, then neurologic status is maintained. 
For a clinically meaningful neurological deficit from Baseline, persistent is defined as lasting 
beyond what would be expected for a transient event in this population and unable to be resolved 
through device reprogramming. 
Definitions 
An adverse event (AE) is any untoward medical occurrence defined as an unintended disease 
or injury or untoward clinical signs (including abnormal laboratory findings deemed clinically 
significant as determined by the Investigator) in a subject whether or not related to the medical 
device or medication. This definition includes events related to the study treatments and events 
related to the study procedures. An AE is also any event related to any underlying medical 
condition, present at Baseline, which increases in severity by a clinically meaningful amount 
during the study as determined by the Investigator.  
For all adverse events, the Investigator will provide an assessment of the adverse event, its 
severity, treatment/intervention provided, relationship to the treatment/procedure, and 
resolution. 
As the primary efficacy measure in this study is pain, lower limb peripheral neuropathic 
pain does not need to be reported as an adverse event unless it meets the definition of a 
serious adverse event. However, Investigators may, at their discretion, report any pain-
related adverse events during the study.   
Pre-existing conditions will not be reported as an adverse event unless there has been a 
substantial increase in the severity or frequency of the problem which has not been 
attributed to natural history. 
A serious adverse event (SAE) is an adverse event that  
• 
Led to death 
• 
Led to serious deterioration in the health of the subject, that either resulted in  
o a life-threatening illness or injury (life-threatening is defined as at risk of death 
at the time of the event), or 
o a permanent impairment of a body structure or a body function, or 
o in-patient hospitalization or prolongation of existing hospitalization (in-patient 
hospitalization is defined as a hospital admission for a period of greater than 24 
hours), or  
o medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
• 
Led to fetal distress, fetal death, or a congenital abnormality or birth defect 

 
 
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An unanticipated adverse device effect (UADE) is a serious adverse device effect that was 
not previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of subjects. 
Those known adverse events related to the device, procedure or therapy are listed in the Risk 
Analysis section. 
Reporting 
All AEs, SAEs, and UADEs (see list in section C.1) occurring during the study will be collected. 
The site will document onset, severity, treatment/intervention provided, relationship to the 
treatment/procedure, and resolution and record the data on the Adverse Event eCRF. Any 
UADEs and/or deaths occurring during the study procedures will also be evaluated to determine 
whether the SCS system or medication might have caused or contributed to the event.  
 
All SAEs/UADEs will be documented and reported to Nevro as soon as possible, but: 
- 
no later than 48 hours after becoming aware of the SAE (US); 
The Nevro contact information for these events is: 
 
 
 
 
 
 
The Investigator or site staff may report an event to the sponsor by email, telephone or fax 
initially, but must follow-up by completing an Adverse Event eCRF. The eCRF should be 
accompanied by copies of source documentation regarding the event (e.g., physician/nurse 
notes or summaries/hospitalizations records; including hospital admission reports, progress 
notes and hospital discharge notes). The Investigator must also report the SAE to the IRB 
according to their local regulations. In the event of a subject death, all available information 
(e.g. autopsy or other post-mortem findings) should be provided with or on the eCRF. 
 
An Investigator shall submit a report to the sponsor of any UADE occurring during the study 
as soon as possible, but in no event later than 10 working days after the Investigator first learns 
of the effect. Nevro will conduct an evaluation of the event to determine whether the event is 
an anticipated event based on labeling and risk analysis. The Investigator must also report the 
event to the IRB if it is determined to be unanticipated. 
All AEs will be followed until the event is resolved (with or without sequelae). If a device-
related event is ongoing at the time of study completion or termination, the subject will be 
followed until resolution or the Investigator determines that the subject’s condition is stable.  
In addition to the above reporting and in accordance with Medical Device Reporting 
requirements of 21 CFR 803, when using commercial medical devices, device related SAEs and 
UADEs must be reported to Nevro’s Product Support Department at the above email, phone 
E-mail: sae@nevro.com 
Tel: +1.650.251.0005 
*Press 2 for Product Support 
Fax: +1.650.251.9415 

 
 
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number, or fax number, as specified in the manufacturer’s labeling/manuals. If the “study 
related” box is checked on the AE eCRF, this reporting applies.  
For all treatments administered as CMM, the Investigator shall report suspected medication-
related or treatment-related AEs to the FDA or manufacturer according the site’s usual practice 
and/or the manufacturer’s label. The FDA contact information for these events is: 
 
 
   
Nevro will convene a Clinical Events Safety Committee with outside physician members to 
review SAEs, unanticipated device or medication-related AEs or SAEs, cases of persistent 
neurological deficits, and overall trends in AE frequencies throughout the course of the study.  
B.7. Data Collection and Analysis 
B.7.1. Data Collection 
Data will be collected using eCRFs via an Electronic Data Capture (EDC) system (M-Core, 
Medrio Inc.). Data will be entered directly into eCRFs in the EDC system at the sites. The 
clinical site will record data on outcome variables as well as adverse events should they occur.  
Subject confidentiality will be maintained and each subject will be identified by his or her 
subject number. Subject names will not be published. Data collection is summarized in Table 
1. 
B.7.2. Data Handling 
The Sponsor is responsible for data analyses. The sponsor and/or its affiliates will be responsible 
for compiling and submitting all required reports to governmental agencies. 
Nevro personnel will follow Nevro’s Standard Operating Procedures and supporting study-
specific documentation when handling data.  
B.7.3. Record Keeping 
Source documents will be maintained by the Investigator and made available to the Sponsor for 
the purpose of monitoring the study. Investigators will be required to keep study records for a 
period of two (2) years or as defined by the local law and regulations where the study is 
conducted. 
Passwords will be issued to appropriate personnel to insure confidentiality and protection of 
data.   
The Investigator must contact the sponsor prior to destroying or archiving at an off-site facility 
any records, reports or study materials pertaining to this investigation to ensure that they no 
longer need to be retained on-site. 
All original patient files must be stored for the longest possible time permitted by the regulations 
at the hospital, research institute, or medical practice or at a secure off-site facility. If archiving 
can no longer be maintained by the site, the investigator will notify the sponsor.  
FDA: (800) FDA-1088  
www.fda.gov/medwatch 

 
 
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All data and documents shall be made available on request of the relevant authorities in case of 
an audit and/or inspection. 
The sponsor will archive and retain all essential clinical investigation documents from prior, 
during and (as specified) after the clinical investigation as per requirements.

