Clinical trial NCT03761277
Conditions: Chronic Non-malignant Pain Chronic Pain Pain, Back Pain, Leg
Keywords: Pain Intrathecal Targeted Drug Delivery (TDD) Non-Malignant Pain Systemic Opioids Opioid Weaning Pain Pump Drug Pump Medtronic Pump
Sponsor: MedtronicNeuro
Start date: 2019-01-16; Completion date: 2021-12-06
Enrollment: 93 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective, multi-center, post market study to evaluate Intrathecal (IT) preservative-free morphine sulfate (PFMS) using the SynchroMed™ II infusion system as an alternative to systemic opioids for the treatment of chronic, intractable, non-malignant primary back pain with or without leg pain.

Detailed description:
Subjects will be assessed for pain control and opioid-related side effects following a route of delivery change from systemic opioids to IT morphine therapy.

Arms: arm 1: Enrolled subjects who successfully wean from all systemic opioids and have a successful intrathecal trial, proceed to the intervention phase. This includes implantation with a SynchroMed™ II infusion system in the intrathecal space for targeted drug delivery of preservative-free morphine sulfate (PFMS).
Interventions: intervention 1: Medtronic SynchroMed™ II infusion system intervention 2: Preservative-free morphine sulfate (PFMS)
Intervention descriptions: intervention 1: Implanted infusion system consisting of a pump and catheter, as well as external components of a clinician programmer, refill and catheter access port kits, and the Personal Therapy Manager (myPTM™). intervention 2: The pharmacological agent used in the pump for this study is limited to a preservative-free morphine sulfate (PFMS).

Protocol documents:
Prot_000.pdf: 
Official Title of Study : Embrace TDD: Prospective, Multi-Center, Post-Market Study to 
Evaluate Intrathecal (IT) Morphine as an Alternative to Systemic Opioids for the Treatment of 
Chronic, Intractable, Non-Malignant Primary Back Pain with or without Leg Pain 
NCT Number: NCT03761277
Date of Document: 26APR2021
Document Type: Study Protocol


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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title Embrace TDD: Prospective, Multi-Center, Post-
Market Study to Evaluate Intrathecal (IT) 
Morphine as an Alternative to Systemic Opioids 
for the Treatment of Chronic, Intractable, Non-
Malignant Primary Back Pain with or without Leg 
Pain 
Clinical Investigation Plan Identifier MDT18026 
Study Product Name Medtronic SynchroMed™ II infusion system and 
preservative-free morphine sulfate, USP (PFMS) 
and preservative free 0.9% Sodium Chloride 
Injections, USP (for dilution) 
Sponsor/Local Sponsor Medtronic Neuromodulation 
7000 Central Avenue NE 
Minneapolis, MN 55432 
USA 
1-763-514-4000
Document Version 3.0 
Version Date 26-Apr-2021
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of 
Medtronic. Any distribution, copying, or disclosure without the prior written authorization of 
Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that it is 
confidential and that it may not be further disclosed by them. 


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1.
Investigator Statement
Participating investigators will be provided with a separate investigator agreement to document their 
obligations and commitment with respect to study conduct. 


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Table of Contents 
1.
Investigator Statement .................................................................................................... 2 
Table of Contents .................................................................................................................... 3 
2.
Glossary ........................................................................................................................... 7 
3.
Synopsis ........................................................................................................................... 9 
4.
Introduction ................................................................................................................... 14 
4.1 Background .................................................................................................................... 14 
4.1.1 
Preclinical Data ............................................................................................................. 15 
4.1.2 
Clinical Data .................................................................................................................. 15 
4.2 Purpose ......................................................................................................................... 16 
4.3 Regulatory Study Classification .......................................................................................... 17 
5.
Objectives and/or Endpoints .......................................................................................... 17 
5.1 Objectives ...................................................................................................................... 17 
5.1.1 
Primary Objective.......................................................................................................... 17 
5.1.2 
Secondary Objectives .................................................................................................... 18 
5.1.4 
Safety Assessment ........................................................................................................ 19 
6.
Study Design .................................................................................................................. 19 
6.1 Duration......................................................................................................................... 22 
6.2 Rationale........................................................................................................................ 22 
7.
Product Description ........................................................................................................ 23 
7.1 General .......................................................................................................................... 23 
7.2 Dosage Form and Route of Administration .......................................................................... 24 
7.3 Manufacturer .................................................................................................................. 24 
7.4 Packaging ...................................................................................................................... 24 
7.5 Intended Population ........................................................................................................ 24 
7.6 Product Use .................................................................................................................... 25 
7.7 Product Training Materials ................................................................................................ 25 
7.8 Product Receipt and Tracking ............................................................................................ 25 
7.9 Product Storage .............................................................................................................. 25 
7.10 Product Return................................................................................................................ 25 


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7.11 Product Accountability ...................................................................................................... 26 
8.
Study Site Requirements ................................................................................................ 26 
8.1 Investigator/Investigation Site Selection ............................................................................. 26 
8.2 Study Site Activation ........................................................................................................ 27 
9.
Selection of Subjects ...................................................................................................... 27 
9.1 Study Population ............................................................................................................. 27 
9.2 Subject Enrollment .......................................................................................................... 28 
9.3 Inclusion Criteria ............................................................................................................. 28 
9.4 Exclusion Criteria ............................................................................................................. 28 
10.
Study Procedures ........................................................................................................ 29 
10.1 Summary of Visits ........................................................................................................... 29 
10.2 Baseline Visit .................................................................................................................. 30 
10.3 Intrathecal Trial Visit........................................................................................................ 31 
10.4 Implant Visit ................................................................................................................... 32 
10.5 Post-Op Visit ................................................................................................................... 33 
10.6 IT Therapy Initiation ........................................................................................................ 33 
10.7 1-, 3-, and 6-Month Visits ................................................................................................. 34 
10.8 Unscheduled Visits........................................................................................................... 35 
10.9 System Modifications ....................................................................................................... 36 
10.10 
Study Exit................................................................................................................ 36 
10.11 
Schedule of Events ................................................................................................... 37 
10.12 
Pump Refills............................................................................................................. 38 
10.13 
IT PFMS Administration and Dosing ............................................................................ 38 
10.14 
Prior and Concomitant Medications ............................................................................. 39 
10.15 
Subject Consent ....................................................................................................... 39 
10.16 
Medication Compliance .............................................................................................. 41 
10.17 
Assessment of Efficacy .............................................................................................. 41 
10.17.1 
Visual Analog Scale (VAS) .............................................................................................. 41 
10.17.2 
Numerical Opioid Side Effect Assessment Tool (NOSE) ................................................. 41 
 
 
 
 
 
 


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10.18 
Assessment of Safety ................................................................................................ 43 
10.19 
Recording Data ........................................................................................................ 44 
10.20 
Deviation Handling ................................................................................................... 44 
10.21 
Subject Withdrawal or Discontinuation ........................................................................ 46 
11.
Risks and Benefits ...................................................................................................... 47 
11.1 Potential Risks ................................................................................................................ 47 
11.2 Pregnancy Risks .............................................................................................................. 49 
11.3 Risk Minimization (Control Measures) ................................................................................. 49 
11.4 Potential Benefits ............................................................................................................ 50 
11.5 Risk-Benefit Rationale ...................................................................................................... 50 
12.
Adverse Events and Device Deficiencies ..................................................................... 50 
12.1 Definitions / Classifications ............................................................................................... 50 
12.2 Reporting of Adverse Events ............................................................................................. 52 
12.3 Non-Reportable Events..................................................................................................... 53 
12.4 Reporting of Device Deficiencies ........................................................................................ 53 
12.5 Emergency Contact Details ............................................................................................... 53 
12.6 Subject Death ................................................................................................................. 53 
13.
Data Review Committees............................................................................................ 54 
14.
Statistical Design and Methods................................................................................... 54 
14.1 General Aspects of Analysis .............................................................................................. 54 
14.1.1 
Sample Size Justification ............................................................................................... 55 
14.1.2 
Investigation Site Pooling .............................................................................................. 56 
14.1.3 
Other Specific Considerations ....................................................................................... 56 
14.1.4 
Reports ......................................................................................................................... 57 
14.2 Demographics ................................................................................................................. 57 
14.3 Primary Objective – Clinical Success at the 6-Month Visit ...................................................... 57 
14.4 Secondary Objectives ....................................................................................................... 59 
14.4.1 
Secondary Objective #1 – VAS Pain Intensity at the 6-Month Visit ............................... 59 
14.4.2 
Secondary Objective #2 – NOSE Score .......................................................................... 60 


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14.4.3 
Secondary Objective #3 – Systemic Opioids Elimination ............................................... 61 
14.6 Safety Assessment .......................................................................................................... 62 
15.
Ethics .......................................................................................................................... 62 
15.1 Statement(s) of Compliance .............................................................................................. 62 
16.
Study Administration .................................................................................................. 63 
16.1 Monitoring ...................................................................................................................... 63 
16.2 Medtronic Representative Role .......................................................................................... 64 
16.3 Data Management ........................................................................................................... 65 
16.4 Direct Access to Source Data/Documents............................................................................ 66 
16.5 Confidentiality ................................................................................................................. 66 
16.6 Liability .......................................................................................................................... 67 
16.7 CIP Amendments ............................................................................................................ 67 
16.8 Record Retention ............................................................................................................ 67 
16.8.1 
Investigator Records ..................................................................................................... 67 
16.8.2 
Investigator Reports ...................................................................................................... 68 
16.9 Publication and Use of Information .................................................................................... 68 
16.9.1 
Publication Committee ................................................................................................. 68 
16.9.2 
Authorship Selection ..................................................................................................... 69 
16.10 
Suspension or Early Termination ................................................................................. 69 
16.10.1 
Study-Wide Termination or Suspension ........................................................................ 69 
16.10.2 
Investigator/Center Termination or Suspension ........................................................... 69 
17.
References .................................................................................................................. 70
18.
Appendices ................................................................................................................. 71 
18.1 Appendix A: Additional Information for Sites ....................................................................... 71 
18.2 Appendix B: Institutional Review Boards ............................................................................. 71 
18.3 Appendix C: Participating Principal Investigators and Institutions ........................................... 72 
19.
Version History ........................................................................................................... 74 


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2. 
Glossary 
Acronym 
Definition 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
BL 
Baseline Visit 
 
 
CEC 
Clinical Event Committee 
CFR 
Code of Federal Regulation 
CIP 
Clinical Investigation Plan (“Protocol”) 
CMM 
Conventional Medical Management 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSF 
Cerebral Spinal Fluid 
DD 
Device Deficiency 
eCRF 
Electronic Case Report Form 
 
 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability 
Act 
IC / ICF 
Informed Consent / Informed Consent Form 
ICH-E6 
International Conference of Harmonization (ICH) 
Guideline for Good Clinical Practice (ICH-E6) 
ICMJE 
International Committee of Medical Journal 
Editors 
IFP 
Information for Prescribers 
IRB 
Institutional Review Board 


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Acronym 
Definition 
ISO 
International Organization for Standardization 
IT 
Intrathecal 
LTFU 
Lost-To-Follow-Up 
MAT 
Medication Assisted Treatment 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MME 
Morphine Milligram Equivalents 
NDA 
New Drug Application 
NOSE 
Numerical Opioid Side Effect Assessment Tool 
NPU 
Neuro Programmer Upload 
 
 
PACC 
Polyanalgesic Consensus Conference 
PFMS 
Preservative-Free Morphine Sulfate 
 
 
PI 
Principal Investigator 
PMA 
Pre-Market Application 
RCT 
Randomized Controlled Trial 
RDC 
Remote Data Capture 
RPA 
Returned Product Analysis 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SUD 
Substance Use Disorder 


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Acronym 
Definition 
TDD 
Targeted Drug Delivery 
US 
United States [of America] 
USP 
Unites States Pharmacopoeia 
VAS 
Visual Analog Scale 
 
3. 
Synopsis 
Title 
Embrace TDD: Prospective, Multi-Center, Post Market Study to 
Evaluate Intrathecal (IT) Morphine as an Alternative Systemic Opioids 
for the Treatment of Chronic, Intractable, Non-Malignant Primary 
Back Pain with or without Leg Pain 
Clinical Study Type 
Post-Market Interventional 
Product Name 
Medtronic SynchroMed™ II infusion system: 
The Medtronic SynchroMed II infusion system consists of an 
implanted infusion pump and catheter, and external components, a 
clinician programmer, refill and catheter access port kits, the Personal 
Therapy Manager® (myPTM™). SynchroMed II infusion system 
components that become commercially available after the 
commencement of this study may also be used in addition to, or in 
lieu of, the currently available components. 
The pharmacological agent used in the study is limited to 
preservative-free morphine sulfate, USP (PFMS) and preservative free 
0.9% Sodium Chloride Injections, USP (for dilution). 
Sponsor  
Medtronic Neuromodulation 
7000 Central Avenue NE 
Minneapolis, MN 55432 
USA 
1-763-514-4000 
Indication Under 
Investigation  
Use of Intrathecal Drug Delivery System (IDDS) to manage subjects 
with chronic, intractable, non-malignant primary back pain with or 
without leg pain. 
Investigation Purpose 
To assess pain control and opioid-related side effects following a 
route of delivery change from systemic opioid therapy to IT morphine 
therapy. 


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Product Status 
All Medtronic products used in this study are commercially available 
in the United States and will be used within the specifications of 
product labeling.  
The pharmacological agent used in the study is limited PFMS and 
preservative free 0.9% Sodium Chloride Injections, USP (for dilution). 
None of the Medtronic products used in this study are investigational. 
Primary Objective 
To characterize the proportion of subjects with Clinical Success at the 
6-Month Visit based on changes in pain intensity using the Visual 
Analog Scale (VAS) and changes in opioid-related side effects using 
the Numerical Opioid Side Effect (NOSE) Assessment Tool. 
Clinical Success is defined as any of the following (refer to grid below 
with matching numbers): 
1) Reduced opioid-related side effects with equal pain 
2) Reduced pain with equal opioid-related side effects 
3) Reduced pain and reduced opioid-related side effects 
 
Criteria for Clinical Success 
Change  
from Baseline  
to the 6-Month Visit  
Opioid-Related Side Effects 
(NOSE) 
≥20% 
Increase 
< ±20% 
Change 
≥20% 
Reduction 
Worse 
Equal 
Better 
Pain Intensity (VAS) 
≥20% 
Increase 
Worse 
  
  
  
< ±20% 
Change 
Equal 
  
  
1  
≥20% 
Reduction 
Better 
  
 2 
 3 
Secondary Objectives 
1. To demonstrate pain intensity scores (VAS) at the 6-Month Visit is 
non-inferior to VAS at Baseline 
2. To characterize the change in opioid-related side effect scores 
(NOSE) from Baseline to the 6-Month Visit 
3. To characterize the proportion of subjects who eliminate systemic 
opioids through the 6-Month Visit 


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Safety Assessments 
To characterize all systemic opioid weaning-related, device-related, IT 
drug-related, and procedure-related adverse events (AEs), all serious 
adverse events (SAEs) (regardless of relatedness), and device 
deficiencies (DD) for all subjects from enrollment until the subject 
exits. 
Study Design 
The Embrace TDD study is a prospective, multi-center, post-market 
study. Subjects with chronic, intractable non-malignant primary back 
pain with or without leg pain will be enrolled in the study and will be 
required to attend a minimum of 7 in-office visits which include: 
Baseline, Intrathecal Trial, Implant, Post-Op, 1-Month, 3-Month, and 
6-Month. Participation in the study can last up to 18 months for a 
subject depending on weaning duration and follow-up requirements 
in place prior to CIP V3.0 implementation. 
Sample Size 
93 subjects have been enrolled into the study with the intent to 
achieve approximately 67 implanted subjects and 50 evaluable 
subjects at the 6-Month Visit. The sample size of 50 evaluable 
subjects was chosen to assure acceptable levels of precision for 
estimation of the primary objective of Clinical Success and provide 
adequate power to test the secondary objective related to pain score. 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
A potential subject may be included for participation in the study if 
the subject has/is: 
1. Willing and able to provide a signed and dated (Medtronic and 
Institutional Review Board (IRB) approved) Informed Consent 
Form (ICF) and Health Insurance Portability and Accountability Act 


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(HIPAA) Authorization Form prior to any study procedures being 
performed 
2. A candidate per labeling for the IDDS 
3. A diagnosis of chronic, intractable non-malignant, primary back 
pain with or without leg, pain treatable with the IDDS 
4. Current daily systemic opioid dose of > 0 and ≤ 120 Morphine 
Milligram Equivalents (MME) 
5. A Visual Analogue Scale (VAS) of ≥50 mm for pain intensity at the 
Baseline Visit and/or a Numerical Opioid Side Effect (NOSE) 
Assessment Tool ≥40 for intolerable side effects at the Baseline 
Visit 
6. Psychological evaluation or investigator assessment of patient 
psychological suitability for study participation  
7. Has an MRI or CT prior to enrollment verifying patent spinal canal 
and no clinical change in status since last imaging 
8. At least 18 years old at time of enrollment 
9. Willing and able to attend visits and comply with the study 
protocol 
10. Male or non-pregnant, non-lactating female. Females must be 
post-menopausal or surgically sterile; or be utilizing a medically 
acceptable form of birth control (i.e. a hormonal contraceptive, 
intra-uterine device, diaphragm with spermicide, or condom with 
spermicide) for the duration of the study 
 
Exclusion Criteria 
A potential subject will be excluded from participating in the study if 
the subject has/is: 
1. Previously trialed or implanted with an IDDS 
2. Concomitant stimulation device implanted for the treatment of 
pain 
3. Any ongoing health condition that would be expected to interfere 
with pain and/or quality of life ratings (i.e. active malignancy, 
other painful conditions not treatable with IT therapy, etc.) 
4. Psychological or other health conditions, financial and/or legal 
concerns that would interfere with the subject’s ability to fulfill 
the requirements of the protocol as per the investigator’s 
discretion 
5. Substance Use Disorder (SUD) within the last 2 years or current 
Medication Assisted Treatment (MAT) for substance use disorder 
6. Currently using cannabinoids or illicit drugs 
7. History of allergy or significant adverse reaction to morphine per 
investigator discretion 
8. Currently participating or plans to participate in another 
investigational study unless written approval is provided by 
Medtronic Study Team 


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Study Procedures and 
Assessments 
Subjects will be considered enrolled at the time they sign the 
informed consent. Subjects will then be required to wean off all 
systemic opioid medications within 5 months (with a minimum of a 7-
day opioid holiday) prior to initiation of IT therapy.  
Scheduled Visits will include the following: Baseline, IT Trial, Implant, 
Post-Op, 1-Month, 3-Month, and 6-Month. 
The following assessments / data will be collected during the study: 
a. IT PFMS Dose 
b. VAS for pain intensity 
c. NOSE for opioid-related side effects  
 
 
 
 
 
 
 
 
j. 
Pain Medications 
k. Adverse Events (AE) 
l. 
Device Deficiencies (DD) 
 Statistics 
For the primary objective of Clinical Success, the proportion of 
subjects with Clinical Success at the 6-Month Visit and its two-sided 
exact binomial 95% confidence interval (CI) will be reported.  
 
For the secondary objective of pain intensity score, a non-inferiority t-
test will be applied; if non-inferiority is met, a superiority t-test will be 
followed. The pain scores at both the Baseline and 6-Month Visits as 
well as the change from Baseline to the 6-Month Visit will be 
reported.   
 
For the secondary objective of NOSE score, descriptive statistics 
(mean and standard deviation, etc.) will be used to report the NOSE 
score at Baseline and the 6-Month Visits, as well as the change from 
Baseline to the 6-Month Visit.  
 
For the secondary objective of proportion of subjects who eliminate 
systemic opioids, the proportion and its exact binomial two-sided 95% 
CI will be reported.  
 
 
  
 
Adverse events and device deficiencies will be summarized using 
summary tables displaying the frequency, percentage, relatedness 
and seriousness. 