 
 
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Table 1.  Schedule of Events – Enrollment through 24 Month Visit 
Assessment 
Enrollment 
Trial & Permanent Phase (SCS only) 
Follow-up Phase 
Visit 
Consent 
Entry 
Criteriaa 
Baseline 
Assessment 
Trial 
Implant 
End of 
Trial 
(EoT) 
Permanent 
Implant 
Device 
Activation 
(DA) 
1 Month 
Visit 
3 Month 
Visit 
6 Month 
Visit 
9 Month 
Visit 
12 Month 
Visit 
18 Month 
Visit 
24 Month 
Visit 
Window 
- 
 
 
- 
0-14 d 
from 
Trial 
Implant 
0-60 d 
from 
EoT 
0-14 d 
from 
Perm. 
Implant 
4 wks ± 
7 d from 
DA (SCS) 
or baseline 
(CMM) 
12 wks ± 14 
d from DA 
(SCS) or 
baseline 
(CMM) 
24 wks ± 30 
d from DA 
(SCS) or 
baseline 
(CMM) 
36 wks ± 30 
d from DA 
(SCS) or 
baseline 
(CMM) 
52 wks ± 30 
d from DA 
(SCS) or 
baseline 
(CMM) 
78 wks ± 30 
d from DA 
(SCS) or 
baseline 
(CMM) 
104 wks ± 
30 d from 
DA (SCS) 
or baseline 
(CMM) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication Usage 
 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diabetes Medication Usage 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Healthcare Utilization 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Pain Assessment (VAS) 
 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
X 
X 
 
 
 
 
 
X 
X 
 
X 
 
X 
Pregnancy Test 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
Psychological Evaluation 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MRI 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
AP/Lateral and/or Oblique X-Raysf 
 
 
 
X 
X 
X 
 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
Neuropathic Pain Assessment (DN4) 
 
 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
Modified Neuropathy Symptom Score (NSS) 
 
 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
Brief Pain Inventory (BPI-DPN) 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Pain Experience (SF-MPQ-2) 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
X 
Diabetes Quality of Life (DQOL) 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
X 
Quality of Life Assessment (EQ-5D-5L) 
 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
X 
Pain and Sleep Assessment (PSQ-3) 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Pt Global Impression of Change (PGIC) 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
Clin Global Impression of Change (CGIC) 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
Assessment of Functioning (GAF) 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
6-Minute Walk Test (6MWT) 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
Labwork 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
Subject Satisfaction 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
Neurological Assessment 
 
 
X 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Work Status & Disability 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
Third-Party Payer Data 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Wound Assessment 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Device Programmingf  
 
 
 
X 
 
X 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
Paresthesia Assessmentf, g 
 
 
 
[X] 
[X] 
[X] 
[X] 
[X] 
X 
[X] 
[X] 
[X] 
[X] 
X 
Pain Mapf 
 
 
 
X 
[X] 
[X] 
 
 
X 
X 
 
X 
 
X 
Additional Symptom Mapf 
 
 
 
[X] 
 
[X] 
 
 
X 
X 
 
X 
 
X 
Crossover 
 
 
 
 
 
 
 
 
 
[X] 
 
 
 
 
Study Completionh 
 
 
 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
X 
aAll Entry Criteria to be completed before the Baseline Assessment. bPain medications must be stable for ≥30 days before VAS may be completed.  cTo be completed for participants of child bearing potential. dPsychological 
evaluation to be completed for subjects who did not have an evaluation performed within the last 12 months. eMRI to be completed for subjects who did not have one within the last 12 months. fFor SCS subjects only. gMay be 
performed as appropriate, as determined by the field clinical engineer. hTo be completed for all subjects upon completion of the study, including those who withdraw early or do not pass the Trial Phase. Trial failure subjects 
who were initially randomized to SCS will be followed for 6 months while subjects who fail trial after crossover will be followed for a minimum of 2 weeks or until resolution of an ongoing adverse event, if applicable, prior 
to completing this form. Wks = weeks, d = days, [X] = optional 

 
 
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B.8. Outcome Measurements 
B.8.1. Effectiveness Measurements 
Effectiveness will be measured for each subject using the following tests: 
Pain Visual Analog Scales:  The visual analog scale (VAS) is a well validated and widely used 
scaled psychometric instrument to report pain severity. Subjects will score the severity of pain 
on a 10 cm line, with 0 indicating no pain and 10 indicating the worst pain imaginable.  
Subjects will complete a chronic upper or lower limb pain VAS worksheet (either a 
questionnaire or CRF) in the clinic during scheduled study visits. Subjects will serve as their 
own control for the pain relief endpoint. Each subject’s baseline pain score will be compared to 
the score at follow-up visits. Mean changes from baseline will be calculated for the entire 
cohort. The percentage of subjects who achieved ≥ 50% pain relief in their primary area of pain 
will also be calculated based on changes from baseline. VAS scores collected during the study 
visits will be used for the primary endpoint. 
Douleur Neuropathique 4 (DN4): DN4 is a well validated survey to help identify subjects 
with neuropathic pain. The questionnaire has 10 yes/no items that describe qualities of pain as 
well as assess the presence of sensory nerve phenomena such as hypoesthesia and allodynia. 
Modified Neuropathy Symptom Score (NSS): The modified NSS is a 5-item questionnaire 
with a maximum score of 9 that evaluates symptoms of neuropathy in the lower limbs. 
Paresthesia assessment: Representatives of Nevro may record where subjects experience 
paresthesia with the SCS system at low (non-therapeutic) frequency. Summary results, if 
available, will be presented. 
Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN): The BPI-DPN is a 
modified version of the Short Form BPI, a brief survey that assesses the severity of the subject’s 
pain and the level of interference with typical life activities, such as sleeping, walking, and 
working. The BPI-DPN has been validated in patients with PDN. 
McGill Pain Questionnaire: The Short Form McGill Pain Questionnaire version 2 (SF-MPQ-
2, hereafter referred to as MPQ) is a well validated and widely used questionnaire used to 
measure the major symptoms of pain. Subjects will be asked to rate the intensity of each of 22 
pain descriptors from 0 (do not experience, or none) to 10 (worst possible) at follow-up visits 
outlined in the schedule of events.  
Four subscale scores (continuous pain, intermittent pain, predominantly neuropathic pain, and 
affective descriptors) and a total score will be calculated. Each subject’s baseline scores will be 
compared to the scores at study visits. Mean change from baseline will be calculated for the 
entire cohort.  
Diabetes Quality of Life Measure (DQOL): The DQOL is a patient-completed questionnaire 
with 46 items that ask the respondent to select a value of 1 to 5, with 1 representing “no impact,” 
“no worries,” and “always satisfied,” while a score of 5 represents “always affected,” “always 
worried,” and “never satisfied.” The measure was specifically developed and validated in 
diabetic patient populations. The total score can be broken down into four subscales: 

 
 
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satisfaction, impact, diabetes worry, and social worry. A lower score indicates a better quality 
of life.    
EuroQol Five Dimensions Questionnaire (EQ-5D-5L): The EQ-5D-5L is a standardized 
quality of life questionnaire applicable to a wide range of health conditions. The questionnaire 
consists of 5 items as well as a health-related VAS and is completed by the subject. 
Pain and Sleep Questionnaire Three-Item Index (PSQ-3): Pain and Sleep Questionnaire 
(PSQ), an eight-item questionnaire developed to assess the impact of pain on sleep. PSQ-3 is a 
subset of PSQ, consisting of questions 1, 4 and 5 and has been validated to assess impact of 
chronic pain on sleep. 
Medication usage: Medication usage will be recorded at all study visits. Changes of usage for 
subjects will be summarized. 
Healthcare Utilization: Doctors’ office visits, ER visits, medical tests, and hospital admissions 
will be recorded at all follow-up visits. 
Global Assessment of Functioning: Investigators will complete a Global Assessment of 
Functioning (GAF) scale to rate subjectively the social, occupational, and psychological 
functioning of subjects. This is a numeric scale, with scores of 0 through 100, with 100 being 
the highest functioning. Mean scores and changes from baseline will be calculated. A higher 
score indicates an improvement. 
6-Minute Walk Test (6MWT): The 6MWT is an easily administered objective test of 
functional exercise capacity that measures the total distance a subject can walk during a finite 
time period. 
Global Impression of Change: Both the subject and clinician will complete a global 
impression of change scale. This 7-point scale is used to assess the subject’s global change in 
activity, limitations, symptoms, emotions and overall quality of life since the beginning of the 
study. Responses range from “no change (or condition has got worse)” to “a great deal better”. 
Summary results will be presented for both the subject and clinician completed scales. 
Subject Satisfaction Questionnaire: Subject satisfaction will be assessed using a 5 point scale. 
Responses range from “very satisfied” to “very dissatisfied.” Summary results will be 
presented. 
B.8.2. Safety Measurements 
Adverse Events: Subjects will be assessed for adverse events starting at enrollment and 
continuing through study completion. If an adverse event occurs, an adverse event eCRF will 
be completed. The event will be followed until resolution or determination that the subject’s 
condition is stable.   
The Investigators shall categorize all adverse events for seriousness, severity, and relationship. 
All determinations of severity, device relation, and resolution are made by the Investigator and 
not by the Sponsor.  
For purposes of consistent adverse event reporting and analysis, adverse events will be 
categorized using the Medical Dictionary for Regulatory Activities (MedDRA®) terminology, 
consistent with the MedDRA® Term Selection: Points to Consider document. Events are 

 
 
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grouped by System Organ Classification (SOC) and Preferred Term (PT), according to 
diagnosis and/or event description as provided by the Investigator on the eCRF.  
Neurological Assessments: Neurological examinations include assessment of motor, sensory 
and reflex functions. Clinicians shall characterize the findings as improved, maintained, or a 
deficit as compared with baseline status, based on the following pre-specified definitions: 
• A clinically meaningful neurological improvement is defined as a significant persistent 
improvement in neurological function that impacts subject’s well-being, is attributable 
to a neurological finding, and is new or improved as compared with the baseline 
assessment. 
• A clinically meaningful neurological deficit is defined as a treatment-related significant 
persistent abnormality in neurological function that impacts subject’s well-being, is 
attributable to a neurological finding, and is new or worsened as compared with the 
baseline assessment. 
• If neither a clinically meaningful neurological improvement nor a clinically meaningful 
neurological deficit is observed, then neurologic status is maintained. 
For clinically meaningful neurological change from baseline, persistent is defined as 
lasting beyond what would be expected for a transient event in this population and 
unable to be resolved through device reprogramming. 
 
B.8.3. Statistical Analysis 
Descriptive statistics will be used to summarize all subject Baseline and outcome data collected 
during the study. Continuous variables will be summarized using means, standard deviations, 
and ranges. Categorical variables will be summarized in frequency distributions. The statistical 
analysis plan (SAP) will be described in detail elsewhere. 

 
 
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C.  Risk Analysis 
C.1. Description and Analysis of All Increased Risks to Subjects 
 
Risks Associated with Study Assessments and Questionnaires: 
The Senza System has received PMA approval and CE Mark for use of the device in the treatment 
of chronic intractable pain. Compared with standard practice, subjects who participate in this study 
will undergo medical assessments and complete questionnaires at scheduled intervals. There are no 
risks associated with completion of these assessments and questionnaires. Blood will also be drawn 
at various points in the study for laboratory tests and this procedure carries a risk of infection. 
 
Risks Associated with Conventional Medical Management (CMM): 
Investigators will follow their standard of care and/or published clinical guidelines (Dworkin, 2010) 
to administer CMM to both treatment groups. Treatments include, but are not limited to, 
pharmacological agents, physical therapy, cognitive therapy, chiropractic care, nerve blocks, and 
other non-invasive or minimally invasive therapies. The risks associated with these treatments are 
typical of routine medical care. 
 
Spinal Cord Stimulation (SCS) Risks: 
A risk analysis was completed in accordance with ISO 14971 – Application of Risk Management 
for Medical Devices. This analysis showed that the Senza System exhibits a safety profile 
equivalent to the other commercially available SCS stimulators. 
There are known risks associated with the use of any SCS system. These risks include those related 
to the implant procedure, those related to stimulation, those related to the device (not associated 
with stimulation) and those related to the external devices such as the charger and remote control. 
Table 3 lists the type and level of risk associated with the use of SCS systems. These anticipated 
risks are typical of all SCS systems and are presented in the study informed consent, Patient Manual 
and Physician Implant Manual. 
 
Table 3: Type and Level of Risk Associated with the Use of SCS Systems 
Type of Risk 
Level of Risk 
Description of Risk 
Implant Procedure 
Possible 
Surgical complications, infection, cellulitis, abscess, fever, sepsis 
Suboptimal lead/IPG placement or migration requiring explant, revision 
Bleeding 
Cerebrospinal fluid leak 
 
 
Epidural hemorrhage 
Temporary pain or persistent tenderness/pain at implant site 
Inadequate wound healing 
Hematoma, seroma or thrombosis 
Risks associated with anesthesia 

 
 
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Unlikely 
Nerve/nerve root/spinal cord injury 
Very Unlikely 
Death 
 
 
Paralysis 
Stimulation  
Possible 
Increased pain (other than at implant site or areas being treated) 
Increased pain (higher than before device implant) in the areas being treated  
 
 
Loss of pain relief 
Undesirable sensation, unpleasant paresthesia 
Undesirable/unwanted stimulation due to cellular changes around electrodes, 
changes in electrode position, loose electrical connections, or lead failure 
Uncomfortable stimulation of tissue around the leads including skin and 
muscle  
Intermittent stimulation 
 
 
Tingling, prickling or numbness in pain area 
 
Unlikely 
Malfunction 
 
Very Unlikely 
Seizure 
Implanted Device 
Possible 
Tissue reaction or allergy to implanted materials 
External sources of electromagnetic interference that cause the device to 
malfunction and could affect stimulation 
Unlikely 
Persistent pain at implant site (electrode or IPG) 
 
 
Failure of device components or the battery including lead breakage or 
movement (migration), hardware malfunctions, loose connections, electrical 
shorts or open circuits and lead insulation breaches 
Failure or malfunction requiring explant and re-implantation 
Very Unlikely 
Skin erosion over lead or IPG site 
Pressure sores 
External Device 
Unlikely 
Malfunction 
Uncomfortable heating effects, discomfort or burns 
 
Other Risks – These warnings and precautions are discussed in the Patient Manual and Physician 
Implant Manual.  
 