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4. 
Introduction 
4.1 Background 
Though morphine use has a documented history going back centuries, intrathecal (IT) use was first 
reported in 1979 as a treatment for cancer pain.1 Anecdotal reports and publications of single-patient or 
small cohort usage increased the use of IT morphine as a treatment for both malignant and non-
malignant pain over the next few years. A 1981 publication reported the first use of an implanted pump, 
the fixed-rate Infusaid Model 400, for chronic infusion of morphine as a treatment for pain. 2 Continued 
use, the recognized need, and pressure from patient advocacy groups prompted the Food and Drug 
Administration (FDA) to publish a request to industry for applications seeking approval for an effective 
treatment for cancer pain. In July 1991, Hikma Maple received New Drug Application (NDA) (N018565) 
approval for Infumorph (10 mg/mL and 25 mg/mL preservative-free morphine sulfate).  
In March 1988, Medtronic, Inc. obtained Pre-Market Application (PMA) (P860004) approval for 
SynchroMed for the delivery of chemotherapeutic agents (intravascular floxuridine [FUDR], doxorubicin 
hydrochloride (Adriamycin), bacteriostatic water, physiological saline and/or heparin). In July 1991, PMA 
supplement P860004/S001, originally filed in August 1987, was approved expanding the SynchroMed 
indication to include IT administration of preservative-free morphine sulfate (PFMS) for the treatment of 
chronic intractable pain of malignant origin. In October 1991, the SynchroMed indication was expanded 
to include chronic intractable pain of non-malignant origin as well. Since the time of these original 
approvals, evidence-based medicine has emerged as a discipline for evaluating safety and efficacy, 
creating the need for a high level of evidence to ensure coverage and use. Since approval, the 
management of IT opioids has evolved and best practices for managing patients with chronic pain have 
been developed. IT drug delivery was originally developed to be a more efficient and efficacious method 
of delivering medication directly to the site of action, reducing the amount of drug needed. This idea 
suggests that targeted drug delivery (TDD) is more effective (e.g., smaller doses, equianalgesia, reduced 
side effects) than systemic drug administration of opioids in the treatment of chronic non-malignant 
pain. 
Clinical evidence comparing systemic opioid administration to intrathecal administration has been 
collected in small scale studies and in a single larger randomized controlled trial (RCT) for malignant 
pain. 3 Given the current opioid epidemic and ongoing pain management crisis, it’s more important than 
ever for patients suffering from chronic pain to have access to proven alternatives. Clinical evidence 
specific to non-malignant pain and IT morphine sulfate is needed. This study is intended to augment 
existing medical evidence specific to the approved indication of treatment for chronic intractable pain of 
non-malignant origin. Current guidelines regarding patient selection, trialing, implant, and dosing for 
this therapy will be followed, allowing for selection and treatment of subjects in a manner similar to 
standard practice. TDD with IT morphine may provide an opportunity to reduce drug dosing 
requirements, minimize opioid side-effects, and provide equivalent or improved analgesia. 


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In addition to an assessment of pain relief, this study will evaluate changes with regard to commonly 
accepted side effects related to opioid use, including sleep disturbances, sedation, clouded thinking, 
constipation, and others. 
4.1.1 Preclinical Data 
IT morphine use in the treatment of malignant pain dates back to the late 1970’s, with chronic infusion 
being used since the early 1980’s. Laboratory studies (in vitro and in vivo) supported this initial clinical 
use of IT morphine and the greater than 30 years of use as a therapy for chronic pain subjects preclude 
the need for additional preclinical data supporting this therapy. One noted exception, however, is the 
dose/concentration-dependent development of catheter tip inflammatory mass formation with chronic 
IT delivery of morphine sulfate.5–7 Animal models have been developed and study results indicate the 
causal effect of IT morphine on inflammatory mass formation.7  Clinical experience supports these 
results and mitigation factors have been incorporated into clinical practice. Mitigation practices 
currently in place include the use of lower concentrations and doses of IT morphine to reduce the risk of 
inflammatory mass formation, and lower catheter tip placement in the spinal column to minimize 
clinical impact should an inflammatory mass develop. 
As this is a post-market study using only commercially available products, a separate Investigator 
Brochure is not required. The Technical Manuals will be provided separately. 
4.1.2 Clinical Data 
The use of SynchroMed along with IT morphine for the treatment of chronic, intractable pain has been 
reported in published scientific literature; however, the level of quality (based on guidelines from the 
Center for Evidence-Based Medicine in Oxford)a is limited.  
IT morphine has been used clinically since 1979 and SynchroMed has been approved for use in chronic 
non-malignant pain since 1991. Over these years of clinical use, numerous publications on safety, drug 
efficacy, and device effectiveness have been published. To date, however, only four Oxford Level 1 
manuscripts have been published supporting the use of the SynchroMed for the treatment of pain; 
three applicable to Prialt® (ziconotide) and one applicable to malignant pain (with morphine).3,9–11  
In 2002, results of the Medtronic-sponsored RCT comparing comprehensive medical management to 
implantable drug delivery for treatment of malignant-related pain were published.3  Prior to this study, 
all available data were from small, open-label, cohort studies. This study was able to demonstrate that 
TDD improved clinical success in pain control, reduced pain, significantly relieved common drug 
toxicities, with a trend toward improved survival in subjects with refractory malignant pain. In this study, 
 
a OCEBM Levels of Evidence Working Group*. "The Oxford 2011 Levels of Evidence". Oxford Centre for Evidence-Based 
Medicine. http://www.cebm.net/index.aspx?o=5653 


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IT drug use was limited to opioids (morphine or hydromorphone, as this was an international study) 
during the first 4 weeks only and then opened to other medications as necessary to treat pain. Endpoint 
assessments were completed at 4 weeks and showed improvement in pain visual analog scale (VAS) 
scores for both Comprehensive Medical Management (CMM) and the Implantable Drug Delivery System 
(IDDS) with a non-statistically significant greater improvement in the TDD group. Improvement in 
toxicity scores was statistically significantly greater in the TDD group. 
Results of 3 prospective 3-year follow-up studies of subjects treated with low-dose intrathecal opioids 
were published in 2012, 2015, and 2016.12,13,15 These studies demonstrated that conversion to IT 
opioids, discontinuation of systemic opioid use, and maintenance on low doses of IT opioids can 
effectively be used to treat chronic pain. In 2012, twelve experienced pain management practitioners 
met to identify and publish a paper discussing best practices in three areas related to safe IT therapy for 
pain: safety and monitoring, patient and device management, and patient selection and trialing, the 
results of which were published in 2014.20 They concluded that intrathecal drug delivery is a valuable 
alternative drug delivery system for many patients with severe chronic or end-of-life pain. They also 
noted that while device-related complications (mostly with catheters) and surgical-site infections can 
occur, the main therapy-related safety issues associated with IT drug delivery arise primarily with 
inadequate patient monitoring (e.g., respiratory depression), inflammatory mass (e.g., high doses and 
concentrations of opioids), wound healing, dosing errors (e.g., medication concentration and pump 
programming), pump fills or refills (e.g., pocket fills), and interaction with concomitant systemic 
medications (e.g., opioids and benzodiazepines). They stated that many of the reported adverse events 
and complications of IT drug delivery can be prevented by adequate clinician training, implementation 
of best practices, and experience. In adopting the therapy, patients must be apprised of its risks and 
benefits. Physicians and patients must partner to achieve both safety and effectiveness. 
In 2000 a Polyanalgesic Consensus Conference (PACC) was convened for the first time to review existing 
data specific to TDD and evaluate medical evidence gaps. The PACC convened most recently in 2014 to 
address IT therapy deficiencies and innovations that occurred since the previous PACC convened in 
2012. Three companion pieces were published in 2017 including best practices and guidelines, 
improving safety and mitigating risks, and intrathecal trialing.17–19 The PACC 2017 recommends the use 
of on-label drugs, including morphine, as first-line therapy, and indicates this placement remains 
supported by available clinical data. Clinical studies, however, are primarily retrospective or single-
center studies, underscoring the need for higher quality clinical data. The current study is intended to 
collect prospective multicenter medical evidence supporting the existing indication and medically 
accepted uses of IT morphine and SynchroMed II for chronic pain. 
4.2 Purpose 
The purpose of this study is to assess pain control and opioid-related side effects following a route of 
delivery change from systemic opioid therapy to IT morphine therapy. 


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4.3 Regulatory Study Classification 
This on-label, post-market clinical study will be using the SynchroMed II infusion system with  
preservative-free morphine sulfate, USP (PFMS) and preservative free 0.9% Sodium Chloride Injections, 
USP (for dilution).  The study will be conducted at approximately 15 sites in the United States and has 
enrolled 93 subjects with chronic, intractable primary back pain with or without leg pain.  The study will 
be conducted in accordance with this protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, all applicable regulatory requirements (21 Code of Federal Regulations [CFR] §50 
Protection of Human Subjects, 21CFR§54 Financial Disclosure by Clinical Investigators, and 21CFR§56 
Institutional Review Boards [IRB], 21CFR§803 Medical Device Reporting), and International Council for 
Harmonization (ICH GCP E6).  This study will be posted on ClinicalTrials.gov as part of Medtronic’s 
commitment to full disclosure for ongoing studies that meet the requirements for public posting. 
Documentation for this study will be produced and maintained to ensure that a complete history of the 
study exists. Documents created for this study, including all versions of original documents, will be 
identifiable and appropriately stored to assure control and traceability of data related to this study. 
5. 
Objectives and/or Endpoints 
5.1 Objectives 
5.1.1 Primary Objective 
To characterize the proportion of subjects with Clinical Success at the 6-Month Visit based on changes in 
pain intensity using the Visual Analog Scale (VAS) and changes in opioid-related side effects using the 
Numerical Opioid Side Effect (NOSE) Assessment Tool. 


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Clinical Success is defined as any of the following (refer to grid below with matching numbers): 
1) Reduced opioid-related side effects with equal pain 
2) Reduced pain with equal opioid-related side effects  
3) Reduced pain and reduced opioid-related side effects  
Criteria for Clinical Success 
Change  
from Baseline  
to the 6-Month Visit  
Opioid-Related Side Effects 
Score (NOSE) 
≥20% 
Increase 
< ±20% 
Change 
≥20% 
Reduction 
Worse 
Equal 
Better 
Pain Intensity (VAS) 
≥20% 
Increase 
Worse 
  
  
  
< ±20% 
Change 
Equal 
  
  
1  
≥20% 
Reduction 
Better 
  
 2 
 3 
5.1.2 Secondary Objectives 
1. To demonstrate pain intensity scores (VAS) at the 6-Month Visit is non-inferior to VAS at 
Baseline 
2. To characterize the change in opioid-related side effect scores (NOSE) from Baseline to the 6-
Month Visit  
3. To characterize the proportion of subjects who eliminate systemic opioids through the 6-Month 
Visit  
 
 
 
 
 
 


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5.1.4 Safety Assessment 
To characterize all systemic opioid weaning-related, device-related, IT drug-related, and procedure-
related adverse events (AEs), all serious adverse events (SAEs) (regardless of relatedness), and device 
deficiencies (DD) for all subjects from enrollment until the subject exits.  
6. 
Study Design 
This is a prospective, multi-center, post market study with commercially available products to evaluate 
the pain control and opioid-related side effects following a route of delivery change from systemic 
opioid therapy to IT morphine therapy in subjects with chronic, intractable, non-malignant primary back 
pain with or without leg pain. The study will be conducted at approximately 15 study sites in the United 
States. 
Patients that meet all inclusion criteria, do not meet any exclusion criteria, and provide written Informed 
Consent Form (ICF)/Health Insurance Portability and Accountability Act (HIPAA) Authorization Form will 
be enrolled in the study. Medtronic products used in this study will be used within the specifications of 
product labeling. The pharmacological agent used in the study is limited to PFMS and preservative free 
0.9% Sodium Chloride Injections, USP (for dilution). 
Ninety-three subjects have been enrolled into the study with the intent to achieve approximately 67 
implanted subjects and at least 50 evaluable subjects at the 6-Month Visit. All subjects implanted with 
the IDDS will be followed through their required study exit visit. The study sample size accounts for the 
expected attrition anticipated throughout the duration of the study, and therefore, subjects who are 
exited or discontinue will not be replaced. 


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If an activated site does not enroll any subject within three months of activation, Medtronic may choose 
to terminate their participation in the study and move forward with another potential study site to 
ensure sufficient subject enrollments. 
To ensure a distribution of data and minimize center bias in study results for analysis of the primary and 
secondary objectives, the maximum number of subjects that may be enrolled at a single site is 15, with 
Medtronic pre-approval required for additional enrollments.   
Selection of subjects, treatment of subjects, and evaluation of study data are potential sources of bias. 
Potential sources of bias that may be encountered in this study have been considered and minimized by 
careful study design. Methods incorporated in the study design to minimize potential bias include (but 
are not limited to) the following: 
• 
Subjects will be screened to confirm eligibility for enrollment with defined inclusion/exclusion 
criteria 
• 
Subject demographics will be collected to assess possible characteristics that may influence 
endpoints 
• 
To ensure widespread distribution and data among centers, the maximum number of subjects 
that may be enrolled at a single site is 15, with Medtronic pre-approval required for additional 
enrollments. Additionally, centers will each be encouraged to enroll at least 5 subjects 
• 
A statistical analysis plan will be developed prior to analyzing data which will document pre-
specified analysis and analysis methods 
• 
All study site personnel and Medtronic personnel will be trained on their respective aspects of 
the study using standardized training materials 
• 
All study site personnel will be trained on and required to follow the Clinical Investigation Plan 
(CIP) 
• 
A Clinical Events Committee (CEC) will be utilized to adjudicate the relatedness and seriousness 
classifications of all reportable AEs and deaths 
 
 
 
 
 
 


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Figure 1: Embrace TDD Study Visit Flowchart 
 


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6.1 Duration 
Enrollment is defined as the date the subject first signs the study informed consent/HIPAA form. 
Enrolled subjects will be required to attend a minimum of 7 in-office visits. Study completion for each 
subject is defined as the conclusion of the 6-Month Visit (Study Exit). Each subject’s participation in the 
study is expected to last approximately 11 months from the date of enrollment to completion of the 6-
Month Visit. 
The duration of time needed to enroll 93 subjects in the study was 2 years and 1 month. The overall 
study duration, from first subject enrollment to last subject visit, is expected to last approximately 3 
years. Study completion is defined as the approval of the Final Study Report and closure of all study 
sites.  
6.2 Rationale 
Information from available literature (Section 4.1) supports the need for clinical studies to assess IT 
morphine as an alternative route of delivery and its impact on efficacy and safety outcomes. Many 
chronic pain patients may not be achieving adequate pain management with systemic agents, are at 
higher risk for dose-limiting side effects or can become tolerant to opioids over time. Additionally, by 
changing the route of delivery, there is potential to eliminate the need for adjunctive chronic systemic 
opioids, which may lead to a reduction of opioid-related systemic side effects. 
Studies of systemic opioids indicate an increase in overdose risk as a function of increased daily dose. 
Dunn et al. reported that adults who started use of opioid analgesics for a pain condition and were 
receiving 100 mg per day or more of an average prescribed daily opioid dose had an 8.9-fold increase in 
overdose risk compared with subjects receiving 1 to 20 mg/day of these medications. Furthermore, 
subjects receiving 50 to 99 mg/day had a 3.7-fold increase in overdose risk compared with subjects in 
the lowest-dose group.24   
A demonstration of overall benefit is required to justify a route of delivery change when a more invasive 
therapy is proposed. A combined endpoint of clinical success was chosen for this study to assess the 
overall benefit of the therapy. Clinical success for this study is the improvement in either pain or opioid-
related side effects, at the individual subject level. Smith et al3 reported the use of a combination 
endpoint with malignant pain subjects, with clinical success defined as a ≥20% reduction in VAS, or equal 
pain scores with ≥20% reduction in opioid-related side effects.  
This study is designed to establish medical evidence that intrathecal morphine is an effective alternative 
for the management of chronic intractable pain and implementing an opioid wean and holiday results in 
positive outcomes.  


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7. 
Product Description 
7.1 General  
The Medtronic SynchroMed II infusion system and related components and accessories used in this 
study are commercially available. SynchroMed II infusion system components that are commercially 
available after commencement of this study may also be used in addition to, or in lieu of the currently 
available components. 
The Medtronic SynchroMed II infusion system will be the only implantable system allowed in this study 
and will be used in accordance with the product labeling.  
The pharmacological agent used in the study is limited to PFMS and preservative free 0.9% Sodium 
Chloride Injections, USP (for dilution).  
Table 1: Study Products 
 
Medtronic Product 
Model 
Implantable 
Components 
Pump 
8637-20 SynchroMed™ II Pump  
8637-40 SynchroMed™ II Pump 
Catheters 
8780 Ascenda™ Intrathecal Catheter Kit 
8781 Ascenda™ Intrathecal Catheter Kit 
8782 Ascenda™ Intrathecal Catheter Spinal Segment 
Revision Kit 
8784 Ascenda™ Intrathecal Catheter Pump Segment 
Revision Kit 
 
Catheter Accessory Kits 
8785 Catheter Accessory Kit 
8786 Needle Catheter, Short 
8787 Needle Catheter, Long 
 
8591-38 Catheter Passer 
8591-60 Catheter Passer 
 
Refill Kit and Catheter 
Access Port Kit 
8540 Catheter Access Port Kit 
8551 Refill Kit 
8555 Refill Kit  
 
Clinician Devices  
CT900 Clinician Programmer (tablet)  
A810 SynchroMed II Clinician Programmer Application 
A901 Communicator Manager Application 
A902 Patient Data Service Application 
8880T2 Communicator 
 
Patient 
Devices/Accessories 
TH90T01 Personal Therapy Manager (myPTM™) 
TM90 Communicator  
HH90 Handset with A820 myPTM Application software  


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SynchroMed II infusion system Manuals are provided with the products and are also available 
electronically at http://manuals.medtronic.com/manuals/main/region. 
7.2 Dosage Form and Route of Administration 
Sites will utilize PFMS per the investigator’s standard of care and in accordance with the IT PFMS dosing 
goals and IT PFMS dose adjustment parameters outlined in Section 10.13. 
Preservative-free (0.9%) Sodium Chloride Injection for IT administration: may be used to dilute PFMS to 
the desired concentration or to fill the pump reservoir prior to introduction of PFMS or if PFMS is 
removed and no other drug is placed in the pump.   
7.3 Manufacturer 
The SynchroMed II infusion system is manufactured by Medtronic, Inc. with operational headquarters in 
Minneapolis, Minnesota 55432-5604, USA. 
7.4 Packaging 
All Medtronic devices that will be used in this study are commercially available for IT drug delivery as an 
aid in the management of chronic, intractable pain. The devices specified in Section 7.1 will be shipped 
in their commercially available form, which includes packaging and labeling. Only commercial device 
products with commercial labeling will be used in this study. Each study site will order devices through 
their standard ordering processes and should follow their own accountability and storage processes, in 
accordance with the product labeling and their institution’s policies and procedures. 
The pharmacological agent used in this study will be PFMS. Each study site will order drug through their 
standard ordering processes and should follow their own accountability and storage processes, in 
accordance with the product labeling and their institution’s policies and procedures, since these are 
controlled substances. No additional product accountability logs will be required for tracking these 
commercially available products in this study. All Medtronic device product manuals can be found 
electronically at http://manuals.medtronic.com/manuals/main/region. 
7.5 Intended Population 
The SynchroMed II infusion system is utilized in this study to deliver PFMS intrathecally in the treatment 
of patients with chronic, intractable, non-malignant, primary back pain with or without leg pain who are 
experiencing inadequate pain relief and/or intolerable side effects with their systemic opioid therapy. 


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7.6 Product Use 
The Medtronic SynchroMed II infusion system and related components and accessories are 
commercially available in the United States and shall be used in accordance with commercial labeling. 
Exposure to the Medtronic study product is considered to occur from the time the subject is first 
exposed to the IDDS (during the device implant visit) until either the IDDS is explanted or the subject 
discontinues from the study.  
7.7 Product Training Materials 
Only investigators who are trained and experienced in implanting the SynchroMed II infusion system will 
perform the pump trial, pump implant, and pump refill procedures required for this clinical study. All 
study site personnel participating in the study will be required to complete all study-specific training as 
required in the Study Training Plan and have proper delegation by the Principal Investigator (PI) on the 
Delegation of Authority Log maintained at the site. 
7.8 Product Receipt and Tracking 
This is a post-market study and the Medtronic SynchroMed II infusion system and PFMS used in this 
study are commercially available. As this is a post-market study, study center personnel will order 
devices through their standard procedure for acquiring commercial product and site personnel should 
follow their standard procedures for tracking and managing supplies. 
7.9 Product Storage 
Sites should ensure proper storage conditions and record keeping for all products used in the study, per 
applicable labeling and per their institutions’ policies and procedures. 
7.10 Product Return 
To fully evaluate product performance, Medtronic requests that explanted Medtronic products be 
returned for complete analysis. Therefore, Medtronic implantable products, explanted or opened, must 
be returned to Medtronic for analysis when permissible by local laws and regulations, when those 
products are no longer in use, regardless of reason for explants or removal from use. Furthermore, 
Medtronic requests the return of explanted product from non-clinical sources, such as funeral homes, 
and will assume responsibility for storage and disposal of the product once received.   
Mailer kits with prepaid US postage are available for use within the United States to send explanted 
devices to Medtronic Neuromodulation Returned Product Analysis Lab. These mailers are sized to 
accommodate the devices from a single subject and are designed to meet postal regulations for mailing 
biohazardous materials. 