SCS Warnings: 
Other Active Implanted Devices – The Senza system may interfere with other implanted 
stimulators, such as cardiac pacemakers and defibrillators which have sensing features, and may 
result in sensing problems or inappropriate responses. The effect of other implanted devices, 
including deep brain stimulators, peripheral nerve stimulators, implanted drug delivery pumps, 
and cochlear implants on the Senza system are unknown. 
Sleep – Patients using therapy that generates paresthesia (tingling sensations caused by 
stimulation) may choose to turn stimulation off to avoid uncomfortable sensations during sleep. 
Therapy at 10 kHz does not generate paresthesia and therefore stimulation can remain on during 
sleep. 
Operation of Vehicles (e.g., driving) or Machinery – Patients using therapy that generates 
paresthesia should not operate motorized vehicles such as automobiles or potentially dangerous 
machinery and equipment with the stimulation on. Stimulation must be turned off first in such 

 
 
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cases. For these patients, any sudden stimulation changes may distract patients from proper 
operation of the vehicle, machinery, or equipment. 
Therapy at 10 kHz does not generate paresthesia and it is less likely that sudden stimulation 
changes resulting in distraction could occur while having stimulation on when operating moving 
vehicles, machinery, and equipment.  
Heat From Charging – The charging coil may become warm while charging. Patients may 
experience discomfort or burn if they charge while sleeping or do not use the provided charging 
belt. Additionally, the charger should not be placed over insensate skin. 
Diathermy Therapy – Do not use shortwave diathermy, microwave diathermy or therapeutic 
ultrasound diathermy on patients implanted with a neuromodulation system. Energy from 
diathermy can be transferred through the implanted system and can cause tissue damage at the 
location of the implanted electrodes, resulting in severe injury or death. The neuromodulation 
system, whether it is turned on or off, may be damaged.  
Computed Tomography (CT) – Before beginning a CT scan, the operator should use CT scout 
views to determine if implanted or externally worn electronic medical devices are present and 
if so, their location relative to the programmed scan range. 
For CT procedures in which the medical device is in or immediately adjacent to the programmed 
scan range, the operator should: 
• Determine the device type; 
• If practical, try to move external devices out of the scan range; 
• Ask patients with neurostimulators to shut off the device temporarily while the scan is 
performed; 
• Minimize x-ray exposure to the implanted or externally worn electronic medical device 
by: 
o Using the lowest possible x-ray tube current consistent with obtaining the required 
image quality; and 
o Making sure that the x-ray beam does not dwell over the device for more than a few 
seconds; 
Important note: For CT procedures that require scanning over the medical device continuously 
for more than a few seconds, as with CT perfusion or interventional exams, attending staff 
should be ready to take emergency measures to treat adverse reactions if they occur. 
After CT scanning directly over the implanted or externally worn electronic medical device: 
• Have the patient turn the device back on if it had been turned off prior to scanning. 
• Have the patient check the device for proper functioning, even if the device was turned off. 
• Advise patients to contact their healthcare provider as soon as possible if they suspect their 
device is not functioning properly after a CT scan. 
Magnetic Resonance Imaging (MRI) – The Senza system is MR Conditional which means 
that safety has been demonstrated only within specifically defined conditions. Scanning under 
different conditions may result in severe patient injury or device malfunction. Refer to the Senza 
system 1.5T and 3T MRI Guidelines (US) manual for MRI-specific warnings and precautions 
on conducting a MRI scan on a patient with the Senza system.  

 
 
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Devices in Hospital/Medical Environments – The use of following medical devices or 
procedures may damage the SCS system or turn the stimulation off. After usage of these devices 
or procedures, the IPG may need to be explanted as a result of permanent damage.  
• Electrocautery: The IPG should not be exposed to electrocautery. If electrocautery is 
necessary with the IPG implanted, use bipolar electrocautery. Do not use monopolar 
electrocautery.  
• External defibrillation: The safety of discharge of an external defibrillator on patients 
implanted with an SCS system has not been established. 
• Lithotripsy or high-output ultrasonics: Do not use these devices in patients with an 
implanted IPG.  
• Radiation therapy: If radiation therapy is needed near the IPG, shield the area over the 
IPG. 
• Ultrasonic scanning: Do not use it over the IPG. 
If a patient is required to undergo lithotripsy, high-output ultrasound, electrocautery, external 
defibrillation, radiation therapy, or ultrasonic scanning, follow these precautions. 
• Turn off the IPG before the procedure. 
• Use the equipment as far away from the IPG as possible. 
• Keep fields, such as current, radiation, or high-output ultrasonic beams, away from the 
IPG. 
• Equipment should be set to the lowest energy setting possible.  
• After the therapy or procedure, check to see that the IPG is functioning properly by 
gradually increasing the IPG’s stimulation to the desired level. 
• If the patient suspects that the device is not functioning properly after the use of these 
therapies or procedures, advise the patient to contact his or her healthcare provider. 
Electromagnetic Interference (EMI) – Electromagnetic energy is generated by equipment 
found in the home, work, medical or public environments. Electromagnetic interference may 
occur when the energy is strong enough to interfere with neurostimulator function. Most 
electrical devices and magnets that patients will encounter in a normal day are unlikely to affect 
the operation of the SCS system. However, some equipment may generate strong 
electromagnetic fields that can turn the stimulator (IPG or trial stimulator [TSM]) off or cause 
shocks or jolts (see below). Patients should keep away from areas of EMI and turn off the 
stimulator if they are in such an area. The following are examples of sources that can potentially 
generate strong EMI.  
• Theft detection systems or security screening devices (scanners and wands) such as 
those found in airport security screenings, retail stores, and libraries.  
Note: It is recommended that patients request assistance to bypass the theft detector or security 
screener. If they must go through a screening device, the patient should turn off the stimulator 
and go through the area as quickly as possible and as far away from the theft detector or 
security screener as possible. 
• Power lines and power generators 
• Arc welders 
• Large, magnetized stereo speakers 
• Radio frequency identification devices (RFID) 

 
 
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If EMI is suspected or encountered, patients will need to turn off the stimulator. Then, the 
patients will need to move away from the EMI area and check whether the therapy is on or off. 
Before therapy can be turned off, the batteries may need to be replaced in the TSM or recharged 
in the IPG. 
Strong electromagnetic interference can result in the following: 
• Serious patient injury, resulting from heating of the implanted components of the 
neurostimulation system and damage to surrounding tissue. 
• System damage, resulting in a loss of or change in symptom control and requiring 
surgical replacement. 
• Operational changes to the neurostimulator, causing it to turn on or off  
• Unexpected changes in stimulation, causing a momentary increase in stimulation or 
intermittent stimulation, which some patients have described as a jolting or shocking 
sensation. Although the unexpected change in stimulation may feel uncomfortable, it 
does not damage the device or injure the patient directly. In rare cases, as a result of the 
unexpected change in stimulation, patients have fallen down and been injured. 
Strong electromagnetic fields arising from closeness to electrical equipment such as mobile 
phones, satellite phones and radio systems may interfere with the radio communication between 
the Remote Control and IPG.  As described in the Troubleshooting section of the Patient 
Manual, communication failure is indicated by three beeps. Communication can be restored by 
moving away from the interfering electrical equipment and retrying the operation. 
Electrostatic Discharge (ESD) is a common source of electromagnetic interference that can 
occur when a person or object accumulates a static charge.  ESD is made worse by low humidity 
and synthetic materials. 
• If the battery terminals of the Trial Simulator are exposed to ESD, the device may reset 
and stop stimulation.  Stimulation can be restarted by following the instructions in the 
“How to Turn ON Stimulation” section of the Patient Manual. To avoid unintentionally 
stopping stimulation, do not open the battery compartment while stimulation is ongoing. 
• ESD may cause the Charger to stop charging the IPG. If this happens, charging can be 
resumed by repeating the steps in the “How to Charge the IPG” section of the Patient 
Manual. ESD events can be minimized by keeping the charger in the Charger Holster 
while recharging the IPG. 
Radio-frequency or microwave ablation – Safety has not been established for radiofrequency 
(RF) or microwave ablation in patients who have an implanted neurostimulation system. 
Induced electrical currents may cause heating, especially at the lead electrode site, resulting in 
tissue damage. 
 