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Please contact your local Medtronic representative to obtain a Returned Product Mailer Kit or to obtain 
instructions on returning products to Medtronic. 
All drugs utilized in this study must be disposed of as required by local laws and each site’s institutional 
policies and procedures. 
Returned Product Analysis 
Devices that are returned to Medtronic, Inc. are analyzed via a Returned Product Analysis (RPA) system 
following specific protocols to identify root cause for failure or deficiency. When programming data are 
available on the IDDS, an expected longevity can be determined, and battery depletion (where 
applicable) can be identified as normal or premature. Upon PI request, a summary report of Medtronic’s 
findings will be provided to the PI after analysis completion. 
7.11 Product Accountability 
Product accountability is not required since the Medtronic SynchroMed II infusion system and PFMS 
used in this study are commercially available. All devices and drugs used during the study will be 
purchased by sites through their standard procedure for acquiring commercial product and maintained 
per the applicable product labeling and the institutions’ standard procedures.  
8. 
Study Site Requirements 
All investigator and site selection activities were complete prior to implementation of CIP V3.0. 
8.1 Investigator/Investigation Site Selection 
All investigators managing the subject’s chronic pain must be qualified practitioners and experienced in 
the diagnosis and treatment of subjects with chronic pain.  All PIs or appropriately delegated Sub-
Investigators must be experienced and/or trained in the implant and management of the Medtronic 
SynchroMed II infusion system. 
The role of the principal investigator is to implement and manage the day-to-day conduct of the clinical 
investigation as well as ensure data integrity and the rights, safety and well-being of the subjects 
involved in the clinical investigation. 
The principal investigator shall: 
• 
Be qualified by education, training, and experience to assume responsibility for the proper 
conduct of the clinical investigation 
• 
Be experienced in the field of application and training in the use of the Medtronic 
SynchroMed II infusion system 


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• 
Disclose potential conflicts of interest, including financial, that interfere with the conduct of 
the clinical investigation or interpretation of results 
• 
Be able to demonstrate that the proposed investigational study site: 
 
Has the required number of eligible subjects needed within the recruitment period 
 
Has one or more qualified investigators, a qualified investigational study site team 
and adequate facilities for the foreseen duration of the clinical investigation 
Study site personnel training will be completed and documented prior to participation in this study. 
8.2 Study Site Activation 
During the activation process (prior to subject enrollment), Medtronic will train study site personnel 
according to their delegated tasks and in accordance with the study training plan. If new members join 
the study site team, they will receive training on the applicable study requirements relevant to their role 
before contributing to the study. 
Prior to performing study related activities, all regulatory requirements shall be fulfilled, including, but 
not limited to the following:  
• 
IRB approval of CIP and site-specific ICF  
• 
Fully executed Clinical Trial Agreement  
• 
Financial disclosure  
• 
Curriculum Vitae of investigators and key members of the investigation study site team   
• 
Documentation of delegated tasks 
• 
Documentation of study training  
• 
Additional requirements imposed by the IRB shall be followed, if appropriate.  
Medtronic will provide each study site with documentation of study site/investigator readiness; this 
letter must be received prior to performing study related activities. 
9. 
Selection of Subjects 
9.1 Study Population 
Patients with chronic, intractable, non-malignant primary back pain with or without leg pain, are the 
intended study population. 


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9.2 Subject Enrollment 
93 subjects with chronic, intractable, non-malignant primary back pain with or without leg pain that met 
eligibility criteria and provided written informed consent/HIPAA were enrolled in this study. Subjects 
were enrolled at 16 study sites in the US, with no more than 15 subjects enrolled at each site, unless the 
site received pre-approval from Medtronic for additional enrollments. 
9.3 Inclusion Criteria 
A potential subject may be included for participation in the study if the subject has/is: 
1. Willing and able to provide a signed and dated (Medtronic and Institutional Review Board (IRB) 
approved) Informed Consent Form (ICF) and Health Insurance Portability and Accountability Act 
(HIPAA) Authorization Form prior to any study procedures being performed 
2. A candidate per labeling for the IDDS 
3. A diagnosis of chronic, intractable, non-malignant primary back pain with or without leg pain, 
treatable with the IDDS  
4. Current daily systemic opioid dose of >0 and ≤ 120 Morphine Milligram Equivalents (MME) 
5. A Visual Analogue Scale (VAS) of ≥50 mm for pain intensity at the Baseline Visit and/or a Numerical 
Opioid Side Effect (NOSE) Assessment Tool ≥40 for intolerable side effects at the Baseline Visit 
6. Psychological evaluation or investigator assessment of patient psychological suitability for study 
participation  
7. Has an MRI or CT prior to enrollment verifying patent spinal canal and no clinical change in status 
since last imaging 
8. At least 18 years old at time of enrollment 
9. Willing and able to attend visits and comply with the study protocol 
10. Male or non-pregnant, non-lactating female. Females must be post-menopausal or surgically sterile; 
or be utilizing a medically acceptable form of birth control (i.e. a hormonal contraceptive, intra-
uterine device, diaphragm with spermicide, or condom with spermicide) for the duration of the 
study 
9.4 Exclusion Criteria 
A potential subject will be excluded from participating in the study if the subject has/is: 
1. Previously trialed or implanted with an IDDS 
2. Concomitant stimulation device implanted for the treatment of pain 
3. Any ongoing health condition that would be expected to interfere with pain and/or quality of life 
ratings (i.e. active malignancy, other painful conditions not treatable with IT therapy, etc.) 
4. Psychological or other health conditions, financial and/or legal concerns that would interfere with 
the subject’s ability to fulfill the requirements of the protocol as per the investigator’s discretion 


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5. Substance Use Disorder (SUD) within the last 2 years or current Medication Assisted Treatment 
(MAT) for substance use disorder 
6. Currently using cannabinoids or illicit drugs 
7. History of allergy or significant adverse reaction to morphine per investigator discretion 
8. Currently participating or plans to participate in another investigational study unless written 
approval is provided by Medtronic Study Team  
10. Study Procedures 
10.1 Summary of Visits 
Study procedures and data collection requirements for the study are provided in detail below for each 
visit and summarized in Table 3: Schedule of Events within Section 10.11. Refer to Section 6, Figure 1: 
Embrace TDD Study Visit Flowchart for a diagram of the required study visits.  
A summary of the required visits are as follows:  
• 
Baseline Visit 
• 
Intrathecal Trial Visit 
• 
Implant Visit 
• 
Post-Op Visit 
• 
1-Month Visit 
• 
3-Month Visit 
• 
6-Month (Study Exit) Visit 
 
Table 2: Visit Windows provides details regarding the study visit windows for all required study visits. 


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Table 2: Visit Windows 
 
Study Visits 
Visit Windows 
Baseline Visit 
Date of Enrollment  
(Date ICF/HIPAA signed and dated) 
Intrathecal Trial Visit 
After Baseline and prior to Implant  
IT Therapy Initiation 
(Day 0) 
Implant to Post-Op 
Visit 
Implant Visit 
 ≤ 150 days after the Baseline Visit 
Post-Op Visit 
14 ± 4 days after the Implant Visit 
 
1-Month Visit 
30 days ± 5 days after Day 0 
3-Month Visit 
90 days ± 10 days after Day 0 
6-Month Visit (Study Exit) 
180 days ± 10 days after Day 0 
 
10.2 Baseline Visit 
Subjects are considered enrolled at the time the study-specific informed consent/HIPAA form is signed.  
At the Baseline Visit, the Medtronic and site Institutional Review Board (IRB) approved informed 
consent/HIPAA form will be reviewed with the potential subject. If the subject agrees to participate, 
they will be consented and assessed for eligibility to the study-specific inclusion and exclusion criteria. 
Each subject must meet all the inclusion criteria and none of the exclusion criteria to be eligible to 
participate in this study.  No study-related procedures or testing will be conducted prior to completing 
the consenting process of a subject. 
Subjects will be asked to complete the VAS for pain intensity and the NOSE assessment tool. Site 
personnel will confirm the subject’s VAS score ≥ 50 mm or the subject’s NOSE score ≥ 40 to be eligible to 
continue in the study.  Female subjects of child-bearing potential (not post-menopausal or surgically 
sterile) must be administered a urine pregnancy test to confirm they are not pregnant at this visit.  A 
subject who has a positive urine pregnancy test will be exited from the study according to Section 10.10. 
In addition, site personnel must confirm the drug testing results are negative for cannabinoids and illicit 
drugs for all subjects. If subjects meet all the eligibility criteria, their chronic back (and leg, if applicable) 
pain history and surgical history will be collected and the study investigator will discuss the process for 
weaning off systemic opioids with the subject.  
Systemic Opioid Weaning and Holiday 


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Investigators should begin weaning the subject off their systemic opioids on the day of their Baseline 
Visit (i.e., enrolment date). The method of the opioid weaning process is at the investigator’s discretion, 
but must be completed within the following constraints: 
• 
Total duration (Baseline to Implant ≤ 5 months) 
• 
Systemic opioid dose of ≤ 60 MME before IT trial 
• 
Minimum opioid holiday of at least 7 days prior to IT Therapy Initiation 
 
If a subject has been enrolled in the study and is determined to be ineligible during the Baseline Visit, or 
they choose to withdraw early, the subject will be exited according to Section 10.10.   
Data Collection Requirements for the Baseline Visit: 
• 
ICF/HIPAA 
• 
Inclusion/exclusion criteria 
• 
VAS 
• 
NOSE 
• 
Demographics 
• 
Back (and leg, if present) pain history/surgical history 
• 
Adjunctive pain management therapies utilized 
• 
Urine pregnancy test results, if applicable 
• 
Drug testing for systemic opioids, cannabinoids, and illicit drug use  
 
 
• 
Pain medications 
• 
AEs  
10.3 Intrathecal Trial Visit 
Site personnel must ensure the subject meets eligibility criteria prior to initiating any IT drug trial 
procedures. Subjects will be asked to complete the VAS for pain intensity and the NOSE assessment tool. 
The investigator must then confirm the subject’s systemic opioid dose is ≤ 60 MME prior to moving 
forward with the IT drug trial. Females of child-bearing potential (not post-menopausal or surgically 
sterile) must be administered a urine pregnancy test at this visit to confirm they are not pregnant. In 
addition, site personnel must confirm each subject’s drug testing results for systemic opioids and 
confirm results are negative for cannabinoids and illicit drugs. If it is determined the subject no longer 
meets eligibility criteria, or they choose to withdraw early, the subject will be exited from the study 
according to Section 10.10.  
The IT trial will be conducted according to the investigator’s standard of care procedures. A successful IT 
trial will be determined by the investigator and documented accordingly. 


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If the investigator determines the IT trial was not successful, the subject will be considered a screen 
failure and will be exited from the study according to Section 10.10. 
Data Collection Requirements for the IT Trial Visit: 
• 
Inclusion/exclusion criteria  
• 
VAS 
• 
NOSE 
• 
Adjunctive pain management therapies utilized 
• 
Urine pregnancy test results, if applicable 
• 
Drug testing results for systemic opioids, cannabinoids, and illicit drugs 
• 
Date systemic opioids were stopped, if prior to trial  
• 
IT trial method, drug name, lot number/identifier, dose(s) and concentration(s) 
• 
Pain medications 
• 
AEs 
10.4 Implant Visit 
The Implant Visit must occur ≤150 days after the Baseline Visit. Females of child-bearing potential (not 
post-menopausal or surgically sterile) must be administered a urine pregnancy test within 2 weeks prior 
to the implant visit to confirm they are not pregnant.  
Only investigators who are trained and experienced in implanting the SynchroMed II infusion system 
and trained by Medtronic on the study requirements will be qualified to perform the implant. The IDDS 
will be implanted per the investigator’s standard procedures. Investigators performing the implant 
should obtain a final intra-operative fluoroscopy or anteroposterior and lateral x-ray to confirm catheter 
placement. Initial device interrogations and data uploads must be completed at implant and final 
interrogation prior to discharge. 
The investigator may determine whether to initiate IT therapy at the Implant Visit or after the Implant 
Visit and up to the date of the Post-Op Visit. If IT therapy is initiated at the Implant, refer to Section 10.6 
for IT Therapy Initiation requirements. PFMS dosing will be managed according to the IT PFMS 
administration and dosing parameters outlined in Section 10.13. If PFMS is not added to the pump at 
the Implant, then preservative-free sodium chloride can be used to fill the pump until the IT Therapy 
Initiation occurs.  
Non-opioid medications and concomitant therapies may be utilized to manage post-operative pain for 
up to 14 days post implant. If IT Therapy is not being initiated at the Implant Visit, systemic opioids may 
be taken to manage post-operative pain but must be discontinued a minimum of 7 days prior to the 
date of IT Therapy Initiation.  Medications prescribed for the treatment of pain will be collected during 
the study and documented in the subject’s medical records and on the applicable Electronic Case Report 
Form(s) (eCRF). 


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Use of myPTM for each subject will be at the discretion of the investigator and subject.  
Data Collection Requirements for the Implant Visit: 
• 
Date systemic opioids were stopped, if prior to the implant 
• 
Adjunctive pain management therapies utilized 
• 
Confirm urine pregnancy test completed within 2 weeks prior to implant, if applicable 
• 
Final AP and lateral fluoroscopic/x-ray images to confirm catheter tip location 
• 
Device information, (including Model # and Serial/Lot #) will be collected for each of the 
following: 
o Pump 
o Catheter 
o myPTM (if distributed) 
• 
Initial and final device interrogation reports (at implant and prior to discharge) 
• 
Pain medications 
• 
AEs/DDs 
10.5 Post-Op Visit 
The Post-Op Visit must occur 14 days ±4 days from the Implant Visit. Investigators should evaluate the 
subject’s implant wound to confirm it has healed appropriately and document any relevant observations 
in the medical records (source records). The following activities must also be completed during the visit: 
initial and final device interrogations and data uploads, if device was interrogated, date systemic opioids 
were stopped (if after implant), pain medications, AEs and DDs must be documented in the subject’s 
source.  
Use of myPTM for each subject will be at the discretion of the investigator and subject.   
If IT therapy is initiated at this visit, refer to Section 10.6 for IT Therapy Initiation requirements. PFMS 
dosing will be managed according to the IT PFMS administration and dosing parameters outlined in 
Section 10.13. 
Data Collection Requirements for the Post-Op Visit: 
• 
Date systemic opioids were stopped, if after implant 
• 
Initial and final device interrogation reports 
• 
Pain medications 
• 
AEs/DDs 
10.6 IT Therapy Initiation 
IT Therapy Initiation may take place any time from the Implant Visit through the Post Op Visit. Subjects 
will be asked to complete the VAS for pain intensity and the NOSE assessment tool prior to site 
personnel performing other visit activities. If the IT Therapy Initiation is occurring on a date other than 
during the Implant Visit, or the Post-Op Visit, females of child-bearing potential (not post-menopausal or 


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surgically sterile) must be administered a urine pregnancy test at this visit to confirm they are not 
pregnant, before initiating IT PFMS. In addition, site personnel must confirm the drug testing results are 
negative for systemic opioids, cannabinoids, and illicit drugs.  
Only PFMS and 0.9% solution of preservative-free sodium chloride injection (USP) for dilution 
will be allowed in the pump from the IT Therapy Initiation Visit through the 6-Month Visit. PFMS dosing 
will be managed according to the IT PFMS administration and dosing parameters outlined in Section 
10.13.  
Use of myPTM for each subject will be at the discretion of the investigator and subject. If myPTM will be 
utilized, the physician may activate myPTM, program the pump accordingly, distribute myPTM to the 
subject and educate the subject on the use of the myPTM during this visit.  
Data Collection Requirements for IT Therapy Initiation: 
• 
VAS 
• 
NOSE 
• 
Date systemic opioids were stopped, if applicable 
• 
Adjunctive pain management therapies utilized 
• 
Urine pregnancy test, if applicable 
• 
Drug testing results for systemic opioids, cannabinoids, and illicit drugs 
• 
Drug information including:  
o Drug name  
o Lot #/identifier 
o Dose 
o Concentration 
• 
Initial and final device interrogation reports 
• 
Pain medications 
• 
AEs/DDs 
10.7 1-, 3-, and 6-Month Visits 
Visits will be required at 1, 3, and 6 months after IT Therapy Initiation (Day 0). Visit windows are as 
follow for these visits: 
1-Month Visit 
30 days ± 5 days after Day 0 
3-Month Visit 
90 days ± 10 days after Day 0 
6-Month Visit 
180 days ± 10 days after Day 0 
 
Subjects will be asked to complete the VAS for pain intensity and the NOSE assessment tool prior to site 
personnel performing other visit activities. VAS and NOSE will be collected at all visits. PFMS dose 
adjustments may be made during these required follow-up visits or during unscheduled visits if 


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necessary, to manage subject pain or opioid-related side effects. PFMS dosing will be managed 
according to the IT PFMS administration and dosing parameters outlined in Section 10.13.  
In the event the subject is unable to be managed on morphine monotherapy from the IT Therapy 
Initiation through the 6-Month Visit, a study deviation eCRF must be completed.  
Data Collection Requirements for the 1-, 3-, and 6-Month Visits: 
• 
VAS 
• 
NOSE 
• 
Urine pregnancy test, if applicable 
• 
Drug testing results for systemic opioids, cannabinoids, and illicit drugs 
• 
Actual residual and fill volume (if pump refill occurs during visit) 
• 
Drug information (if pump refill occurs during visit) including:  
o Drug name  
o Lot #/identifier 
o Dose 
o Concentration 
• 
Initial and final device interrogation reports 
• 
Pain medications 
• 
AEs/DDs 
 
 
  
 
  
 
  
 
  
 
 
 
10.8 Unscheduled Visits 
Unscheduled visits may occur during the study for reasons including dose adjustments, programming 
adjustments, pump refills, medication changes (if subject is unable to be successfully managed on 
morphine monotherapy), AEs, and DDs.  
Subjects will be asked to complete the VAS for pain intensity and the NOSE assessment tool prior to site 
personnel performing other visit activities.  
PFMS dose adjustments may be made during unscheduled visits if necessary, to manage subject pain or 
opioid-related side effects. PFMS dosing will be managed according to the IT PFMS administration and 
dosing parameters outlined in Section 10.13 and pump refills will be handled as required in Section 
10.12. 


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Data Collection Requirements for Unscheduled Visits: 
• 
VAS 
• 
NOSE 
• 
Reason for the unscheduled visit 
• 
Actual residual and fill volume (if pump refill occurs during visit)  
• 
Drug information (if pump refill occurs during visit) including:  
o Drug name  
o Lot #/identifier 
o Dose 
o Concentration 
• 
Initial and final device interrogation reports 
• 
Pain medications 
• 
AEs/DDs 
10.9 System Modifications 
A system modification must be reported in the event the catheter and/or pump require surgical 
modification. Programming of a new PFMS dose or refilling the pump are not considered system 
modifications. In the event of a system modification, the follow-up schedule for the subject will remain 
unchanged. 
Data Collection Requirements for System Modifications: 
• 
VAS 
• 
NOSE 
• 
Reason for system modification and all affected components 
• 
Initial and final device interrogation reports for the existing pump  
• 
Actual residual volume of existing pump   
• 
Drug information (if pump refill occurs during visit) including:  
o Drug name  
o Lot #/identifier 
o Dose 
o Concentration 
• 
Initial and final device interrogation reports for new pump, if applicable 
• 
Pain medications 
• 
AEs/DDs 
10.10 Study Exit 
Normal study completion occurs when the subject has completed the required study visits through the 
6-Month Visit (refer to required procedures described in Section 10.7), at which time the subject will 
end their participation in the study and site personnel will then complete required eCRFs. If a subject 
has already completed their 6-Month visit, they will be brought into re-consent, and be exited from the 


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study.  If the subject is an early withdrawal, refer to Section 10.21 for subject withdrawal or 
discontinuation procedures. 
10.11 Schedule of Events 
Table 3: Schedule of Events 
Study Procedures, 
Tasks, and Data 
Collection (row) by Visit 
(column) 
Baseline Visit (Enrollment) 
Intrathecal Trial Visit 
Implant Visit 
Post-Op Visit 
IT Therapy Initiation  
1-Month Visit  
3-Month Visit 
6-Month Visit (Study Exit) 
Unscheduled Visits 
Informed Consent Process 
√ 
 
 
 
 
 
 
 
 
Demographics 
√ 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
√ 
√ 
 
 
 
 
 
 
 
Urine Pregnancy Test 
√ 
√ 
√1 
 
√ 
√ 
√ 
√ 
 
Drug Test 
√ 
√ 
 
 
√ 
√ 
√ 
√ 
 
Adjunctive pain 
management therapies  
√ 
√ 
√ 
 
√ 
 
 
 
 
Back and Leg Pain/Surgical 
History 
√ 
 
 
 
 
 
 
 
 
VAS 
√ 
√ 
 
 
√ 
√ 
√ 
√ 
√ 
NOSE Assessment 
√ 
√ 
 
 
√ 
√ 
√ 
√ 
√ 
IT PFMS Dose 
 
 
 
 
√ 
√ 
√ 
√ 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fluoroscopy/x-ray  
 
 
√ 
 
 
 
 
 
 
Device information (model, 
serial/lot #) 
 
 
√ 
 
 
 
 
 
 
Drug information (name, 
lot #/identifier, dose & 
concentration) 
 
√ 
 
 
√ 
√ 
√ 
√ 
√ 
Initial and final device 
interrogation reports 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Collect AEs/DDs 
√2 
√ 
√2 
√ 
√ 
√ 
√ 
√ 
√ 
Pain Medications 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
1Confirm pregnancy test completed within 2 weeks prior to implant visit 
2Device Deficiencies will be collected and reported from the Implant Visit through the 6-Month Visit/Study Exit 


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10.12  Pump Refills 
Pump refills will be performed by study investigators or appropriately delegated personnel experienced 
with the use, filling, and dose modification of SynchroMed II infusion system.  
• 
Pump refill procedures may occur at scheduled or unscheduled visits. 
• 
Careful monitoring of the refill schedule must be done to prevent reservoir depletion and 
potential adverse events. 
• 
Any drug remaining in the pump reservoir at the time of refill should be removed and discarded, 
and the pump reservoir should be refilled (document the actual residual volume, the refill 
volume, the drug concentration, and dose in the subject’s medical record). 
 
Refer to Section 10.13, for managing IT PFMS dose increases and decreases, including information on 
dosing limits. Refer to the SynchroMed II Programmable Pumps Implant Manual for the complete 
instructions pertaining to pump refill procedures. 
10.13  IT PFMS Administration and Dosing 
Intrathecal study drug will be administered using commercially available Medtronic SynchroMed II 
infusion systems. IT PFMS initiation and subsequent dosing adjustments are determined based on 
specific patient needs and clinician standard practices but must be within the following evidence-based 
consensus guidelines and remain in line with study dosing goals. 
IT PFMS Dosing Goal:  
To maintain or improve pain control and/or opioid-related side effects (compared to Baseline) with 
utilization of the lowest reasonable daily dose of IT PFMS following discontinuation of all systemic 
opioids and implant of the SynchroMed II infusion system.  
PFMS, at a concentration not exceeding 25 mg/mL and 0.9% solution of preservative-free sodium 
chloride injection (USP) for dilution, will be the only drug allowed in the pump from the IT Therapy 
Initiation Visit through the duration of the study, if possible. 
IT PFMS Dose Initiation Parameters: 
IT PFMS may be initiated at Implant, the Post-Op Visit, or any time in between per investigator standard 
practice and patient-specific therapy needs. Standard guidelines for intrathecal PFMS dosing initiation 
include: 
• 
A starting PFMS dose of 0.1 to 0.5 mg/day, or half the effective trial dose, with lower initial 
PFMS doses considered, as needed, dependent upon the duration of opioid holiday. 
Determination of IT PFMS dosing based on previous systemic opioid dosing is not 
recommended. 
• 
A starting concentration to achieve an estimated pump refill interval of 120 days, but not to 
exceed 180 days 


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• 
Patients may initiate myPTM use at any point during the study.  
 
IT PFMS Dose Adjustment Parameters: 
Study investigators or appropriately trained and delegated designees experienced with the use, filling, 
and dose modification of the SynchroMed II infusion system will be responsible for administering and 
adjusting PFMS doses in this study. The investigator is responsible for overseeing and managing dosing 
in accordance with the IT dosing goal and the following instructions: 
• 
IT PFMS dose increases or decreases can be made any time throughout the duration of study. 
• 
IT PFMS Dose adjustments (increase or decrease) completed outside of a protocol-required visit 
will be considered an Unscheduled Visit. Initial PFMS dose increases following implant may be 
higher depending on the starting IT PFMS dose. Subsequent increases should only be made in 
response to inadequate pain control with increases as low as possible, but not exceeding 25%, 
to achieve adequate pain control 
10.14  Prior and Concomitant Medications  
Only those subjects who are on a daily dose of > 0 and ≤120 MME of systemic opioids (at the time of 
enrollment) will be eligible for participation in the study.  Medications prescribed for the treatment of 
pain will be collected during the study and documented in the subject’s medical records and on the 
applicable eCRF(s). Non-opioid medications and concomitant therapies may be utilized throughout the 
study and to manage post-operative pain at the discretion of the investigator, although it is 
recommended that these medications remain as stable as possible or be decreased as appropriate. 
Increases in these medications are discouraged. Systemic opioids may be taken to manage post-
operative pain, if IT therapy is not being initiated at the Implant Visit, as long as the subject has a 
minimum of a 7-day opioid holiday prior to the date of IT Therapy Initiation.  
10.15  Subject Consent 
Investigators shall consider for enrollment all subjects who meet eligibility requirements for study 
participation to avoid any bias in the subject population. Prior to enrolling subjects, each investigational 
site’s IRB will be required to approve the CIP, ICF and HIPAA/data protection authorization or other 
privacy language (where required by law), and any other written study information to be provided to 
the subjects (e.g. CA Bill of Rights if applicable, subject assessments). The document(s) must be 
controlled (i.e. version number and date) to ensure it is clear which version(s) were approved by the IRB. 
Any adaptation of the informed consent form must be reviewed and approved by Medtronic as well as 
the IRB prior to enrolling subjects. The ICF will be provided separately. 
Patient informed consent is defined as legally effective, documented confirmation of a subject’s 
voluntary agreement to participate in a clinical study after information has been given to the subject on 
all aspects of the clinical study that are relevant to the subject’s decision to participate. The informed 


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consent process will be performed and documented by the study team in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki and in accordance with 21 CRF Part 50.      
Prior to entering the study, the PI, or appropriately delegated designee, will explain to each subject all 
aspects of the clinical investigation that are relevant to the subject’s decision to participate throughout 
the clinical investigation including, but not limited to, the following: purpose and nature of the study, 
study procedures, expected study duration, available alternative therapies, and the benefits and risks 
involved with study participation and the potential treatment. 
The investigator shall seek such consent only under circumstances that provide the prospective subject 
sufficient opportunity to consider whether to participate, and that minimize the possibility of coercion 
or undue influence. No informed consent, whether oral or written, may include any exculpatory 
language through which the subject is made to waive or appear to waive any of the subject’s legal rights, 
or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability 
for negligence.  
Subjects are considered enrolled at the time the study-specific ICF is signed. Informed consent must be 
obtained from the subject prior to initiation of any study-specific procedures. Subjects must be able to 
personally sign and date the consent form to participate in this study. Signing and dating of the ICF or 
HIPAA authorization form by a legally authorized representative will not be permitted for this study. 
Subjects will be required to sign and date a HIPAA authorization form before participating sites can 
collect, use and submit subject information to the study sponsor. The Consent Form and Authorization 
to Use and Disclose Personal Health Information/ Research Authorization/other privacy language, as 
required by law, must be given to the subject in a language he/she is able to read and understand.  
As the ICF is expected to be signed on the same day, but prior to any Baseline Visit study-related 
procedures, it will be documented in the subject’s case history and consent documentation that consent 
was obtained prior to participation in any study related procedures.   
The signed and dated ICF must be filed in the hospital/clinical chart and/or with the subject’s study 
documents. A copy of the informed consent form and signed Authorization to Use and Disclose Personal 
Health Information/Research Authorization/other privacy language, as required by law, must also be 
provided to the subject.  
The signed and dated informed consent form and Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language, as required by law, as well as 
documentation of the individual informed consent process must be available for monitoring and 
auditing.  
Any changes to a previously approved informed consent form throughout the course of the study must 
be submitted to and approved by Medtronic and the IRB reviewing the application before being used to 


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consent a prospective study subject. The document(s) must be controlled (i.e. versioned and dated) to 
ensure it is clear which version(s) are approved and current by the IRB.  
The investigator must notify the subject of any significant new findings about the study that become 
available during the study which are pertinent to the safety and well-being of the subject, as this could 
impact a subject’s willingness to continue participation in the study. 
10.16  Medication Compliance 
Subjects will be required to wean off all systemic opioids prior to IT Therapy Initiation. Drug testing 
(urine, blood, or oral fluid) will be administered at the Baseline Visit to confirm the subject is not 
currently taking any cannabinoids or illicit drugs. Patients will be weaned off all systemic opioids and 
adhere to a strict opioid-free holiday period of at least 7 days prior to initiating IT PFMS therapy. 
Confirmation that the patient has successfully ceased taking systemic opioids and is not taking any 
cannabinoids or illicit drugs will be confirmed via drug testing prior to the initiation of IT PFMS therapy. 
Drug testing will be completed at each scheduled follow-up visit after the initiation of IT morphine 
monotherapy through the 6-Month/Study Exit Visit to confirm they are compliant and not taking any 
systemic opioids, cannabinoids, or illicit drugs. 
10.17 Assessment of Efficacy 
10.17.1 Visual Analog Scale (VAS) 
Pain will be assessed using VAS. The VAS is a 100 mm line, with “No pain” on the left side of the line and 
“Worst pain imaginable” on the right side of the line. Subjects will be asked to mark a line perpendicular 
to the VAS line that best describes their average pain in the last 24 hours.  
10.17.2 Numerical Opioid Side Effect Assessment Tool (NOSE) 
The Numerical Opioid Side Effect (NOSE) Assessment Tool is a tool to evaluate 10 opioid-related side 
effects using a 11-point numeric scale.19 Subjects are asked to evaluate each of the 10 opioid-related 
side effects on a scale of 0-10 with 0 being not present and 10 being as bad as you can imagine. A total 
sum score can range from 0-100. The opioid side effects included: 1) Nausea, vomiting, and/or lack of 
appetite; 2) Fatigue, sleepiness, trouble concentrating, hallucinations, and/or drowsiness/somnolence; 
3) Constipation; 4) Itching; 5) Decreased sexual desire/function and/or diminished libido; 6) Dry mouth;
7) Abdominal pain or discomfort/cramping or bloating; 8) Sweating; 9) Headache and/or dizziness; 10)
Urinary retention. The score from each side effect as well as the total sum score from all side effects
may be reported.


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10.18  Assessment of Safety 
Subjects will be assessed from enrollment through the end of the study for AEs related to the following: 
• 
Systemic opioid weaning 


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• 
Device 
• 
IT drug 
• 
Procedure 
 
In addition, all SAEs (regardless of relatedness) and device deficiencies reported during the study will be 
collected. All subject deaths (regardless of relatedness) must be reported to Medtronic according to 
Section 12.6.  
10.19  Recording Data 
This study will be utilizing a Remote Data Capture (RDC) system to collect study required Case Report 
Form (CRF) information.  Electronic CRFs (eCRFs) will be provided by the sponsor; required data will be 
recorded from source documents and entered into the study database via the eCRFs by the 
appropriately delegated site personnel, in accordance with applicable regulations.  Source 
documentation for VAS and other subject assessments will be captured in a paper format and 
completed confidentially by the subject only.  Source documentation for NOSE will be captured in a 
paper format and completed by the PI or delegated sub-investigator.  Data from the paper assessments 
will be entered into the database by delegated site personnel after ensuring the completeness and 
accuracy of the data.   
The PI or appropriately delegated individuals are responsible for entering data for the study on the 
eCRFs. The PI or delegated sub-investigator (physician only) is required to approve all data on eCRFs via 
electronic signature. 
SynchroMed II programming data (interrogation and pump programming parameters) captured and 
recorded by the Clinician Programmer Model A810 application will be uploaded to a secure database. 
The Clinical Data Upload application is a tool available for installation on and use with the Clinician 
Programmer that allows clinicians to electronically transfer and save session data files to a secure 
Medtronic database. 
10.20  Deviation Handling 
A deviation is defined as an instance(s) of failure to follow, intentionally or unintentionally, the 
requirements of the clinical investigational plan. The investigator is not allowed to deviate from the CIP, 
except under emergency circumstances to protect the rights, safety and well-being of human subjects.  
All study deviations must be reported on the eCRFs regardless of whether medically justifiable, pre-
approved by Medtronic, an inadvertent occurrence, or taken to protect the subject in an emergency.  


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Study deviations must be reported to Medtronic as soon as possible upon the site becoming aware of 
the deviation. Reporting of deviations must comply with IRB policies, local laws, and/or regulatory 
agency requirements.  
If a deviation involves a failure to obtain a subject’s consent or the deviation is made to protect the life 
or physical well-being of a subject in an emergency, the deviation must be reported to the IRB as well as 
Medtronic within five (5) working days.  
In situations where the investigator anticipates, contemplates, or makes a conscious decision to deviate 
from the CIP, the investigator must provide Medtronic with his/her request to deviate from the CIP. 
Medtronic will respond to all requests in writing. If approved, and the deviation affects a subject’s rights, 
safety and well-being, or the scientific integrity of the study, prior approval from IRB is also required.  
Prior written approval from Medtronic is not required when a deviation is necessary to protect the 
rights, safety or well-being of a subject in an emergency or in unforeseen situations beyond the 
investigator’s control (e.g. subject failure to attend scheduled follow-up visits, inadvertent loss of data 
due to computer malfunction, inability to perform required procedures due to subject illness). 
Medtronic is responsible for analyzing deviations, assessing their significance, and identifying any 
additional corrective and/or preventive actions (e.g. amend the CIP, conduct additional training, or 
terminate the investigation). Repetitive or serious investigator compliance issues may result in initiation 
of a corrective action plan with the investigator and site, and in some cases, necessitate suspending 
enrollment until the problem is resolved or ultimately terminating the investigator's participation in the 
study. 
Examples of study deviations include but are not limited to the following: 
• 
Failure to obtain informed consent or HIPAA authorization prior to study enrollment 
• 
Failure to re-consent when new information is added and approved 
• 
Use of an outdated consent 
• 
Unqualified or non-delegated personnel perform consent process 
• 
Violation of inclusion/exclusion criteria 
• 
Failure to collect protocol required assessments procedures (e.g., VAS data, subject assessment 
missing) 
• 
Missed visits 
• 
Visits outside of window 
• 
Missing source documentation 
• 
Use of expired device or unapproved device 
• 
Use of drug(s) not allowed per the protocol (i.e. systemic opioids after initiation of IT therapy, 
cannabinoids, illicit drugs) 
• 
Addition of infusion drugs other that PFMS  
• 
Unauthorized personnel performing study procedures 


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10.21 Subject Withdrawal or Discontinuation 
A subject has the right to withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the PI or institution.  Subjects will be provided standard medical care by 
their physician after their study participation ends.  
The study sample size accounts for potential attrition. Therefore, subjects that discontinue after 
enrollment in the study will not be replaced. 
If a subject is withdrawn from the study, the reason for withdrawal shall be recorded on a study exit 
eCRF and in the subject’s medical record.   
Examples of reasons for study discontinuation include, but are not limited to, the following: 
• 
Eligibility criteria not met (prior to implant) 
• 
Pregnancy 
• 
Subject death 
• 
Subject lost to follow-up (LTFU)  
• 
Subject voluntarily withdraws from the study 
• 
Adverse events  
• 
Normal study completion 
A study exit eCRF must be completed for any enrolled subject who permanently discontinues from the 
study regardless of whether they discontinue early or complete the protocol-required study follow-up 
and has completed the study.  
Study site personnel must make a minimum of three attempts to contact a subject before a subject can 
be considered LTFU for this study. Site personnel must document those attempts and the method of 
attempt (e.g. two by phone and one by certified letter) to contact the subject in the subject’s medical 
and/or study records. In addition, any other requirements set forth by the governing IRB must be 
followed. 
The investigator should make all attempts to conduct an in-office discontinuation visit prior to subject 
withdrawal if the subject is withdrawn after the device is implanted. All eCRFs should be completed for 
visits that occurred prior to the subject’s withdrawal. In addition, regardless of when the discontinuation 
occurs, site personnel should request an update on the status of any medications, ongoing adverse 
event or device deficiency. If a subject discontinues prior to completing the 6-Month Visit, site personnel 
should request the subject complete all applicable subject assessments required at the 6-Month Visit, if 
the subject is willing, to ensure final assessments for the study are obtained whenever possible.   