SCS Precautions: 
Patients Who Are Poor Surgical Candidates – Do not implant an SCS system if a patient is 
considered a poor surgical candidate. Implanting an SCS system has risks similar to surgical 
procedures of the spine, including spinal fluid leak, headaches, swelling, bruising, bleeding, 
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Pregnancy – The safety and effectiveness of spinal cord stimulation has not been established 
for use during pregnancy and nursing.  
Patient Activities – Patients using therapy that generates paresthesia (see Warning regarding 
Stimulation Frequencies) may experience increased paresthesia when changing posture or 
making abrupt movements. Such patients should lower the amplitude or turn off the stimulation 
before making posture changes, such as stretching and moving their arms over their head. If 
unpleasant sensations occur, the IPG should be turned off.  
Stimulation at 10 kHz does not generate paresthesia, so patients should not experience 
unpleasant sensations caused by posture changes or movement. As such, patients would not 
need to change amplitudes in their programs in response to posture changes or movement.  
Patient Activities Related to Lead Movement – Advise patients to not make sudden and 
excessive bending, stretching, or twisting movements, particularly within the first weeks after 
the surgery. An implanted lead can move from its original location during such movements, 
which might affect delivery of therapy. In such cases, the patient may need to be reprogrammed 
or the lead may need to be repositioned through another operation. 
Scuba Diving and Hyperbaric Chambers – Patients with IPGs should avoid scuba diving to 
depths greater than 35 meters and hyperbaric chambers with pressure greater than 4.5 ATM. 
Pressure greater than 35 meters or 4.5 ATM may damage the Senza system.  
Storage – Store the system components and accessories between the prescribed temperatures. 
Excessively hot or cold temperatures may damage the components, particularly high heat. 
Devices should be kept in temperature regulated areas within the acceptable temperature range. 
Do not expose the components to liquids or excessive moisture.  
• The storage temperature for the IPG, Lead, Lead Extension, and Charger should not 
exceed the range of 0° C to 45° C (32° F to 113° F).  
• The storage temperature for the Trial Stimulator and the Patient Remote Control should 
not exceed the range of -20 to 60 °C (-4 to 140 °F).  
• The storage temperature for the Charger should not exceed 0 to 45°C (32 to 113 °F). 
Sterilization – This device is for single use only and is not intended to be re-sterilized. 
• Prior to opening the sterile package, inspect the sterilization indicator and the sterile 
package.  
• Do not use the contents if the package is broken or torn, or if contamination is suspected 
because of a defective sterile package seal. 
• Do not use any component that shows signs of damage. 
• Do not re-sterilize the package or the contents. There is risk of infection and device 
malfunction. 
• Do not use if "Use by" date has passed. 
• All implanted components are intended for single use only. Do not re-use. 
Handling – Use care when handling the system components and accessories. Do not drop them 
or submerge them in water. Do not impact the system components against hard surfaces and 
avoid rough handling. Although reliability testing has been performed to ensure quality 
manufacturing and performance, dropping the devices on hard surfaces or in water or other 
rough handling, can permanently damage the components and accessories. Do not plug the 
charger into a power source near water. 

 
 
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Handling the Leads and Lead Extensions - Follow these guidelines when handling the 
Leads or Lead Extensions: 
• Lead and lead extension should be handled with care at all times. 
• Do not make sharp bends to the lead or lead extension. 
• Do not severely kink, crush or stretch the lead or lead extension. 
• Do not apply severe torque (twist) to the lead or lead extension. Do not tie suture 
directly to the lead or the lead extension. 
• When placing a suture around the lead, use the provided lead anchors. 
• Do not force the lead into the epidural space. Use the lead blank prior to inserting the 
lead. 
• Create a stress relief loop to minimize tension on the lead. 
• Do not stretch the lead. 
• Do not use sharp instruments to handle the lead or lead extension.  
• Wipe off any bodily fluids (e.g. blood) from the lead’s proximal end before 
connecting it to any other component.  
• Wipe off any bodily fluids (e.g. blood) from the lead stylet before inserting or 
reinserting it into the lead. 
• When inserting the stylet into the lead, do not use excessive force. 
Handling the IPG - Follow these guidelines when handling the IPG: 
• Avoid rough handling of the IPG. 
• Take care not to drop the IPG. If it has been dropped on a hard surface, do not use 
the device and send it back to Nevro Corp. 
System Compatibility – Do not use any cables or adaptors unless they are explicitly approved 
by Nevro Corp.  
Transcranial Magnetic Stimulation (TMS) and Electroconvulsive Therapy (ECT) – Safety 
has not been established for TMS or ECT in patients who have an implanted neurostimulation 
system. Induced electrical currents may cause heating, especially at the lead electrode site, 
resulting in tissue damage. 
Transcutaneous Electrical Nerve Stimulation – Do not place transcutaneous electrical nerve 
stimulation (TENS) electrodes so that the TENS current passes over any part of the 
neurostimulation system. If patients feel that the TENS may be interfering with the implanted 
neurostimulator, patients should discontinue using the TENS until they talk with their doctor. 
Post-Operative Pain – In the days after the surgery, the patient may experience pain in the 
implant area, which is typical in SCS surgeries.  
IPG Location and Patient Manipulation – Advise patients not to twist or rotate the IPG. If 
the IPG flips over in the body, the charger may not be able to charge the IPG. The patient’s 
manipulation of the IPG in his or her body may cause the skin over the IPG to become thinner 
over time. 
Infection – Use proper infection control procedures. If a patient experiences persistent 
discomfort or excessive redness around the wound areas, the patient may need to be checked 
for infection. Infections related to the SCS may require the implanted components to be 
explanted. Do not use the charger if the incision is not sufficiently healed. The charger and the 
charging belt are not sterile and should not be in contact with the incision. 