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11. Risks and Benefits 
11.1 Potential Risks 
The SynchroMed II infusion system, which includes a SynchroMed II implantable pump, implantable 
catheters, accessory kits, and clinician and patient therapy applications, is commercially available in the 
United States.  The risks associated with the products and procedures are no different than those for 
SynchroMed II infusion system patients outside of this clinical study. Risks are disclosed in the device 
labeling included with each product. Refer to the appropriate device labeling for all current risks, 
contraindications, warnings and precautions. Risks associated with the use of PFMS are no different for 
subjects participating in this study than they are for patients who receive PFMS outside of this clinical 
study. Risks are disclosed in the drug labeling included with the product.  Refer to the appropriate drug 
labeling for all current risks, contraindications, warnings, precautions, dosage and administration 
information and screening procedures. As such there is no incremental risk associated with the 
participation in the Embrace TDD Clinical Study.  
Systemic Opioid Weaning Risks: 
Investigators must review risks associated with systemic opioid weaning with each study subject. Opioid 
withdrawal symptoms may vary depending on each’s subjects current regimen of systemic opioids, and 
the method(s) utilized to assist with the weaning may impact any associated risks. Examples of 
withdrawal symptoms may include, but are not limited to the following: 
• 
Headache 
• 
Muscle aches, restlessness 
• 
Anxiety 
• 
Insomnia 
• 
Diarrhea 
• 
Nausea and vomiting 
• 
Rapid heartbeat 
 
Risks associated with Implantation or Use of an infusion system: 
• 
Pocket seroma, hematoma, erosion, or infection 
• 
Infection 
• 
Pump inversion (“flipping”) 
• 
Placement of the catheter may expose patients to risks of postlumbar puncture (spinal 
headache), cerebral spinal fluid (CSF) leak and CSF subcutaneous collection or rare central 
nervous system (CNS) pressure-related problems, radiculitis, arachnoiditis, bleeding, spinal cord 
damage, or meningitis 
• 
Inflammatory mass could result in neurological impairment, including paralysis 


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Allergic or immune system response to the implanted materials. A listing of device materials can 
be found in the Device Specifications sections of the implant manuals for the pump and 
catheters 
 
System- and Procedure-Related Complications: 
Possible system complications listed below can result in overdose symptoms, tissue damage, or a loss of 
or change in therapy, which might lead to a return of underlying symptoms, drug withdrawal symptoms, 
serious injury, or death and might require surgery to replace or remove the pump, catheter, or catheter 
fragment. These complications include: 
• 
End of device service life or component failure, requiring surgical replacement 
• 
Component failure, resulting in loss of therapy, drug overdose, or inability to program the pump 
• 
The pump, catheter, or catheter fragment could migrate within the body or erode through the 
skin 
• 
The implanted materials could cause an allergic or immune system response 
• 
There could be undesirable changes in therapy, possibly related to cellular changes around the 
tip of the catheter 
• 
An inflammatory mass that could result in serious neurological impairment, including paralysis 
• 
The catheter could leak, tear, or become disconnected, resulting in delivery of medication into 
the area under the skin where the pump is implanted or along the catheter path 
• 
The catheter could kink or become blocked resulting in no delivery of medication 
• 
The pump could stop because it has reached end of service life or because of a component 
failure 
• 
Catheter damage, dislodgement, migration, disconnection, kinking or occlusion, fibrosis, or 
hygroma, resulting in tissue damage or a loss of or change in therapy, and contributing to over 
infusion or other potentially serious adverse health consequences 
 
Risks of implanting an infusion system has risks similar to other surgical procedures, including pain or 
infection at the implant site after surgery. Implanting an infusion system that will deliver drug to a 
patient’s spine, has risks similar to spinal procedures, including: 
• 
Pump implanted upside down 
• 
Improper handling of components before, during, or after implantation 
• 
Reservoir contamination 
• 
Improper injection through the catheter access port 
• 
Injection into the pocket or subcutaneous tissue 
• 
Activation of the reservoir valve (if present) 
• 
Over pressurization of the reservoir, including by overfilling 
• 
Programming error 
• 
Tunneling during the catheter implant procedure may expose patients to risks of serious injury 
or death due to perforation of vital organs and/or major blood vessels 
• 
Detached catheter tip or catheter fragment(s) in the intrathecal space 


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• 
Residual catheter fragments may migrate, including rarely into the intracranial cavity, potentially 
resulting in serious adverse health consequences that may require surgical removal 
• 
Residual catheter fragments in the CSF may compromise antibiotic effectiveness in the presence 
of a concomitant CSF infection 
 
Drug-Related Complications: 
• 
Local or systemic drug toxicity and related side effects 
• 
Symptoms of overdose or underdose 
• 
Inflammatory mass formation at the tip of the implanted catheter particularly in patients who 
receive intraspinal morphine or other opioid drugs 
 
Refer to the applicable product manual(s) for all current risks, warnings, precautions and 
contraindications associated with the SynchroMed II infusion system. Product manuals are provided 
with the products and are also available electronically at: 
http://manuals.medtronic.com/manuals/main/region 
There may be other risks related to the SynchroMed II infusion system and/or PFMS used in this study 
that are not foreseen at this time. All anticipated adverse events are the same as those foreseeable risks 
listed in Section 11.1. 
11.2 Pregnancy Risks 
Pregnant women are not able to take part in this study.  Female subjects must agree to not become 
pregnant during the study by using a medically acceptable method of birth control. If subjects become 
pregnant during this study, there may be risks to the subject or their unborn child that are not yet 
known.  Subjects must notify the study doctor immediately if they think they are pregnant or if they 
become pregnant during the study. Site personnel are responsible for the following:  
• 
Documenting all available information regarding the pregnancy in the source documents and 
notifying Medtronic study personnel 
• 
Notifying the IRB per the study site’s requirements 
• 
Exiting the subject from the study and completing the appropriate eCRF(s) according to Section 
10.21 
 
11.3 Risk Minimization (Control Measures) 
Each investigator must be familiar with the SynchroMed II infusion system and PFMS. The frequent 
monitoring of study subjects by an experienced investigator will reduce the risks associated with this 
study. Each study center will have a staff of physicians and nurses experienced, educated, and trained to 
care for subjects implanted with a SynchroMed II infusion system. Medtronic will conduct study protocol 


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training for all study center personnel prior to study initiation. All study personnel will be provided with 
emergency instructions in the event an underdose or overdose of PFMS causes life-threatening 
symptoms (Refer to the Technical Manual, “Indications, Drug Stability, and Emergency Procedures for 
SynchroMed® and IsoMed® Implantable infusion systems” provided separately). 
11.4 Potential Benefits 
Subjects might not receive any direct medical benefits from participation in this study relative to 
receiving the therapy outside of the study. By participating in this study, subjects will have access to 
additional medical oversight or procedures. The information gained from this study may result in 
improved understanding of this therapy. Subjects may also experience better pain control and fewer 
side effects. Additionally, information collected from this study may assist in the design of future 
studies. The study results will be published to increase the body of knowledge about this therapy. 
11.5 Risk-Benefit Rationale 
Consensus statements and evidence-based systematic reviews have been developed to guide the use of 
infusion therapy with morphine for chronic intractable pain. Both the SynchroMed II infusion system 
and PFMS are commercially available, with a positive risk-benefit ratio established for each. 
12. Adverse Events and Device Deficiencies 
 
12.1 Definitions / Classifications 
Any adverse event (AE) meeting the definition of systemic opioid weaning-related, device-related, IT 
drug-related, and procedure-related, all serious adverse events and deaths (regardless of relatedness) 
for all subjects from Baseline to the 6-Month Visit, and device deficiencies (DD) for all subjects from 
Implant to the 6-Month Visit will be collected. All anticipated AEs and adverse device effects are the 
same as those foreseeable risks listed in Section 11.1. 
This post-market study is not within the scope of ISO 14155:2011 but will use AE definitions according to 
ISO 14155:2011 for consistency in reporting. Each adverse event is classified according to ISO 
14155:2011. Adverse events and device deficiencies are defined below in Table 4 as follows: 
Table 4: Adverse Event and Device Deficiency Definitions 
Term 
Definition 
Adverse Event (AE):  
(ISO 14155:2011 3.2) 
Any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, 


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Term 
Definition 
 
users or other persons, whether or not related to the investigational medical 
device.  
NOTE 1:  This definition includes events related to the investigational 
medical device or the comparator. 
NOTE 2: This definition includes events related to the procedures 
involved. 
NOTE 3: For users or other persons, this definition is restricted to 
events related to investigational medical devices. 
Adverse Device Effect 
(ADE):  
(ISO 14155:2011 3.1) 
Adverse event related to the use of an investigational medical device. 
NOTE 1: This definition includes adverse events resulting from 
insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the 
investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or 
from intentional misuse of the investigational medical device. 
Device Deficiency 
(DD):  
(ISO 14155:2011 3.15) 
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. 
NOTE: Device deficiencies include malfunctions, use errors, and 
inadequate labeling. 
Malfunction:  
(ISO 14155:2011 3.27) 
Failure of an investigational medical device to perform in accordance with its 
intended purpose when used in accordance with the instructions for use or 
(CIP). 
Use Error:  
(ISO 14155:2011 3.43) 
 
Act or omission of an act that results in a different medical device response 
than intended by the manufacturer or expected by the user. 
NOTE 1: Use error includes slips, lapses, and mistakes. 
NOTE 2: An unexpected physiological response of the subject does 
not in itself constitute a use error.  
Term 
Seriousness 
Serious Adverse 
Event (SAE):  
(ISO 14155:2011 3.37) 
 
Adverse event that 
a) led to death, 
b) led to serious deterioration in the health of the subject, that either 
resulted in 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, 
or 
3) in-patient or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body structure or 
a body function,  
c) led to fetal distress, fetal death or a congenital abnormality or birth 
defect. 
NOTE: Planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP, without serious deterioration in 
health, is not considered a serious adverse event. 


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Term 
Definition 
Serious Adverse 
Device Effect (SADE):  
(ISO 14155:2011 3.36) 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event 
Term 
Relatedness 
Systemic Opioid 
Weaning-Related  
An adverse event related to the systemic opioid weaning process (i.e. opioid-
related withdrawal symptoms) 
Device-Related 
An adverse event that results from the presence or performance (intended 
or otherwise) of the SynchroMed II infusion system.  
IT Drug-Related 
Event related to the IT drug delivered by the device. Normally IT drug-related 
events resolve when the device is turned off or reprogrammed, or the drug is 
removed from the pump. This category should not include events that 
resulted from a malfunction of the device (i.e. hardware-related events). 
Procedure-Related 
An adverse event that occurs due to any procedure related to the IT trial, 
implant, pump refills, programming, or surgical modification of the system. 
12.2 Reporting of Adverse Events 
Any AE meeting the definition of systemic opioid weaning-related, device-related (i.e. SynchroMed II 
infusion system), IT drug-related, and procedure-related (i.e. IT trial, implant or pump 
refill/reprogramming, system modification), and all serious adverse events and deaths (regardless of 
relatedness), for all subjects from the Baseline Visit through study exit will be collected. 
It is the responsibility of the investigator to identify the occurrence of any reportable adverse events and 
to ensure all required information is accurately recorded in the subject’s medical record and reported to 
Medtronic on an event eCRF. IRB reporting must be completed in accordance with the policies of the 
governing IRB. Refer to the eCRF for the information to be reported for each AE.  
For AEs that require immediate reporting, initial reporting to Medtronic may be done by phone, fax, or 
e-mail, or on the eCRF by completing as much information as is available. The AE eCRF must be 
completed as soon as possible.  
In case the investigator requires information from the sponsor in an emergency, the investigator can 
contact Medtronic using the contact details provided in the synopsis and Section 12.5. 
The clinical course of each AE must be followed until the adverse event is resolved, the subject is in a 
stable condition, or until the subject discontinues from the study. “Ongoing” AEs must be assessed at 
each study visit. The AE eCRF should be updated when there is a change to the information provided on 
the form (e.g. change in intervention, outcome, relatedness, etc.). 
At the last study visit, the investigator will instruct the subject to provide an update on the status of any 
ongoing events and report any AE they believe may be related to participation in the study.     


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12.3 Non-Reportable Events 
Examples of events that are not reportable as adverse events for this study include: 
• 
Inability to successfully perform a procedure, unless injury occurs 
• 
A documented pre-existing condition unless there is a worsening of the nature, severity, 
duration or frequency of that condition if it meets the defined criteria for a reportable adverse 
event (i.e. systemic opioid weaning, device, IT drug and/or procedure-related) 
Table 5 provides a list of common expected surgical AEs. An expected surgical event will not be 
considered reportable unless it worsens or is present outside the stated timeframe post-procedure. 
Table 5: Expected Surgical Adverse Events and Durations 
Event Description 
Timeframe After Surgical 
Procedure 
Low-grade fever (˂ 100° or ˂37.8° C) 
48 hours 
Anesthesia-related nausea/vomiting 
24 hours 
Mild to moderate bruising/ecchymosis 
7 days 
Pocket site / incisional pain 
14 days 
Seroma 
72 hours 
Sleep problems (insomnia) 
72 hours 
12.4 Reporting of Device Deficiencies 
Device Deficiency (DD) information will be collected for all subjects from the Implant Visit through the 6-
Month Visit and reported to Medtronic on a DD CRF, one for each DD.  At the last study visit, the 
investigator will instruct the subject to provide an update on the status of any ongoing events and 
report any issue with the device they believe may be related to participation in the study. 
12.5 Emergency Contact Details 
For emergency contact regarding a SADE/DD, contact the Clinical Study Manager immediately. 
24-hour Medtronic contact information for reporting SADEs/DD:  
Email: 
  
Fax: 
 
12.6 Subject Death 
The investigator must notify Medtronic immediately and the IRB (as required), after learning of a 
subject’s death (regardless of relatedness).  The death should be reported to Medtronic on the event 
eCRF as soon as possible. The investigator should also attempt to determine, as conclusively as possible, 
whether such deaths are related to the systemic opioid weaning, device, IT drug, or procedure.  


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If it is determined that the cause of death was related to systemic opioid weaning, device, IT drug, or 
procedure: 
• 
A copy of an autopsy report should be provided to Medtronic, if an autopsy is performed 
• 
Medtronic requests that all device system components that were being used at the time of the 
death be returned to Medtronic for analysis per Section 7.11 
• 
Requested death certificates and/or source documentation if obtained, should be redacted and 
sent to Medtronic 
If the death occurs at a location remote from the study site, it is the study site’s responsibility to make 
three attempts to retrieve all pertinent information related to the subject’s death and submit the 
investigator’s death summary of the known events surrounding the death to Medtronic. 
13. Data Review Committees 
This study will utilize a Clinical Events Committee (CEC) to adjudicate the relatedness and seriousness 
classifications of all reportable adverse events.  
The CEC may request clarification and/or additional information from the PI who reported the event. If 
the conclusion of the review differs from the PI’s assessment, both opinions will be reported back to the 
investigator and noted in the final study report. Incidence rates will be tabulated using the final CEC 
determination. 
The CEC will be external to Medtronic and independent of the study investigators. The members will 
have specialties appropriate to the therapeutic area and meet requirements established in the CEC 
charter. 
14. Statistical Design and Methods 
14.1 General Aspects of Analysis 
Data analysis will be performed by Medtronic-employed statisticians or designees. A validated statistical 
software package will be used for the analyses of the study results (e.g. SAS version 9.4 or higher). 
The Statistical Analysis Plan (SAP) will be developed prior to data analysis and will include a 
comprehensive description of the statistical methods and reports to be included in the final study 
report. Any change to the data analysis methods described in the CIP will require an amendment only if 
it changes a principal feature of the CIP. Any other change to the data analysis methods described in the 
CIP, and the justification for making the change, will be described in the clinical study report. 


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14.1.1 
Sample Size Justification 
Ninety-three subjects have been enrolled into the study with the intent to achieve approximately 67 
implanted subjects and at least 50 evaluable subjects at the 6-Month Visit. The sample size of 50 
evaluable subjects was chosen to assure acceptable levels of precision for estimation of the primary 
objective of Clinical Success and provide adequate power to test the secondary objective related to pain 
score.  
There were no available data in the target population on the primary objective of Clinical Success, nor 
on the secondary objective of opioid-related side effects score. The secondary objective of pain intensity 
score is used for sample size calculation. It is hypothesized that the pain intensity score of VAS at the 6-
Month Visit is non-inferior to those at Baseline using a non-inferiority approach. 
The PASS 11 Non-Inferiority Tests for One Mean was used to calculate the power for pain intensity of 
VAS with the following assumptions: Sample size = 50, Alpha = 0.025, Non-Inferiority Margin = 1, True 
Difference = 0, Standard Deviation = 1.9, with Higher Means are Better (one-sided) t-test. A sample size 
of 50 would achieve 95% power with the above assumptions. This power calculation was performed 
using a pain scale of 0-10; however, the power calculation is identical to one with a non-inferiority 
margin of 10 and assuming a standard deviation of 19 on a VAS pain scale of 0-100. 
The non-inferiority margin of 10 points (for the VAS of 0-100) was chosen based on a review of pain 
study literature. Non-inferiority margins between 1 and 1.5 were reported for pain scales of 0-10, 
including one study in a similar population of chronic non-malignant pain subjects comparing 2 oral 
opioids that utilized a margin of 1d. The non-inferiority margin of 1 on a pain scale of 0-10 is equivalent 
to a non-inferiority margin of 10 on a VAS pain scale of 0-100. The estimated actual difference was 
assumed to be 0 because the goal is to achieve same or better pain control as compared to Baseline. 
 
 
 
 
 
  
A 33% attrition between enrollment and subject implant is assumed and a 25% attrition between 
Implant and the 6-Month Visit is assumed. Under CIP V2.0, approximately 100 subjects were to be 
enrolled; 93 subjects have been enrolled into the study with the intent to achieve approximately 67 
implanted subjects and 50 evaluable subjects at the 6-Month Visit.  
 
d Binsfeld H, Szczepanski L, Waechter S, Richarz U, Sabatowski R.  A randomized study to demonstrate noninferiority of once-daily 
OROS® hydromorphone with twice-daily sustained-release oxycodone for moderate to severe chronic noncancer pain, Pain Pract. 
2010;10(5):404–415. 


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The 33% attrition between enrollment and subject implant accounts for the subjects who don’t meet 
inclusion and/or exclusion criteria, those who can’t follow the weaning process to eliminate systemic 
opioids, those who don’t have a successful IT trial, those who have AE that can no longer be followed in 
the study, withdrawals, and lost-to-follow-up, etc. The attrition between implant and the 6-Month Visit 
is conservatively set at 25% to potentially account for the subjects who have adverse events that can no 
longer be followed in the study, withdrawals, are LTFU, or subjects who can’t be effectively managed on 
morphine monotherapy.  
14.1.2 
Investigation Site Pooling 
The investigators of this study will conduct the study according to this protocol and use the same CRFs 
to collect study data. The site study personnel will be trained prior to the study initiation at each site. 
Periodic study monitoring by Medtronic will ensure compliance with protocol requirements.  
There is no a priori provision to exclude any sites from the analysis. The data from all sites will be pooled 
for analysis. To reduce the possibility of atypical results from a site overly influencing the combined 
results, no more than 15 subjects will be enrolled at each site unless the site gets pre-approval from the 
Medtronic for additional enrollments.  
14.1.3 
Other Specific Considerations 
Adjustment for Baseline Covariates 
There is no plan to make adjustment for Baseline covariates for the primary objective.  
Handling Missing Data 
Missing data are a potential source of bias when analyzing study data. A rigorous study design and 
execution will help prevent the incidence of missing data from occurring.  
The primary analysis of the primary and secondary objectives will include subjects who maintain 
morphine monotherapy and provide data (per-protocol population). Sensitivity analyses will be 
performed for the primary and secondary objectives using the Multiple Imputation (MI) methodology 
for missing data in VAS and NOSE scores for all implanted subjects. Details of the imputation method are 
described in Sections 14.4.1 and 14.4.2. 
Adjustment for Multiple Endpoints 
As there is no hypothesis testing for the primary objective, adjustment for multiple endpoints is not 
required.  
Interim Analysis 
There is no planned interim analysis for the primary and secondary objectives in this study. 


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14.1.4 
Reports 
A final clinical study report will be generated for this study. Periodic progress reports may also be 
generated for the study. 
14.2 Demographics 
Demographics and Baseline characteristics will be summarized in the report for enrolled subjects, 
implanted subjects, and per-protocol subjects for the primary objective.  
14.3 Primary Objective – Clinical Success at the 6-Month Visit 
To characterize the proportion of subjects with Clinical Success at the 6-Month Visit based on changes in 
pain intensity using the Visual Analog Scale (VAS) and changes in opioid-related side effects using the 
Numerical Opioid Side Effect (NOSE) Assessment Tool.  
Hypothesis 
There is no formal hypothesis. The objective is to estimate the proportion of Clinical Success at the 6-
Month Visit.  
Experimental Design 
The Clinical Success is comprised of 2 separate measures, pain intensity and opioid-related side effects. 
The measurements of pain intensity using VAS and opioid-related side effects using NOSE are described 
in Sections 10.17.1 and 10.17.2. Both pain intensity and opioid-related side effects are measured as a 
percent change from Baseline to the 6-Month Visit to calculate the Clinical Success.  
Pain Intensity: 
Percent change in pain intensity will be calculated as VAS at the 6-Month Visit minus VAS at Baseline, 
then divided by VAS at Baseline, expressed as a percentage. Individual subject percent change in pain 
intensity is categorized into three responder groups at the 6-Month Visit: 
• 
Worse than Baseline: percent of change in VAS ≥ 20% (increased equal or more than 20%) if 
Baseline VAS is ≥10 or change in VAS is ≥ 2 if Baseline VAS is < 10 
• 
Equal to Baseline: percent of change in VAS < 20% and > -20% (increased less than 20% or 
decreased less than 20%) if Baseline VAS is ≥10 or change in VAS is between -2 and 2 if Baseline 
VAS is < 10 
• 
Better than Baseline: percent of change in VAS ≤ -20% (decreased equal or more than 20%) if 
Baseline VAS is ≥10 or change in VAS is ≤ -2 if Baseline VAS is < 10 
 
Opioid-Related Side Effects: 


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Percent change in NOSE will be calculated as NOSE at the 6-Month Visit minus NOSE at Baseline, then 
divided by NOSE at Baseline, expressed as a percentage. Individual subject percent change in NOSE is 
categorized into three responder groups at the 6-Month Visit: 
• 
Worse than Baseline: percent of change in NOSE ≥ 20% (increased equal or more than 20%) if 
Baseline NOSE is ≥10 or change in NOSE is ≥ 2 if Baseline NOSE is < 10 
• 
Equal to Baseline: percent of change in NOSE < 20% and > -20% (increased less than 20% or 
decreased less than 20%) if Baseline NOSE is ≥10 or change in NOSE is between -2 and 2 if 
Baseline NOSE is < 10 
• 
Better than Baseline: percent of change in NOSE ≤ -20% (decreased equal or more than 20%) if 
Baseline NOSE is ≥10 or change in NOSE is ≤ -2 if Baseline NOSE is < 10 
 
Clinical Success: 
A subject’s Clinical Success is defined as any of the following and displayed in Figure 2: 
1. Reduced opioid-related side effects with equal pain 
2. Reduced pain with equal opioid-related side effects 
3. Reduced pain and reduced opioid-related side effects 
Figure 1: Clinical Success 
Change  
from Baseline  
to the 6-Month Visit  
Opioid-Related Side Effects 
(NOSE) 
≥20% 
Increase 
< ±20% 
Change 
≥20% 
Reduction 
Worse 
Equal 
Better 
Pain Intensity (VAS) 
≥20% 
Increase 
Worse 
  
  
  
< ±20% 
Change 
Equal 
  
  
1  
≥20% 
Reduction 
Better 
  
 2 
 3 
 
Analysis Methods 
The proportion of subjects with Clinical Success and its exact binomial two-sided 95% confidence 
interval will be reported. The primary analysis method will use all the implanted subjects who maintain 


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morphine monotherapy and provide data at both Baseline and the 6-Month Visits (per-protocol 
population). Assuming the estimated proportion of Clinical Success is 70%, with a sample size of 50 
subjects, the exact two-sided 95% confidence interval (CI) would be 55.4-82.1%, with a confidence width 
of 26.7%. The widest 95% CI would be at 28.9% for an estimated proportion of Clinical Success of 50% 
(95% CI 35.5-64.5%). 
Two sensitivity analyses will be performed: the proportion of subjects with Clinical Success and its 95% 
CI will be reported in subjects who provide data at the 6 Month Visit (completers) as well as in all 
implanted subjects with imputation method of MI for those who has missing VAS or NOSE at the 6-
Month Visit. Details of the imputation method are described in Sections 14.4.1 and 14.4.2. 
14.4 Secondary Objectives 
There are three secondary objectives in the study.  
14.4.1 
Secondary Objective #1 – VAS Pain Intensity at the 6-Month Visit 
To demonstrate pain intensity scores (VAS) at the 6-Month Visit is non-inferior to VAS at Baseline.  
Hypothesis 
The mean change in pain intensity using VAS from Baseline to the 6-Month Visit is not worse than 0 by 
more than 10 points.  
H0: μ ≥ 0 + |M| 
HA: μ < 0 +|M| 
Where μ is the mean change in VAS from Baseline to the 6-Month Visit and |M| is the absolute value of 
non-inferiority margin of 10. 
Experimental Design 
The measurements of pain intensity using VAS is described in Section 10.17.1. The change in VAS is 
calculated using VAS at the 6-Month Visit minus VAS at the Baseline Visit. A negative change is an 
improvement.  
Analysis Methods 
The change in VAS as well as VAS at both Baseline and the 6-Month Visit will be summarized using 
descriptive statistics, (e.g., mean, standard deviations, etc.). The non-inferiority null hypothesis will be 
tested using a one-sided 0.025 alpha level one sample t-test. The upper bound of the 95% CI of the 
mean change must be less than 10. If non-inferiority is met, a two-sided 0.05 alpha level t-test for 
superiority (vs. 0 change from Baseline) will be performed. If the distribution of the change in VAS 
doesn’t meet normality assumption, an appropriate non-parametric analysis will be performed. The 


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primary analysis will use all the implanted subjects who maintain morphine monotherapy and provide 
data at both Baseline and 6-Month Visits. 
Two sensitivity analyses will be performed, one will include subjects who provide data (completers) and 
one will include all implanted subjects. The sensitivity analysis of all implanted subjects will be 
performed using MI method for missing data at the 6-Month Visit. For scheduled 6-Month Visit, if an 
Unscheduled Visit occurred within the 6-Month Visit window, and the VAS is collected at the 
Unscheduled Visit, the VAS from the Unscheduled Visit will be used in the analysis of the 6-Month Visit. 
Otherwise, the missing VAS will be imputed using MI. Prior to the use of MI, the distributions of the 
continuous variables will be assessed for normality and the need for transformation if they are not 
normally distributed. The model variables in MI may include study site, subject age, gender, primary 
diagnosis, VAS at Baseline, 1-Month Visit, 3-Month Visit. The fully conditional specification method with 
10 burn-in iterations within SAS and 10 repetitions (M = 10) will be used for imputation. Constraints will 
be set so that the imputed VAS are restricted to values ranging from 0-100. Following imputation, the 
objective will be evaluated using MI analysis method.  
In addition, percentage of change in VAS will be calculated using change in VAS divided by VAS at 
Baseline. A negative percentage of change in VAS is a percentage of reduction in VAS, thus an 
improvement. The percentage of change in VAS will be summarized using descriptive statistics, (e.g., 
median and inter-quartile range) 
14.4.2 
Secondary Objective #2 – NOSE Score 
To characterize the change in opioid-related side effects scores (NOSE) from Baseline to the 6-Month 
Visit. 
Hypothesis 
There is no formal hypothesis. The objective is to estimate the change in NOSE from Baseline to the 6-
Month Visit.  
Experimental Design 
The measurements of opioid-related side effects NOSE are described in Section 10.17.2. The change in 
NOSE is calculated using NOSE at the 6-Month Visit minus NOSE at Baseline. A negative change is an 
improvement.  
Analysis Methods 
The change in NOSE will be summarized using descriptive statistics, (e.g., mean, standard deviations, 
etc.). The analysis will use all the implanted subjects who maintain morphine monotherapy and provide 
data at both Baseline and the 6-Month Visits. 
Two sensitivity analyses will be performed, one will include subjects who provide data (completers) and 
one will include all implanted subjects. The sensitivity analysis of all implanted subjects will be 


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performed using MI method for missing data at the 6-Month Visit.  For scheduled 6-Month Visit, if an 
Unscheduled Visit occurred within the 6-Month Visit window, and NOSE is collected at the Unscheduled 
Visit, the NOSE from the Unscheduled Visit will be used in the analysis of the 6-Month Visit. Otherwise, 
the missing NOSE will be imputed using MI. Prior to the use of MI, the distributions of the continuous 
variables will be assessed for normality and the need for transformation if they are not normally 
distributed. The model variables in MI may include study site, subject age, gender, primary diagnosis, 
NOSE at Baseline, 1-Month Visit, 3-Month Visit. The fully conditional specification method with 10 burn-
in iterations within SAS and 10 repetitions (M = 10) will be used for imputation. Constraints will be set so 
that the imputed NOSE are restricted to values ranging from 0-100. Following imputation, the objective 
will be evaluated using MI analysis method. 
In addition, percentage of change in NOSE will be calculated using change in NOSE divided by NOSE at 
Baseline. A negative percentage of change in NOSE is a percentage of reduction in NOSE, thus an 
improvement. The percentage of change in NOSE will be summarized using descriptive statistics, (e.g., 
median and inter-quartile range, etc.). 
14.4.3 
Secondary Objective #3 – Systemic Opioids Elimination 
To characterize the proportion of subjects who eliminate systemic opioids through the 6-Month Visit.  
Hypothesis 
There is no formal hypothesis. The objective is to estimate the proportion of subjects who eliminate 
systemic opioids through the 6-Month Visit.   
Experimental Design 
The test for systemic opioids, cannabinoids, and illicit drug use will be collected at all scheduled study 
visits except the Implant Visit. If a subject has a negative test for systemic opioid use, this subject will be 
considered as having eliminated systemic opioids at the scheduled study visit.  
Analysis Methods 
The proportion of subjects who eliminate systemic opioids and its exact binomial two-sided 95% CI will 
be reported at the 6-Month Visit as well as for those having eliminated systemic opioids from therapy 
initiation through the 6-Month Visit. The primary analysis method will use all the implanted subjects 
who maintain morphine monotherapy and provide data at the 6-Month Visit. Assume the estimated 
proportion is 80%, with a sample size of 50 subjects, the exact two-sided 95% CI would be 66.3-90.0%, 
with a confidence width of 23.7%.  The widest 95% CI would be at 28.9% for an estimated proportion of 
50% (95% CI 35.5-64.5%). 
Two sensitivity analyses will be performed, one will include subjects who provide data (completers) and 
one will include all implanted subjects. The sensitivity analysis in all implanted subjects’ analysis will 
display the full range on the potential impact of missing data by running an analysis assuming all missing 


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values had eliminated systemic opioids to none of the missing values having eliminated systemic 
opioids.  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.6 Safety Assessment 
To characterize all systemic opioid weaning-related, device-related, IT drug-related, and procedure-
related adverse events (AEs), all serious adverse events (SAEs) (regardless of relatedness), and device 
deficiencies (DD) for all subjects from enrollment until the subject exits. 
15. Ethics 
15.1 Statement(s) of Compliance 
This study will be conducted in compliance with this CIP and Good Clinical Practices according to the 
United States (US) Code of Federal Regulations (CFR) on Electronic records (21 CFR§11), Protection of 
Human Subjects (21 CFR§50), Institutional Review Boards (21 CFR §56), Medical Device Reporting 
(21CFR§803), International Conference on Harmonization (ICH GCP E6) the ethical principles that 


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originate from the Declaration of Helsinki, and applicable local regulatory requirements and laws in the 
states in which the study will be conducted. This study is posted on http://www.ClinicalTrials.gov 
(NCT03761277) as part of Medtronic’s commitment to full disclosure for ongoing studies that meet the 
requirements for public posting. 
The principles of the Declaration of Helsinki have been implemented through the patient informed 
consent process, IRB approval, study training, clinical trial registration, preclinical testing, risk-benefit 
assessment and publication policy. 
Prior to enrolling subjects in this study, each study site’s IRB will be required to approve the current CIP 
or CIP amendments, the subject ICF/HIPAA, including any other written information to be provided to 
the subjects and, if applicable, any materials used to recruit subjects. IRB approval letters must contain 
sufficient information to identify the version and/or date of the documents that were approved, or the 
information must be retrievable from the corresponding submission letter. Sites must also receive 
written approval of activation from Medtronic prior to initiating subject enrollments. 
Investigators will be required to sign a Statement of Investigator Commitment form stating their intent 
to adhere to applicable regulations. 
The sponsor shall avoid improper influence on, or inducement of, the subject, monitor, any 
investigator(s) or other parties participating in, or contributing to, the clinical investigation. All 
investigators shall avoid improper influence on or inducement of the subject, sponsor, monitor, other 
investigator(s) or other parties participating in or contributing to the clinical investigation. 
16. Study Administration 
16.1 Monitoring 
Medtronic is responsible for ensuring the proper conduct of this study in terms of adherence to 
applicable regulations, protocol compliance, and the validity and accuracy of the study data entered on 
eCRFs.  As such, investigational sites will be monitored to ensure the safety and well-being of study 
subjects is preserved, and to ensure site compliance with the study protocol, applicable regulations, and 
IRB requirements to ensure study data is accurate and complete.  
Monitoring and monitoring oversight will be provided by Medtronic personnel or by representatives of 
Medtronic (i.e. contractors and other designees) who will support the study investigation including site 
qualification, site initiation, interim monitoring, and study closure visits. 
Contact information for the study monitoring: 
 


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The PI and study staff will provide the Medtronic monitors with complete and direct access to source 
data (e.g., paper and electronic hospital/clinical charts, appointment books, laboratory records) that 
support the data on the eCRFs, as well as other documentation supporting the conduct of the study.  
Monitors will perform source data verification and routine reviews of study-related regulatory 
documents during scheduled monitoring visits and work to secure compliance should any deficiencies 
be observed. The monitoring plan contains the strategy for frequency of monitoring visits and source 
data verification to be performed for this study. 
It is an expectation that the PI must make every effort to meet with the monitor during each monitoring 
visit. 
16.2 Medtronic Representative Role 
Medtronic representatives who are qualified and trained on the protocol may participate in the conduct 
of the study under the direct supervision of the PI as described below.  The PI or other study site 
personnel designated on the delegation of authority form must collect all required data, record the 
study activities, and be responsive to the subject’s needs during an activity performed by a Medtronic 
representative. 
Medtronic representatives may provide technical support to the investigator and other health care 
personnel as needed during study visits.  This support may include the training of site personnel on use 
of the Medtronic equipment or the protocol-related procedures and data collection. 
In addition, Medtronic personnel may perform certain activities to ensure study quality.  These activities 
may include: 
• 
Provide technical support during IT trial, implant, and follow-up visits 
• 
Perform device programming, while under the direction of the investigator or study site 
personnel delegated responsibility for device programming 
• 
Discuss any issues with programming or subject compliance with the PI or other site personnel  
• 
Clarify and/or troubleshoot device behavior, operation, or diagnostic output as requested by the 
PI or other health care professional 
• 
Perform device interrogation, printing or uploading of device information while under the 
direction of the investigator or study site personnel delegated responsibility for the collection of 
study data from equipment and upload into the NPU database 
 
Medtronic personnel may not perform the following: 
• 
Practice medicine provide medical diagnoses or make decisions related to subject 
treatment/care 


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• 
Discuss a subject’s condition or medical treatment with the subject or a member of the subject’s 
family 
• 
Express opinions about the product/feature under study 
• 
Assist the subject by direct physical contact except as required by the specific protocol-related 
task to be conducted 
• 
Provide the subject with any form/questionnaires related to the products under investigation 
• 
Enter data on eCRFs, with the exception of the Medtronic Use Only fields/forms 
  
16.3 Data Management 
This study will use the Oracle Clinical RDC system, which allows the study centers to enter data directly 
on the eCRF within the sponsor’s database over a secure internet connection. This system is a fully 
validated system and 21CFR§11 Part E compliant. The RDC system controls user access, ensures data 
integrity, and maintains an audit trail of entries, changes and corrections made to the eCRFs. User access 
will be granted by Medtronic to each applicable individual at a site based upon his or her delegation of 
authority for the study and only upon completion of the required training. The investigator and 
applicable study site personnel will be given access to the electronic eCRF system; user IDs and 
passwords may not be shared. 
The PI is responsible for the completeness, accuracy and timeliness of the data entered on the eCRFs 
and the data in all other required reports.  The PI or sub-investigator (physician only) must review all 
data for accuracy and provide his/her approval of the eCRF and sign each form with an electronic 
signature. Data reported on the eCRFs, must be derived from and consistent with source documents, 
unless otherwise stated in this section or the study monitoring plan. If discrepancies in source are 
identified during monitoring, these need to be corrected or a justification noted with a documented 
rationale, and then signed and dated by the PI, or authorized delegate, to be maintained as a part of the 
subject’s records. If a person only authorized to complete eCRFs makes changes to an already signed 
eCRF, the system will require the PI, or authorized delegate, to re-sign the eCRF. 
The eCRF may be considered the source for the following data collection elements: 
• 
Investigator assessment of adverse event relatedness and seriousness 
• 
Details pertaining to and reason for protocol deviation 
 
Even when the eCRF may be considered as source (as noted above), an alternative method of source 
documentation is always strongly encouraged.  
Medtronic personnel will perform routine edit and consistency checks, internally and during monitoring 
visits, for items such as missing data or inconsistent data.  Identified data inconsistencies will be 


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resolved by use of data discrepancies within the RDC system; investigators and site personnel will review 
data discrepancies and respond to them in a timely manner. The resolved discrepancy will become a 
part of the eCRF record for the subject.  
At the end of the study, the eCRF data will be frozen (locked) and will be retained indefinitely by 
Medtronic. Each subject’s device programmer interrogation data will be stored in the NPU database. 
16.4 Direct Access to Source Data/Documents 
Source documentation is defined as the original documents, data and records and may include all 
clinical records, hospital records, laboratory notes, surgery reports, autopsy reports, and other 
documents, electronic or paper, that contain original information to support study data collections or AE 
reporting. The PI is responsible for ensuring source documentation is complete, legible, and accurate; 
and entries are made in a timely manner by appropriately delegated study staff.   
The PI and site personnel will provide the Medtronic monitor(s) with direct access to source 
documentation or certified copies that supports the data on the eCRFs as well as other documentation 
supporting the conduct of the study.   
Medtronic or third-party auditors representing Medtronic may perform clinical site audits to verify the 
performance of the monitoring process, study conduct, and to ensure compliance with applicable 
regulations. Representatives from regulatory bodies such as the FDA may also perform site inspections 
related to this clinical study.  The PI, site personnel, and institution will provide monitors, auditors, and 
FDA with direct access to source documentation and all study-related documentation.  
Medtronic will investigate all suspected cases of fraud or misconduct as appropriate. 
16.5 Confidentiality 
All records and other information about subjects participating in this clinical study will be treated as 
confidential. Subject confidentiality will be maintained throughout the clinical study to the extent 
permitted by law. For this purpose, a unique study-specific subject identification code (study - site - 
subject number) will be assigned and used to allow identification of all data reported to Medtronic for 
each subject. Subject confidentiality is assured through use of the study-specific subject identification 
numbers, use of initials only, and the de-identifying of subjects’ records obtained by or provided to the 
Sponsor.  
For purposes of monitoring this study, access to clinic and hospital records must be available to 
Medtronic, representatives of Medtronic (i.e. contractors and other designees), the FDA and other 
regulatory agencies.  Study data may be made available to third parties (e.g., in the case of an audit or 
inspection performed by regulatory authorities), provided the data are treated confidentially and the 


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subject’s privacy is guaranteed. The identity of a subject will never be disclosed in the event study data 
are published. Only anonymized data will be analyzed and published. 
In addition to the review of records at the center, release of de-identified records to Medtronic may be 
necessary. The investigational site personnel must make every effort to de-identify and label source 
documentation with the subject’s study-specific identification number prior to submission of the records 
to Medtronic. 
Health Insurance Portability and Accountability Act (HIPAA) language will be required to be included at 
every center. HIPAA language may be included within the ICF, or separately, according to the center’s 
policy. 
16.6 Liability 
The compensation and covered liability associated with this study conduct will be documented in a 
separate financial agreement signed by Medtronic, the PI, and/or the management of the study 
site/institution. 
16.7 CIP Amendments 
Protocol amendments may be initiated by Medtronic to address changes to the scope or conduct of the 
study. Protocol amendments, and associated documents, must be approved by Medtronic and 
submitted to the reviewing IRBs for approval prior to implementation except when necessary to 
eliminate an immediate or apparent immediate hazard to participating subjects. 
16.8 Record Retention 
16.8.1 
Investigator Records 
Documentation for this study will be produced and maintained to ensure that a complete history of the 
study exists.  Documents created for this study, including all versions of original documents, will be 
identifiable and appropriately stored to assure control and traceability of data related to this study. 
The PI is responsible for ensuring that all essential study documentation is retained and accessible for a 
minimum of 2 years (or longer as local law or facility administration requires) after the investigation is 
terminated or completed.  The retention period may be longer if required by Medtronic, local or global 
regulatory requirements. Medtronic will be responsible for notifying sites of extensions to the 2-year 
minimum record retention requirements.  Medtronic must be notified in writing by site personnel of any 
transfer of study documentation.  The PI will ensure that essential study documents are not destroyed 
until written permission has been obtained from Medtronic or if allowed per contract.   