 
 
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Operating Temperature – The operating temperature range for the Patient Remote Control is 
10 to 40 °C (50 to 104 °F). The operating temperature range for the Trial Stimulator is 10 to 38 
°C (50 to 100 °F). While the Charger is plugged into the wall and charging itself, the operating 
temperature range for the Charging System is 10 to 40 °C (50 to 104 °F). While the Charger is 
charging the IPG, the operating temperature for the Charging System is 10 to 30 °C (50 to 86 
°F). 
Caring for the Trial Stimulator, Remote Control, and Charging System – These 
components can be cleaned by rubbing all surfaces without undue pressure with soft cloth 
damped with water, isopropyl alcohol or mild detergent. The remaining residue should be 
removed by wiping the surfaces with a dry cloth. Do not use abrasive cleansers for cleaning. 
Do not allow moisture to get inside the components. 
Cell Phones – The impact of cell phones on the neuromodulation system is unknown at this 
time.  
IPG Failure – If the patient’s IPG does not provide stimulation even after complete charging 
of the IPG or replacement of the batteries in the Patient Remote Control, turn off the IPG and 
contact Nevro Corp. When frequency of recharging becomes too inconvenient for your patient, 
the IPG may need to be replaced. Contact Nevro Corp. 
Device Disposal – Do not dispose the IPG, Patient Remote Control or Charger in fire. The 
battery in these devices can explode in fire. The IPG should be explanted in the case of 
cremation. All explanted IPGs should be returned to Nevro Corp. Do not dispose of electrical 
components, including batteries, in the unsorted municipal waste stream. Dispose of electrical 
components, including batteries, according to local regulations. 
 
Risk Mitigation - The design of this study minimizes the potential for serious risk to the health, 
safety or welfare of the subject. At all times during this study, all subjects are under a physician’s 
supervision and care. SCS implantation, the delivery of electrical stimulation, and CMM are also 
under the supervision and care of a physician. 
The treatments used in this study involve routine medical procedures using standard 
products/technology (e.g., implantable pulse generator (IPG), electrodes, etc.) and CMM, in 
conjunction with known medical skills (e.g., surgical placement of IPGs and electrodes, imaging 
techniques, dosage titration, etc.).  Examples include: 
• Imaging of lead placement by fluoroscopy 
• Surgical procedure for placement of the electrodes in the spinal epidural space, tunneling of 
the lead/electrode, and placement of the IPG 
• Use of stimulation electrodes  
• Setting of stimulation parameters and threshold levels 
• Stimulation system removal 
• Medication prescribing and titration to effect 
• Administration of appropriate adjunctive therapies such as physical therapy, cognitive 
therapy, and chiropractic care. 
• Pain, functional and quality of life measures  

 
 
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Overall, the potential risks associated with this study are identical to those of commercially 
available medical treatments, including the use of the Senza System or other commercially available 
SCS systems as well as CMM.   
C.2. Potential Benefits to the Subject 
It is possible that individual subjects will experience no benefit from participation in this study. 
Additionally, if the subject receives a reduction in pain from study treatments, it is not known how 
long the benefit will last. 
C.3. Minimization of Risks 
The Senza System used in this study is identical to the commercially available Senza System and 
is designed to operate in a similar fashion as other commercially available SCS devices. The risks 
associated with the use of SCS systems have been well characterized and are minimal compared to 
the side effects associated with most surgical procedures or the use of many drugs used to treat 
chronic pain conditions. Additionally, the treatment is reversible in that the SCS device may be 
turned off and/or explanted at any time for any reason. CMM as defined in this study is identical to 
routine, commercially available medical care for patients with neuropathic limb pain. 
Investigators will be experienced in the diagnosis and treatment of chronic pain, including 
prescribing medications, proper surgical and clinical training, and will take adequate steps to ensure 
subject safety during implant procedures and throughout the study. As is done with commercial 
SCS device systems, Investigators and study personnel will receive product training to become 
familiar with the components of the Senza System and their functions.  
C.4. Justification for the Investigation 
A justification for the study is provided in the rationale section (section B.1).  In brief, if HF10 
therapy proves safe and effective in reducing pain and disability associated with chronic 
neuropathic pain of the lower limbs due to painful diabetic peripheral neuropathy it would have 
important health, quality of life, and economic benefits for many thousands of people. This potential 
benefit outweighs the potential risk of harm to the subjects in this study. 
C.5. Description of the Subject Population 
Subjects participating in the study will be subjects who have been clinically diagnosed with chronic 
neuropathic pain of the lower limbs as a result of painful diabetic peripheral neuropathy.  
In the study, up to 432 subjects will be enrolled in order to obtain 108 subjects randomized to each 
of two treatment groups: HF10 therapy plus CMM subjects and CMM only subjects.  
Standardized, validated, and reliable tests of pain, disability, functioning, healthcare utilization 
(including medications, office visits, and hospital admissions), health-related quality of life, and 
sleep will be administered to each subject at Baseline, and followed through the course of treatment 
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After patient enrollment, patient demographic and third party payer coverage data will be collected.  
This will allow an understanding of the third party payer coverage landscape for the study patients, 
including the percentage of Medicare-eligible patients. This information is not for the purpose of 
assessing safety and effectiveness, but is expected to help determine the degree to which 
beneficiaries may be affected by the device under investigation and how the generalizability of the 
study results to the Medicare beneficiary population in relation to age, disability, or other eligibility 
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D. Description of the Study Interventions 
D.1. Each Important Component, Ingredient, and Property of the Device 
D.1.1. Device System Overview 
The Senza System is a totally implantable spinal cord stimulation system that is intended to aid 
in the management of chronic intractable pain of the trunk and/or limbs, including unilateral or 
bilateral pain associated with the following: failed back surgery syndrome, intractable low back 
pain, and leg pain, and received CE Mark in May 2010, Therapeutic Goods Administration 
(TGA) approval in Australia in June 2011, and FDA PMA approval in May 2015. The Senza 
System is similar to other commercially available SCS systems in design and function.     
The Senza System consists of a rechargeable implantable pulse generator (IPG) with 16 output 
channels. The IPG is implanted in a subcutaneous pocket and is capable of stimulating the spinal 
cord nerves when used with one or two 8-contact percutaneous leads. The IPG is controlled by 
a Patient Remote and/or the Programmer.   
Other components of the system include an external Trial Stimulator capable of delivering the 
same stimulation as the IPG, Lead, Extensions, Charger and charging system, operating room 
(OR) cables and surgical accessories. 
D.1.2. Device System Details  
D.1.2.1. 
Major Components 
Implantable Pulse Generator (Figure 2): The Implantable Pulse Generator (IPG) is a 
rechargeable implantable device with 16 output channels. Each of the 16 outputs can be 
programmed as a cathode or an anode. The IPG is powered by a nominal Li-Ion 
rechargeable battery (single cell). It is capable of stimulating the spinal cord nerves through 
the electrodes of the leads connected to any combination of the output terminals, using a 
single current source. The IPG is designed to produce a charge-balanced, biphasic 
capacitively-coupled rectangular output pulse. The IPG is current-regulated and capable of 
delivering an output energy level between 0-15 µC/per phase. This is equivalent to the 
commercially available SCS devices. 
The hermetic IPG enclosure is made of Titanium Grade 1 or 2, with the dimensions of 54.5 
mm (height without header, with header 72.5 mm), 47.5 mm (width) and 11.5 mm 
(thickness). The epoxy header contains the charging coil, feed thru, RF antenna, and two 
ports to allow the insertion of two 8-contact leads. The battery housing is hermetically sealed 
and fits inside the hermetic IPG enclosure. Currently FDA-approved IPG models, including 
Senza® and Senza II®, as well as future FDA-approved IPG models with similar capabilities 
may be incorporated into this clinical study. 