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At a minimum, the investigator is responsible for the preparation, review, submission to Medtronic and 
retention of all signed and dated case report forms, reportable adverse events, device deficiencies, 
subject deaths, deviations from the CIP. In addition, investigators are also responsible for maintaining all 
correspondence with another investigator, an IRB, the sponsor, a monitor, or FDA, related to this study 
(including approval documentation), records of each subject’s case history and exposure to the device 
(including signed and dated informed consent forms & HIPAA authorizations, as well as source 
documentation of the consent process), final report, and all other study-related documentation. 
16.8.2 
Investigator Reports 
The PI is responsible for the preparation (review and signature) and submission to the sponsor of all 
case report forms, adverse events, device deficiencies, deaths, and any deviations from the CIP. If any 
action is taken by an IRB with respect to this clinical study, copies of all pertinent documentation must 
be forwarded to Medtronic in a timely manner. Reports are subject to inspection and to the retention 
requirements as described above for investigator records.  
Investigator reporting requirements for termination or suspension are listed in Section 16.10. The 
investigator shall prepare and submit in a complete, accurate and timely manner the reports listed in 
this section. 
16.9 Publication and Use of Information 
It is intended that study results will be published in scientific literature. Information provided related to 
patent applications, technical design, or manufacturing processes supplied to the investigator as a part 
of the investigational plan is considered confidential and is not to be included in publications without 
the consent of Medtronic. If required by a publisher, the PI agrees to obtain all necessary authorizations 
from study subjects prior to submitting study-related information for publication. Specific requirements 
regarding publication of study data will be provided in the study center agreement and in the 
publication strategy. 
16.9.1 
Publication Committee 
Medtronic will form a publication committee to develop a publication strategy and to oversee the 
development and review of publications related to the study. The publication committee may include 
representation from physician study advisors, the designated participating investigators, and Medtronic. 
The publication committee will be responsible for overseeing and ensuring that the publication strategy 
is executed according to the established plan. Publication committee membership does not guarantee 
or provide privileges in terms of authorship. 
The publication committee members will be responsible for reviewing all primary and secondary 
manuscripts prior to submission to the target journal and for reviewing abstracts prior to submission to 
conferences. In addition, publication committee members will review and approve requests for 


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secondary (ancillary) multicenter publications not included in the publication strategy. Requests will be 
reviewed to determine scientific validity, potential conflicts with previously submitted publications, and 
the need for Medtronic resources. 
16.9.2 
Authorship Selection 
Authorship will follow the Ethical Considerations in the Conduct and Reporting of Research as defined by 
the International Committee of Medical Journal Editors (http://www.icmje.org). 
16.10 Suspension or Early Termination 
Early Termination is the closure of a clinical study that occurs prior to meeting defined endpoints. This is 
possible for the whole study or a single center. Suspension is a temporary postponement of study 
activities related to enrollment. This is possible for the whole study or a single center. Medtronic 
reserves the right to suspend or terminate the study or an individual study site at any time.  In the event 
the study is terminated, the subject’s devices will be programmed as per the investigator’s discretion 
and once exited from the study, subjects will be managed by their physician. 
16.10.1 Study-Wide Termination or Suspension 
Medtronic reserves the right to suspend or terminate the study at any time.  Reasons may include, but 
are not limited to, the following: 
• 
Insufficient enrollment to complete the study within the expected timeframe 
• 
Identification of adverse events or safety issues with the product or system that may impact the 
safety or welfare of study subjects 
• 
Product performance/product supply issues 
16.10.2 Investigator/Center Termination or Suspension 
Medtronic reserves the right to suspend or terminate the study at an individual site.  Reasons may 
include, but are not limited to, the following: 
• 
Noncompliance with the protocol  
• 
IRB approval lapse/expiration 
• 
Serious or repeated deviations at the site 
• 
Failure to implement required corrective and preventive actions 
• 
Insufficient enrollment to complete the study within the expected timeframe 
• 
Loss of appropriately trained site personnel 
• 
Investigator request (e.g. no longer able to support the study) 
 


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Investigators are required to notify the IRB of study suspension/termination.  Subjects will be notified by 
the investigator of suspension/termination due to unacceptable risk or of termination due to any other 
cause. 
17. References 
1.  
Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. 
Anesthesiology. 1979;50(2):149-51. 
2.  
Onofrio BM, Yaksh TL, Arnold PG. Continuous low-dose intrathecal morphine administration in 
the treatment of chronic pain of malignant origin. Mayo Clin Proc. 1981;56(8):516-20. 
3.  
Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery 
system compared with comprehensive medical management for refractory cancer pain: impact 
on pain, drug-related toxicity, and survival. J Clin Oncol. 2002;20(19):4040-9. 
4.  
LS S. Relieving pain in America: A blueprint for transforming prevention, care, education, and 
research. 2012. 
5.  
Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference--2012: consensus on 
diagnosis, detection, and treatment of catheter-tip granulomas (inflammatory masses). 
Neuromodulation. 2012;15(5):483-95; discussion 496. 
6.  
Allen JW, Horais KA, Tozier NA, et al. Time course and role of morphine dose and concentration 
in intrathecal granuloma formation in dogs: a combined magnetic resonance imaging and 
histopathology investigation. Anesthesiology. 2006;105(3):581-9. 
7.  
Allen JW, Horais KA, Tozier NA, Yaksh TL. Opiate pharmacology of intrathecal granulomas. 
Anesthesiology. 2006;105(3):590-8. 
8.  
Yaksh TL, Hassenbusch S, Burchiel K, Hildebrand KR, Page LM, Coffey RJ. Inflammatory masses 
associated with intrathecal drug infusion: a review of preclinical evidence and human data. Pain 
Med. 2002;3(4):300-12. 
9.  
Staats PS, Yearwood T, Charapata SG, et al. Intrathecal ziconotide in the treatment of refractory 
pain in patients with cancer or AIDS: a randomized controlled trial. JAMA. 2004;291(1):63-70. 
10.  
Rauck RL, Wallace MS, Leong MS, et al. A randomized, double-blind, placebo-controlled study of 
intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. 
2006;31(5):393-406. 
11.  
Wallace MS, Charapata SG, Fisher R, et al. Intrathecal ziconotide in the treatment of chronic 
nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial. 
Neuromodulation. 2006;9(2):75-86. 
12.  
Hamza M, Doleys D, Wells M, et al. Prospective study of 3-year follow-up of low-dose intrathecal 
opioids in the management of chronic nonmalignant pain. Pain Med. 2012;13(10):1304-13. 
13.  
Grider JS, Etscheidt MA, Harned ME, et al. Trialing and Maintenance Dosing Using a Low-Dose 
Intrathecal Opioid Method for Chronic Nonmalignant Pain: A Prospective 36-Month Study. 
Neuromodulation. 2016;19(2):206-19. 
14.  
Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery 
system compared with comprehensive medical management for refractory cancer pain: impact 
on pain, drug-related toxicity, and survival. J Clin Oncol. 2002;20(19):4040-9. 


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15.  
Hamza M, Doleys DM, Saleh IA, Medvedovsky A, Verdolin MH, Hamza M. A Prospective, 
Randomized, Single-Blinded, Head-to-Head Long-Term Outcome Study, Comparing Intrathecal 
(IT) Boluses With Continuous Infusion Trialing Techniques Prior to Implantation of Drug Delivery 
Systems (DDS) for the Treatment of Severe Intractable Chronic Nonmalignant Pain. 
Neuromodulation. 2015;18(7):636-48; discussion 649. 
16.  
Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference 2012: recommendations for 
the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary 
expert panel. Neuromodulation. 2012;15(5):436-64; discussion 464-6. 
17.  
Deer TR, Pope JE, Hayek SM, et al. The Polyanalgesic Consensus Conference (PACC): 
Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines. 
Neuromodulation. 2017;20(2):96-132. 
18.  
Deer TR, Pope JE, Hayek SM, et al. The Polyanalgesic Consensus Conference (PACC): 
Recommendations for Intrathecal Drug Delivery: Guidance for Improving Safety and Mitigating 
Risks. Neuromodulation. 2017;20(2):155-176. 
19.  
Deer TR, Hayek SM, Pope JE, et al. The Polyanalgesic Consensus Conference (PACC): 
Recommendations for Trialing of Intrathecal Drug Delivery Infusion Therapy. Neuromodulation. 
2017;20(2):133-154. 
20.  
Prager J, Deer T, Levy R, et al. Best practices for intrathecal drug delivery for pain. 
Neuromodulation. 2014;17(4):354-72; discussion 372. 
21.  
Deer TR, Hayek SM, Pope JE, et al. The Polyanalgesic Consensus Conference (PACC): 
Recommendations for Trialing of Intrathecal Drug Delivery Infusion Therapy. Neuromodulation. 
2017;20(2):133-154. 
22.  
Deer TR, Pope JE, Hayek SM, et al. The Polyanalgesic Consensus Conference (PACC): 
Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines. 
Neuromodulation. 2017;20(2):96-132. 
23.  
Deer TR, Pope JE, Hayek SM, et al. The Polyanalgesic Consensus Conference (PACC): 
Recommendations for Intrathecal Drug Delivery: Guidance for Improving Safety and Mitigating 
Risks. Neuromodulation. 2017;20(2):155-176. 
24.  
Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose: a 
cohort study. Ann Intern Med. 2010;152(2):85-92. 
25.  
 
 
18. Appendices 
18.1 Appendix A: Additional Information for Sites 
Detailed sponsor contact information not outlined in the Clinical Investigational Plan will be provided 
under a separate cover. 
18.2 Appendix B: Institutional Review Boards 
The table below represents all IRBs that were active at any time during the study. Information contained 
in this table is subject to change and will not require CIP revision. 


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IRB Name 
Location 
Leadership/Chair 
WIRB Copernicus Group (WCG) IRB 
1019 39th Ave., SE 
Suite 120 
Puyallup, WA 98374 
 
Eastern Virginia Medical School Office 
Research IRB* 
721 Fairfax Ave. 
Suite 128 
Norfolk, VA 23507 
 
University of Texas Medical Branch 
Health IRB 
301 University Blvd. 
Galveston, TX 77555 
 
Lehigh Valley Health Network IRB* 
1255 S. Cedar Crest Blvd. 
Suite 3200 
Allentown, PA 18103 
 
* Study was closed with the IRB under CIP V2.0 
18.3 Appendix C: Participating Principal Investigators and 
Institutions 
The table below represents all sites that were activated for participation, regardless of if they enrolled 
subjects or not. 
Investigator Name 
Institution / Site Name 
Site Address 
 
Northwest Pain Care 
  
  
Spokane, WA 99201 
 
Premier Pain Treatment 
Institute 
 
Mount Orab, OH 45154 
 
Coastal Pain and Spinal 
Diagnostics 
  
 
Carlsbad, CA 92009 
* 
University of Virginia Pain 
Management Center 
 
  
Charlottesville, VA 22908 
 
Regional Brain & Spine 
 
  
Cape Girardeau, MO 63701 
 
The Pain Management Center   
 
 
Voorhees, NJ 08043 


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Investigator Name 
Institution / Site Name 
Site Address 
* 
University of Texas Medical 
Branch 
 
Galveston, TX 77555-0591 
 
Clinical Investigations 
                     
Edmond, OK 73013-3023 
 
Christian Hospital  
  
St. Louis, MO 63136 
* 
Lehigh Valley Health Network 
Office of Research and 
Innovation 
  
  
Allentown, PA 18103 
* 
Eastern Virginia Medical School 
  
   
Norfolk, VA 23507 
 
Comprehensive and 
Interventional Pain 
Management 
  
 
Henderson, NV 89052 
 
Moss Rehab - Einstein 
Healthcare Network 
 
Elkins Park, PA 19027 
 
Florida Pain Institute Merritt 
Island 
  
 
Merritt Island, FL 32953 
 
Precision Spine Care 
 
Tyler, TX 75701 
 
Napa Valley Orthopaedic 
Medical Group 
 
 
Napa, CA 94558 
 
Neuroversion 
 
 
Anchorage, AK 99508 
* Site closed under CIP V2.0 
 
 


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19. Version History 
Version 
Summary of changes 
Author(s)/Title 
1.0 
• 
Not Applicable, New Document 
 Pr. CRS 
2.0 
Amendment 1 includes the following updates and 
clarifications: 
a. patients using cannabinoids (including cannabidiol) 
are excluded from the study 
b. patients must be on a minimum daily systemic opioid 
dose > 0 MME at the time of enrollment in the study 
c. psychological evaluation to be conducted per 
standard of care 
d. patient must have an MRI or CT and no clinical 
change in status since last imaging 
e. drug testing may be conducted using urine, blood, or 
oral fluid, per standard of care 
f. 
removed VAS, NOSE, and drug screen from the 
Implant visit 
g. confirm urine pregnancy test completed within 2 
weeks prior to implant, per standard of care 
Pr. CRS 
3.0 
Amendment 2 includes the following updates: 
• 
Transitioned to 056-F275 CIP template vB 
• 
Updated language on study follow-up duration to 
include study exit at 6 months throughout (removal 
of 9 Month and 12 Month visits) 
• 
 
 
• 
Entered final enrollment number of 93 subjects 
throughout 
• 
Inserted Section 8: Study Site Requirements in 
alignment with new CIP Template 
• 
Updated section 10.5 (Post-Op) to include “Initial and 
Final device interrogation reports” missed under V2.0 
• 
Updated section 10.1, Table 2, section 10.7, and 
section 10.11 (Table 3) to remove reference to 9 and 
12 month visits 
• 
 
• 
Updated language in section 14.1.1 and 14.4.1 to 
correct the non-inferiority margin for VAS from 1 to 
10 and to clarify sample size calculations 
• 
Updated section references throughout CIP 
Sr. CRS 
 

SAP_001.pdf: 
Official Title of Study : Embrace TDD: Prospective, Multi-Center, Post-Market Study to
Evaluate Intrathecal (IT) Morphine as an Alternative to Systemic Opioids for the Treatment of
Chronic, Intractable, Non-Malignant Primary Back Pain with or without Leg Pain
NCT Number: NCT03761277
Date of Document: 03JUN2021
Document Type: Statistical Analysis Plan


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Statistical Analysis Plan 
Clinical Investigation Plan Title Embrace TDD: Prospective, Multi-Center, Post 
Market Study to Evaluate Intrathecal (IT) Morphine 
as an Alternative to Systemic Opioids for the 
Treatment of Chronic, Intractable, Non-Malignant 
Primary Back Pain with or without Leg Pain 
Clinical Investigation Plan Identifier MDT18026 
Clinical Investigation Plan Version Version 3.0 
Sponsor/Local Sponsor Medtronic, Inc. 
Medtronic Neuromodulation 
7000 Central Avenue NE 
Minneapolis, MN 55432 
USA 
1-763-514-4000
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Medtronic. 
Any distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly 
prohibited. Persons to whom the information is disclosed must know that it is confidential and that it 
may not be further disclosed by them. 


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Table of Contents 
1. 
Version History ........................................................................................................................ 3 
2. 
List of Abbreviations and Definitions of Terms ............................................................................ 3 
3. 
Introduction............................................................................................................................. 4 
4. 
Study Objectives ...................................................................................................................... 4 
4.1 
Primary Objective ...................................................................................................................... 4 
4.2 
Secondary Objectives ................................................................................................................ 5 
 
 
4.4 
Safety Assessment .................................................................................................................... 6 
5. 
Investigation Plan .................................................................................................................... 6 
5.1 
Study Design .............................................................................................................................. 6 
5.2 
Study Measures ......................................................................................................................... 6 
6. 
Determination of Sample Size ................................................................................................. 11 
7. 
Statistical Methods ................................................................................................................. 12 
7.1 
Study Subjects ......................................................................................................................... 12 
7.2 
General Methodology ............................................................................................................. 13 
7.3 
Center Pooling ......................................................................................................................... 13 
7.4 
Handling of Missing, Unused, and Spurious Data and Dropouts ............................................ 14 
7.5 
Adjustments for Multiple Comparisons .................................................................................. 14 
7.6 
Demographic and Other Baseline Characteristics .................................................................. 14 
7.7 
Treatment Characteristics ....................................................................................................... 14 
7.8 
Interim Analyses ...................................................................................................................... 15 
7.9 
Evaluation of Objectives ......................................................................................................... 15 
7.10 
Safety Evaluation..................................................................................................................... 25 
7.11 
Changes to Planned Analysis................................................................................................... 25 
8. 
Validation Requirements ......................................................................................................... 25 
9. 
References ............................................................................................................................ 26 
 
 


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1. 
Version History 
Version 
Summary of Changes 
Author(s)/Title 
1.0 
• 
Not Applicable, New Document 
 Principal Statistician 
2.0 
• 
Transferred content to new template (vB) 
• 
Updated non-inferiority margin for 
Secondary Objective #1 to 10 from 1 
• 
Added considerations due to COVID-19, 
including: 
o Exits and deviations 
o Data handling of remote visits  
• 
 
• 
Updated primary analysis for primary 
objective  
• 
Added explanation of differing follow-up 
duration for CIP v3 
• 
Added analysis clarifications and minor 
edits throughout 
 Principal 
Statistician 
2. 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
 
 
CI 
Confidence Interval 
CIP 
Clinical Investigational Plan 
COVID-19 
Coronavirus Disease 2019 
DD 
Device Deficiency 
 
 
FCS 
Fully Conditional Specification  
IDDS 
Intrathecal Drug Delivery System  
IT 
Intrathecal 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MI 
Multiple Imputation 
MME 
Morphine Milligram Equivalents 
NOSE 
Numerical Opioid Side Effect  
 
 
PFMS 
Preservative-Free Morphine Sulfate 
 
 


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Abbreviation 
Definition 
AE 
Adverse Event 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SOC 
System Organ Class 
 
 
TDD 
Target Drug Delivery 
VAS 
Visual Analog Scale 
WHO 
World Health Organization  
 
3. 
Introduction 
This statistical analysis plan (SAP) is based on Version 3 of the Embrace TDD Study Clinical Investigational 
Plan (CIP). CIP v3.0 changed the last study visit from the 12-Month Visit to the 6-Month Visit. Some 
subjects will have follow-up in the study past the 6-Month Visit, and other subjects will not have follow-
up through the 12-Month Visit due to being consented and exited under CIP v3.0. The SAP presents the 
details of the methods to be used to analyze and report the study results of the Embrace TDD study, 
protocol number MDT18026.  
4. 
Study Objectives 
4.1 Primary Objective 
To characterize the proportion of subjects with Clinical Success at the 6-Month Visit based on changes in 
pain intensity using the Visual Analog Scale (VAS) and changes in opioid-related side effects using the 
Numerical Opioid Side Effect (NOSE) Assessment Tool. 
Clinical Success is defined as any of the following (refer to grid below with matching numbers): 
1) Reduced opioid-related side effects with equal pain 
2) Reduced pain with equal opioid-related side effects  
3) Reduced pain and reduced opioid-related side effects  
 


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Criteria for Clinical Success 
Change  
from Baseline  
to the 6-Month Visit  
Opioid-Related Side Effects 
(NOSE) 
≥20% 
Increase 
< ±20% 
Change 
≥20% 
Reduction 
Worse 
Equal 
Better 
Pain Intensity (VAS) 
≥20% 
Increase 
Worse 
  
  
  
< ±20% 
Change 
Equal 
  
  
1  
≥20% 
Reduction 
Better 
  
 2 
 3 
 
4.2 Secondary Objectives 
1. To demonstrate pain intensity scores (VAS) at the 6-Month Visit is non-inferior to VAS at 
Baseline 
2. To characterize the change in opioid-related side effect scores (NOSE) from Baseline to the 6-
Month Visit  
3. To characterize the proportion of subjects who eliminate systemic opioids through the 6-Month 
Visit 
 
 
 
  
 
 
 
 
 
 
 
  


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4.4 Safety Assessment 
To characterize all systemic opioid weaning-related, device-related, IT drug-related, and procedure-
related adverse events (AEs), all serious adverse events (SAEs) (regardless of relatedness), and device 
deficiencies (DD) for all subjects from enrollment until the subject exits. 
5. 
Investigation Plan 
5.1 Study Design 
The purpose of the study is to assess pain control and opioid-related side effects following a route of 
delivery change from systemic opioid therapy to IT morphine therapy. 
This is a prospective, multi-center, post market study with commercially available products to evaluate 
the pain control and opioid-related side effects following a route of delivery change from systemic 
opioid therapy to IT morphine therapy in subjects with chronic, intractable, non-malignant primary back 
pain with or without leg pain. The study will be conducted at approximately 15 study sites in the United 
States. 
5.2 Study Measures 
5.2.1 
Efficacy Measures 
5.2.1.1 Visual Analog Scale (VAS) 
Pain will be assessed using VAS. The VAS is a 100 mm line, with “No pain” on the left side of the line and 
“Worst pain imaginable” on the right side of the line. Subjects will be asked to mark a line perpendicular 
to the VAS line that best describes their average pain in the last 24 hours. 
5.2.1.2 Numerical Opioid Side Effect Assessment Tool (NOSE) 
The Numerical Opioid Side Effect (NOSE) Assessment Tool is a tool to evaluate 10 opioid-related side 
effects using a 11-point numeric scale. 4 Subjects are asked to evaluate each of the 10 opioid-related side 
effects on a scale of 0-10 with 0 being not present and 10 being as bad as you can imagine. A total sum 
score can range from 0-100. The opioid side effects included: 1) Nausea, vomiting, and/or lack of 
appetite; 2) Fatigue, sleepiness, trouble concentrating, hallucinations, and/or drowsiness/somnolence; 
3) Constipation; 4) Itching; 5) Decreased sexual desire/function and/or diminished libido; 6) Dry mouth; 
7) Abdominal pain or discomfort/cramping or bloating; 8) Sweating; 9) Headache and/or dizziness; 10) 
Urinary retention. The score from each side effect as well as the total sum score from all side effects 
may be reported. 