 
 
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Figure 2. Implantable Pulse Generator 
 
 
 
 
IPG/Trial Stimulator interface with other Senza components (Figure 3): A bi-
directional communication link exists between the IPG and the Charger.  Similar to other 
commercial SCS systems, the Charger uses transcutaneous RF energy transmission in order 
to recharge the IPG battery. Energy is transmitted from the Charger to the IPG using a 
frequency between 410 kHz and 485 kHz. The IPG is capable of communicating with the 
Charger to control the recharging function.   
The IPG/Trial Stimulator uses the MedRadio band frequency between 402 MHz and 405 
MHz (RF) in order to communicate with the Patient Remote or Programmer (a personal 
computer, PC) via the Programmer Wand. The Programmer Wand is used to program the 
IPG/Trial Stimulator and retrieves diagnostic information from either the IPG/Trial 
Stimulator. The RF antenna is located in the header of the IPG.  
The subject is also able to send commands to the IPG/Trial Stimulator directly using the 
Patient Remote. The wireless telemetry technology in the Senza System allows 
communication between the IPG/Trial Stimulator and Patient Remote of greater than 2 feet. 
The IPG also includes a magnetic switch for turning the therapy off by using an external 
magnet.   
 
 

 
 
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Figure 3. Graphical Representation of the Senza System  
 
 
 
Trial Stimulator (Figure 4): The Trial Stimulator is a handheld device powered by 2 
lithium 3.6V AA batteries and is capable of providing the same stimulation as the IPG. 
During the Trial Phase of SCS, the subject wears this external Trial Stimulator for a period 
of time to evaluate the effectiveness of the stimulation prior to receiving a permanent 
implant. The Trial Stimulator is connected to the subject’s implanted leads by the use of OR 
cables. 

 
 
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Figure 4. Trial Stimulator 
 
Patient Remote (Figure 5): The Patient Remote is a handheld battery operated unit able to 
communicate via RF with the IPG/Trial Stimulator. It is used by the subject to select the 
stimulation program to be applied, to activate and deactivate the IPG/Trial Stimulator and 
change stimulation amplitude.   
 
 
Figure 5. Patient Remote  
 
Charger (Figure 6): This Charger is used by the subject to transcutaneously charge the IPG 
battery. It is a portable device powered by a rechargeable battery and can be held in one 
hand.  
 
 
Figure 6. Charger 
 

 
 
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Programmer: The Programmer is an off-the-shelf laptop installed with proprietary Nevro 
software to allow the programming of the IPG/Trial Stimulator and Patient Remote via the 
Programmer Wand. 
 
Programmer Wand (Figure 7): The Programmer Wand is the Programmer interface that 
allows the communication with an IPG or Trial Stimulator. The Programmer Wand connects 
to the Programmer laptop through a USB port and communicates via RF with the IPG or 
Trial Stimulator. 
 
Figure 7. Programmer Wand 
 
 
Percutaneous Leads (Figure 8) and Lead Extensions (Figure 9): Similar to available 
commercial SCS systems, the Nevro Lead is intended to be used with the IPG or Trial 
Stimulator for use in delivering stimulation in the spinal cord. The Percutaneous Lead is 
intended to be single use and interfaces with the IPG, Lead Extensions, OR Cable, and lead 
accessories. 
The Percutaneous Lead has an isodiametric body made out of Pellathane 55D, which carries 
eight low impedance cables that conduct signals from the contact rings on the proximal end 
of the lead to the distal electrodes. The proximal connector end has eight (8) individual 
contacts which interface with the Nevro IPG and Lead Extensions. The Lead proximal end 
also has an electrically isolated retention ring to reversibly anchor the Lead in the IPG or 
Lead Extension using a set screw. 
 

 
 
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Figure 8. Percutaneous Lead 
 
The Lead Extension is intended to be used when the implant site for the IPG is located too 
far from the stimulation site to directly connect to the Percutaneous Lead. The design, 
material and construction methods on the proximal end and lead body of the Lead Extension 
are identical to the Percutaneous Lead. The distal end of the Lead Extension is designed to 
accept the proximal end of the Percutaneous Lead. The Lead Extension is the same size and 
diameter as the Percutaneous Lead except at the distal end where the Extension has a larger 
diameter to accept the proximal portion of the Percutaneous Lead.  
The construction of the Lead Extension is identical along its length to the Percutaneous 
Lead.  
 
 
Figure 9. Lead Extension 
 
D.1.2.2. 
Surgical Accessories 
Torque Wrench: The Torque Wrench is used to tighten the set screws that lock the 
Percutaneous Lead into the IPG or to lock the Percutaneous Lead into a Lead Extension.   
Lead anchors: The Lead Anchors are used to anchor the Percutaneous Lead to the fascia 
or supraspinous ligament. Lead Anchors are designed to slide freely over the lead length to 

 
 
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the required fixation position and sutures are then tied around the anchor clamping the 
sleeve in place on the lead. Lead anchors may be used to possibly prevent lead migration 
and/or lead strain. 
Insertion Needle: The Insertion Needle is used during implant surgery to introduce the 
Percutaneous Lead between the vertebrae into the epidural space. The Insertion Needle is a 
two part needle that contains a cannula and Stylet to facilitate access to the spinal canal for 
lead placement. This Insertion Needle is a 14GA epidural needle with thin wall and a Touhy 
non-coring tip. The Stylet and cannula are designed to lock together to maintain the 
orientation of the tip of each component, and the hub has a standard luer fitting. 
Coiled Lead Blank: The Coiled Lead Blank made out of stainless steel is optionally used 
during surgery to clear a path for the introduction of the Percutaneous Lead into the epidural 
space. The Lead Blank has an outer diameter similar in size to the Lead and is designed to 
be flexible. 
Stylets: The Stylets are used to push and “steer” the Lead into place. There are two different 
configurations of the Stylet's distal end, “straight” and “curved”. These are standard 
commercial configurations offering the implanter the flexibility to choose the configuration 
to best maneuver the Leads through the epidural space to the desired implant location. 
IPG Port Plug: The IPG Port Plug is provided to seal the port of the IPG that is not in use 
when only one Lead is implanted. 
OR Cables: The OR Cables with extension and connector are used during the Percutaneous 
Lead implant procedure and subject Trial Phase to make electrical and mechanical 
connections between the Trial Stimulator and the Percutaneous Leads or Lead Extensions. 
Tunneling Tool: The Tunneling Tool creates a subcutaneous tunnel for the leads from the 
IPG site to the midline incision. This single use tool is provided with two versions of 
tunneling tips; one (1) trocar tip and one (1) blunt tip.   
IPG Template: The IPG Template acts as an aid for the physician in proper sizing of the 
pocket for the IPG within each subject. 
D.2. Principle of Operation of the Device 
The Senza System works on the same basic principle as commercially marketed spinal 
cord/electrical stimulators/IPGs and epidural electrodes. Spinal cord stimulation has been used for 
decades and studied extensively.  
Manufacturing and quality testing is performed to verify the proper functionality of the Senza 
System prior to device shipment. Additional testing is performed at the clinical site to verify Senza 
System function prior to implantation - refer to the Senza Physician's Implant Manual. 
D.3.  Description of Conventional Medical Management (CMM) 
CMM may include a variety of non-invasive or minimally invasive treatments that comprise the 
standard of care for neuropathic limb pain. Investigators will follow their standard of care and/or 
published clinical guidelines (Dworkin, 2010) to administer CMM to both treatment groups. 
Treatments include, but are not limited to, pharmacological agents, physical therapy, cognitive 
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D.4. Labeling, Supply and Storage of Device 
Instructions for Use:  The Senza System will be used in accordance to the Physician Implant 
Manual.  
Labeling:  For this study, the Senza System labeling will be consistent with the FDA-approved 
labeling for commercial distribution in the U.S. 
 
The clinical sites will be responsible for safely storing components of the Senza System. All study 
supplies will be maintained in a locked, limited access area and stored at room temperature. 
D.5. Any Anticipated Changes in the Device 
For any changes to the device, Nevro will comply with the regulations for modifications to a PMA-
approved device. 
D.6. Device Accountability 
Investigators or designees are responsible for maintaining accurate accountability records of the 
study products throughout the clinical study. Device accountability will be recorded on a Device 
Billing and Registration Form.  

 
 
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E. Administrative Procedures 
E.1. Monitoring  
E.1.1. Study Monitor 
The Clinical Monitor(s) assigned to the study will fulfill the required Sponsor and monitor 
responsibilities. He/she will be responsible for monitoring subject eCRF data, reviewing the 
regulatory documentation, ensuring that the investigational plan has been approved by the IRB 
and assuring compliance with this investigational plan.    
E.1.2. Monitoring Procedures 
Monitoring visits to the clinical sites will be made periodically for the purpose of ensuring that 
Investigators and their staff understand and accept their defined responsibilities, assessing 
compliance with current Good Clinical Practices (GCP) guidelines, evaluating clinical trial 
progress, assessing the continued acceptability of the clinical site facilities, assessing 
compliance with this investigational plan, and verifying the data recorded on the eCRFs.  
eCRFs, designed by Nevro, will be used for the collection and recording of data at the clinical 
site. Investigators will be responsible for the timely completion of these forms to Nevro.   
• Investigators are to maintain all source documents as required by the investigational 
plan, including laboratory results, supporting medical records, informed consents and 
applicable electronic files. The source documents will be used at the regular monitoring 
visits to verify information submitted on the eCRFs. Clinical monitoring will include 
review and resolution of missing or inconsistent results to assure the accuracy of the 
reported data. Where any discrepancies are noted, they will be resolved with the 
Investigator and/or an individual designated by the Investigator. Where the data are 
incomplete, attempts will be made to obtain the missing data. The source documents 
will remain at the clinical sites.   
Subject safety will be ensured by noting that the consent was properly documented, the 
investigational plan was followed, and that adverse events were reported and followed-up as 
appropriate. 
The Clinical Monitor will evaluate and summarize the results of each clinical site visit in written 
reports, identifying any repeated data problems with any Investigator and specifying 
recommendations for resolution of noted deficiencies. 
The conduct and monitoring of the clinical investigation will be conducted in accordance with 
Nevro’s internal procedures (including the Monitoring Plan) as required by the regulations.   
   
E.2. Data Quality Assurance 
The eCRF data will be entered into an EDC (M-Core, Medrio Inc.) at the sites. The data will be 
reviewed to identify inconsistent or missing data and potential adverse events. Data discrepancies 
will be addressed by written communication or by telephone with the clinical site and/or during 
clinical site monitoring visits. The data management department at Nevro will ensure that all hard 
copy forms and data files are secured in order to maintain confidentiality. 

 
 
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E.3. Study Conduct 
The Investigator agrees that the study will be conducted according to this investigation plan and the 
ICH guidelines on GCP and principles of cGCPs as outlined in the United States Code of Federal 
Regulations (CFR) - 21 CFR Parts 50, 56, and 812, the Declaration of Helsinki (version 2013) and 
other applicable regulatory requirements. The Investigator will conduct all aspects of the study in 
accordance with all Federal and local laws of pertinent regulatory authorities. All clinical data will 
be recorded promptly, accurately, legibly, directly and indelibly manually on appropriate 
sheets/forms or eCRFs. 
The Investigator will assure correct implementation and conduct of the trial including those study 
related duties delegated to other appropriately qualified individuals and designated in the delegation 
of authority documentation. The Investigator will assure that study staff cooperates with monitoring 
and audits, and will demonstrate due diligence in recruiting, screening, and retaining study subjects. 
All clinical study findings and documents will be regarded as confidential. Investigators and 
designees will not disclose such information without prior written approval from the sponsor as 
spelled out in the clinical trial agreement (CTA).  
Subjects may be reimbursed for their participation in this study as referenced in the informed 
consent form (ICF). 
E.4. Informed Consent Materials 
Written informed consent must be obtained from all subjects prior to study participation. Consent 
will be obtained by the Investigator or an Investigator-designated healthcare professional. The 
original signed consent, as approved by the respective clinical site Institutional Review Board 
(IRB), will be retained in the subject's study records at the clinical site. The informed consent is in 
compliance with the requirements set forth in 21 CFR 50, Protection of Human Subjects. 
Subjects may be reimbursed for their participation in this study as referenced in the informed 
consent form (ICF). 
E.5. IRB Information 
IRB approval is required prior to initiation of the study at the clinical site.  Approval will be obtained 
by the clinical Investigator who will submit the investigational plan and supportive information for 
IRB review and approval. 
E.6. Investigators and Institutions 
This is a multicenter study. The clinical Investigators participating in this study will be chosen 
based on their qualifications and experience. All sites will obtain IRB approval prior to enrolling 
subjects in the study. 
E.7. Amendments and Deviations 
The investigational plan is to be followed by Investigators and all personnel involved in the clinical 
study. Changes to the study covered by this investigational plan must be documented on a formal 
investigational plan amendment prior to implementation in the study. Amendments to the 
investigational plan may be initiated by Nevro or at the request of the Investigator. A formal 

 
 
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amendment cannot be initiated by an Investigator or clinical site personnel without Nevro’s 
approval or IRB approval (if applicable), and Investigator approval. 
• Exception for Emergency Deviation: The exception to the policy noted above is an 
emergency deviation to the investigational plan which may be initiated by the 
Investigator without prior approval from Nevro only in cases where a change is 
necessary to eliminate immediate apparent hazard to subjects. Emergency deviations 
must be reported to Nevro and the IRB no later than 24 hours following the emergency. 
Deviations from the investigational plan and study requirements (including cGCP guidelines) will 
be reviewed by Nevro and evaluated on an ongoing basis and appropriate corrective actions will be 
implemented as necessary. 
E.8. Additional Record and Reports 
Sponsor/Investigator Records and Reports will be maintained and provided in accordance to 21 
CFR 312.50-312.68, 812.140 and 812.150. No additional records or reports will be maintained. 
 
 
 

 
 
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