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5.2.2 
Safety Measures 
Subjects will be assessed from enrollment through the end of the study for AEs related to the following: 
• 
Systemic opioid weaning 
• 
Device 
• 
IT drug 
• 
Procedure 
In addition, all SAEs (regardless of relatedness) and device deficiencies reported during the study will be 
collected. All subject deaths (regardless of relatedness) must be reported to Medtronic. 
5.2.3 Schedule of Events by Visit and Visit Windows 
Study procedures and data collection requirements for the study are summarized in Table 5-1. The study 
visit windows for all the required study visits are provided in Table 5-2. The 9- and 12-Month Visits were 
required under CIP v1.0 and v2.0; they are not scheduled study visits under CIP v3.0. 


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Table 5-1 Schedule of Events by Visit 
Study Procedures, 
Tasks, and Data 
Collection (row) by Visit 
(column) 
Baseline Visit (Enrollment) 
Intrathecal Trial Visit 
Implant Visit 
Post-Op Visit 
IT Therapy Initiation  
1-Month Visit  
3-Month Visit 
6-Month Visit 
9-Month Visit 1 
12-Month Visit 1 
Unscheduled Visits 
Informed Consent Process 
√ 
 
 
 
 
 
 
 
 
 
 
Demographics 
√ 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
√ 
√ 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
√ 
√ 
√2 
 
√ 
√ 
√ 
√ 
√ 
√ 
 
Drug Test 
√ 
√ 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
 
Adjunctive pain 
management therapies  
√ 
√ 
√ 
 
√ 
 
 
 
 
 
 
Back and Leg Pain/Surgical 
History 
√ 
 
 
 
 
 
 
 
 
 
 
VAS 
√ 
√ 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
NOSE Assessment 
√ 
√ 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
IT PFMS Dose 
 
 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fluoroscopy/x-ray  
 
 
√ 
 
 
 
 
 
 
 
 
Device information (model, 
serial/lot #) 
 
 
√ 
 
 
 
 
 
 
 
 
Drug information (name, 
lot #/identifier, dose & 
concentration) 
 
√ 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Initial and final device 
interrogation reports 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Collect AEs/DDs 
√3 
√ 
√3 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Pain Medications 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
1Required visits under CIP v1.0 and v2.0, not required under CIP v3.0. 
2Confirm pregnancy test completed within 2 weeks prior to implant visit 
3Device Deficiencies will be collected and reported from the Implant Visit through the 12-Month Visit/Study Exit 
 


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Table 5-2 Visit Windows 
 
Study Visits 
Visit Windows 
Baseline Visit 
Date of Enrollment  
(Date ICF/HIPAA signed and dated) 
Intrathecal Trial Visit 
After Baseline and prior to Implant  
IT Therapy Initiation 
(Day 0) 
Implant to Post-Op 
Visit 
Implant Visit 
 ≤150 days after the Baseline Visit 
Post-Op Visit 
14 ± 4 days after the Implant Visit 
 
1-Month Visit 
30 days ± 5 days after Day 0 
3-Month Visit 
90 days ± 10 days after Day 0 
6-Month Visit1 
180 days ± 10 days after Day 0 
9-Month Visit2 
270 days ± 15 days after Day 0 
12-Month Visit (Study Exit)2 
360 days ± 15 days after Day 0 
1 Study Exit Visit under CIP v3.0 
2 Required Visits under CIP v1.0 and 2.0 
 
6. 
Determination of Sample Size 
Approximately 100 subjects will be enrolled into the study to get a minimum of 67 implanted subjects 
and at least 50 evaluable subjects at the 6-Month Visit. The sample size of 50 evaluable subjects was 
chosen to assure acceptable levels of precision for estimation of the primary objective of Clinical Success 
and provide adequate power to test the secondary objective related to pain score.  
There were no available data in the target population on the primary objective of Clinical Success, nor 
on the secondary objective of opioid-related side effects score. The secondary objective of pain intensity 
score is used for sample size calculation. It is hypothesized that the pain intensity score of VAS at the 6-
Month Visit is non-inferior to those at Baseline using a non-inferiority approach. 
The PASS 11 Non-Inferiority Tests for One Mean was used to calculate the power for pain intensity of 
VAS with the following assumptions: Sample size = 50, Alpha = 0.025, Non-Inferiority Margin = 1, True 
Difference = 0, Standard Deviation = 1.9, with Higher Means are Worse (one-sided) t-test. A sample size 
of 50 would achieve 95% power with the above assumptions. This power calculation was performed 
using a pain scale of 0-10; however, the power calculation is identical to one with a non-inferiority 
margin of 10 and assuming a standard deviation of 19 on a VAS pain scale of 0-100. 


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The non-inferiority margin of 10 points was chosen based on a review of pain study literature. Non-
inferiority margins between 1 and 1.5 were reported for pain scales of 0-10, including one study in a 
similar population of chronic non-malignant pain subjects comparing 2 oral opioids that utilized a margin 
of 1.1 The estimated actual difference was assumed to be 0 because the goal is to achieve same or 
better pain control as compared to Baseline. 
 
 
 
 
 
The non-inferiority margin of 1 on a pain scale of 0-10 is 
equivalent to a non-inferiority margin of 10 on a VAS pain scale of 0-100. 
A 33% attrition between enrollment and subject implant is assumed and a 25% attrition between 
Implant and the 6-Month Visit is assumed. To achieve at least 50 evaluable subjects at the 6-Month 
Visit, a minimum of 67 subjects are required to be implanted and approximately 100 subjects to be 
enrolled.  
The 33% attrition between enrollment and subject implant accounts for the subjects who don’t meet 
inclusion and/or exclusion criteria, those who can’t follow the weaning process to eliminate systemic 
opioids, those who don’t have a successful IT trial, those who have adverse events that can no longer be 
followed in the study, withdrawals, and lost-to-follow-up, etc. The attrition between implant and the 6-
Month Visit is conservatively set at 25% to potentially account for the subjects who have adverse events 
that can no longer be followed in the study, withdrawals, are lost-to-follow-up, or subjects who can’t be 
effectively managed on morphine monotherapy.  
7. 
Statistical Methods 
7.1 Study Subjects 
7.1.1 
Disposition of Subjects 
Subject disposition will be summarized using a flow diagram.  Reasons for subject discontinuations, 
including those due to COVID-19 and/or the pump supply shortage, will be summarized.  
7.1.2 
Clinical Investigation Plan (CIP) Deviations 
All CIP deviations will be summarized by type of deviation.  Details of CIP deviations that affect scientific 
integrity or patient safety will be presented. Additionally, separate summaries of study deviations due to 
COVID-19 and due to the pump supply shortage with their respective impact on the study data will be 
provided. 
7.1.3 
Analysis Sets 
Full Analysis Set 
All enrolled subjects will be included in the Full Analysis Set. This data set is also used for safety analysis, 
as well as for the analysis of systemic opioids weaning and holiday process.  
IT Trial Analysis Set 
All subjects who experience the IT trial will be included in the IT Trial Analysis Set.   


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Implanted Analysis Set 
All subjects who are implanted with the Intrathecal Drug Delivery System (IDDS) will be included in the 
Implanted Analysis Set. This data set is used for supporting analysis for the primary and secondary 
objectives, as well as the analysis of adverse events that are related to device, IT drug, and procedure, 
and device deficiencies.  
Completers Analysis Set 
The implanted subjects who provide data at both the Baseline and the 6-Month Visit will be included in 
the Completers Analysis Set. This data set is used for supporting analysis for the primary and secondary 
objectives, as well as some additional measures at the 6-Month Visit. Completers Analysis Set may vary 
for different measures based on the subjects who provide data. 
Per-protocol Analysis Set 
The implanted subjects who maintain morphine monotherapy and provide data at both the Baseline and 
the 6-Month Visit will be included in the Per Protocol Analysis Set. This data set is used for a supporting 
analysis for the primary objective and the primary analyses for the secondary objectives, as well as some 
additional measures at the 6-Month Visit. Per-protocol Analysis Set may vary for different measures 
based on the subjects who provide data. 
Primary Objective Analysis Set 
The implanted subjects who maintain morphine monotherapy and provide data at both the Baseline and 
the 6-Month Visit through the date of the snapshot that will be conducted in November 2021 will be 
included in the Primary Objective Analysis Set. This data set is used for primary analysis for the primary 
objective. This analysis set may be a subset of subjects in the Per-Protocol and Completers Analysis Sets, 
as additional subjects may complete their 6-Month Visit following the November 2021 snapshot. 
Long-term Analysis Sets 
The implanted subjects who provide data at both the Baseline and the 12-Month Visit will be included in 
the Long-term Analysis Sets. These analysis sets include both per-protocol population (who maintain 
morphine monotherapy throughout the 12-Month Visit) and completers population. 
7.2 General Methodology 
Data analysis will be performed by Medtronic-employed statisticians or designees. A validated statistical 
software package will be used for the analyses of the study results (e.g., SAS). 
This SAP is developed prior to data analysis and will include a comprehensive description of the 
statistical methods to be included in the final study report. Any change to the data analysis methods 
described in the CIP will require an amendment only if it changes a principal feature of the CIP. Any 
other change to the data analysis methods described in the CIP, and the justification for making the 
change, will be described in the clinical study report. 
7.3 Center Pooling 
The investigators of this study will conduct the study according to a common protocol and use the same 
CRFs to collect study data. The site study personnel will be trained prior to the study initiation at each 
site. Periodic study monitoring by Medtronic will ensure compliance with protocol requirements.  


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There is not a priori provision to exclude any sites from the analysis. The data from all sites will be 
pooled for analysis. To reduce the possibility of atypical results from a site overly influencing the 
combined results, no more than 15 subjects will be enrolled at each site, unless the site gets pre-
approval from Medtronic for additional enrollments. 
Due to the relatively small number of subjects expected at each center, there is no plan to use statistical 
methods to test for a difference among centers. Primary objective results will be summarized by center 
to verify there is not a site that unduly influences the results, and will be included in reports if there are 
concerns about the center effect. 
7.4 Handling of Missing, Unused, and Spurious Data and 
Dropouts 
Missing data are a potential source of bias when analyzing study data. A rigorous study design and 
execution will help prevent the incidence of missing data from occurring.  
The primary analysis of the primary and secondary objectives will include subjects who maintain 
morphine monotherapy and provide data (per-protocol population). Sensitivity analyses will be 
performed for the primary and secondary objectives for VAS and NOSE using the Multiple Imputation 
(MI) methodology for missing data in VAS and NOSE scores for all implanted subjects. Details of the 
imputation method are described in Sections 7.9.2.3 and 7.9.3.3.  
7.4.1 
Data collected via remote visits due to COVID-19 
With the onset of the COVID-19 pandemic in 2020, some study visits will be conducted remotely with 
the patient reported outcome data collected via telephone. Data captured via remote visit will be 
included in the main analyses of the primary, secondary, and additional objectives, where applicable. If 
more than 10% of the 6-Month Visits are completed remotely, sensitivity analyses of the Primary 
Objective and Secondary Objectives #1 and #2 will be conducted separately for subjects whose 
responses were collected exclusively during in-clinic visits and for subjects whose 6-Month data were 
collected remotely.  
7.5 Adjustments for Multiple Comparisons 
As there is only one hypothesis testing for one secondary objective, adjustment for multiple endpoints is 
not required.  
7.6 Demographic and Other Baseline Characteristics 
Demographics and baseline characteristics will be summarized in the report for enrolled subjects, 
implanted subjects, and per-protocol subjects who complete the 6-Month Visit.  
7.7 Treatment Characteristics  
The implanted pump and catheter models as well as catheter tips and locations will be summarized. The 
exposure to the IT therapy is defined as duration from the date of IT Therapy Initiation to the date of last 
study follow-up.  
Subjects’ pain medications will be collected and summarized. All pain medications will be coded using 
the appropriate version of the World Health Organization (WHO) Drug Dictionary at the appropriate 
Anatomical Therapeutic Chemical (ATC) level.  


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7.8 Interim Analyses  
There is no planned interim analysis for the primary and secondary objective #1 for VAS in this study. 
The primary objective analysis will include all subjects in the Per-protocol Analysis Set who have 
completed their 6-Month Visit by the snapshot date in November 2021 (Primary Objective Analysis Set). 
Supporting analyses for the primary objective will include all subjects who complete the 6-Month Visit. 
Additional details are provided in Section 7.9.1. 
7.9 Evaluation of Objectives 
7.9.1 
Primary Objective - Clinical Success at the 6-Month Visit 
To characterize the proportion of subjects with Clinical Success at the 6-Month Visit based on changes in 
pain intensity using the Visual Analog Scale (VAS) and changes in opioid-related side effects using the 
Numerical Opioid Side Effect (NOSE) Assessment Tool. 
7.9.1.1 Hypothesis 
There is no formal hypothesis. The objective is to estimate the proportion of Clinical Success at the 6-
Month Visit. 
7.9.1.2 Experimental Design 
The Clinical Success comprises 2 separate measures, pain intensity and opioid-related side effects. The 
measurements of pain intensity using VAS and opioid-related side effects using NOSE are described in 
Sections 5.2.1.1 and 5.2.1.2. Both pain intensity and opioid-related side effects are measured as a 
percent change from Baseline to the 6-Month Visit to calculate the Clinical Success.  
 
Pain Intensity: 
Percent change in pain intensity will be calculated as VAS at the 6-Month Visit minus VAS at Baseline, 
then divided by VAS at Baseline, expressed as a percentage. Individual subject percent change in pain 
intensity is categorized into three responder groups at the 6-Month Visit: 
• 
Worse than Baseline: percent of change in VAS ≥20% (increased equal to or more than 20%) if 
Baseline VAS is ≥10, or change in VAS is ≥2 if Baseline VAS is <10 
• 
Equal to Baseline: percent of change in VAS <20% and > -20% (increased less than 20% or 
decreased less than 20%) if Baseline VAS is ≥10, or change in VAS is between -2 and 2 if 
Baseline VAS is <10 
• 
Better than Baseline: percent of change in VAS ≤ -20% (decreased equal to or more than 20%) 
if Baseline VAS is ≥10, or change in VAS is ≤ -2 if Baseline VAS is <10 
 
Opioid-Related Side Effects: 
Percent change in NOSE will be calculated as NOSE at the 6-Month Visit minus NOSE at Baseline, then 
divided by NOSE at Baseline, expressed as a percentage. Individual subject percent change in NOSE is 
categorized into three responder groups at the 6-Month Visit: 


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• 
Worse than Baseline: percent of change in NOSE ≥20% (increased equal to or more than 20%) if 
Baseline NOSE is ≥10, or change in NOSE is ≥2 if Baseline NOSE is <10 
• 
Equal to Baseline: percent of change in NOSE <20% and > -20% (increased less than 20% or 
decreased less than 20%) if Baseline NOSE is ≥10, or change in NOSE is between -2 and 2 if 
Baseline NOSE is <10 
• 
Better than Baseline: percent of change in NOSE ≤ -20% (decreased equal to or more than 20%) 
if Baseline NOSE is ≥10, or change in NOSE is ≤ -2 if Baseline NOSE is <10 
 
Clinical Success: 
A subject’s Clinical Success is defined as any of the following and displayed in Figure 7-1: 
1. Reduced opioid-related side effects with equal pain 
2. Reduced pain with equal opioid-related side effects 
3. Reduced pain and reduced opioid-related side effects 
 
Figure 7-1 Clinical Success 
Change  
from Baseline  
to the 6-Month Visit  
Opioid-Related Side Effects 
(NOSE) 
≥20% 
Increase 
< ±20% 
Change 
≥20% 
Reduction 
Worse 
Equal 
Better 
Pain Intensity (VAS) 
≥20% 
Increase 
Worse 
  
  
  
< ±20% 
Change 
Equal 
  
  
1  
≥20% 
Reduction 
Better 
  
 2 
 3 
 
7.9.1.3 Analysis Methods 
The proportion of subjects with Clinical Success and its exact binomial two-sided 95% confidence 
interval will be reported. The primary analysis method will use all the implanted subjects who maintain 
morphine monotherapy and provide data at both Baseline and the 6-Month Visits through the snapshot 
date in November 2021 (Primary Objective Analysis Set). Assuming the estimated proportion of Clinical 


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Success is 70%, with a sample size of 50 subjects, the exact two-sided 95% confidence interval (CI) would 
be 55.4-82.1%, with a confidence width of 26.7%. The widest 95% CI would be at 28.9% for an estimated 
proportion of Clinical Success of 50% (95% CI 35.5-64.5%). 
Three sensitivity analyses will be performed: (1) the proportion of subjects with Clinical Success and its 
95% CI will be reported in subjects who maintain morphine monotherapy and provide data at the 
Baseline and the 6-Month Visits (Per-protocol Analysis Set), (2) the proportion of subjects with Clinical 
Success and its 95% CI will be reported in subjects who provide data at the Baseline and the 6-Month 
Visits (completers), (3) the proportion of subject with Clinical Success and its 95% CI will be reported in 
all implanted subjects with imputation method of MI for those who have missing VAS or NOSE at the 
Baseline or the 6-Month Visit. Details of the imputation method are described in Sections 7.9.2.3 and 
7.9.3.3. 
If more than 10% of the 6-Month Visits within the Per-protocol Analysis Set are conducted remotely, an 
additional sensitivity analysis of the Per-protocol Analysis Set will be performed as described in Section 
7.4.1. 
7.9.2 
Secondary Objective #1 – VAS at the 6-Month Visit 
To demonstrate pain intensity scores (VAS) at the 6-Month Visit is non-inferior to VAS at Baseline. 
7.9.2.1 Hypothesis 
The mean change in pain intensity using VAS from Baseline to the 6-Month Visit is not worse than 0 by 
more than 10 points.  
H0: μ ≥ 0 + |M| 
HA: μ < 0 + |M| 
Where μ is the mean change in VAS from Baseline to the 6-Month Visit and |M| is the absolute value of 
non-inferiority margin of 10. 
7.9.2.2 Experimental Design 
The measurement of pain intensity using VAS is described in Section 5.2.1.1. The change in VAS is 
calculated using VAS at the 6-Month Visit minus VAS at the Baseline Visit. A negative change is an 
improvement.  
7.9.2.3 Analysis Methods 
The change in VAS as well as VAS at both Baseline and the 6-Month Visit will be summarized using 
descriptive statistics, (e.g., mean, standard deviations, etc.). The non-inferiority null hypothesis will be 
tested using a one-sided 0.025 alpha level one sample t-test. The upper bound of the 95% CI of the 
mean change must be less than 10. If non-inferiority is met, a two-sided 0.05 alpha level t-test for 
superiority (vs. 0 change from Baseline) will be performed. If the distribution of the change in VAS 
doesn’t meet normality assumption (Shapiro-Wilk test), an appropriate non-parametric analysis such as 
Wilcoxon signed rank test will be performed. The primary analysis will use all the implanted subjects 
who maintain morphine monotherapy and provide data at both Baseline and 6-Month Visits. 
Two sensitivity analyses will be performed, one will include subjects who provide data (completers) and 
one will include all implanted subjects. The sensitivity analysis of all implanted subjects will be 
performed using MI method for missing data at the Baseline and the 6-Month Visits. For missing VAS at 


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the scheduled 6-Month Visit, if an Unscheduled Visit occurred within the 6-Month Visit window, and the 
VAS is collected at the Unscheduled Visit, the VAS from the Unscheduled Visit will be used in the analysis 
of the 6-Month Visit. Otherwise, the missing VAS will be imputed using MI. Prior to the use of MI, the 
distributions of the continuous variables will be assessed for normality and the need for transformation 
if they are not normally distributed. The model variables in MI may include the following when deemed 
appropriate: study site, subject age, gender, primary diagnosis, VAS at Baseline, 1-Month Visit, 3-Month 
Visit. The fully conditional specification (FCS) method with 10 burn-in iterations within SAS and 10 
repetitions (M = 10) will be used for imputation. Constraints will be set so that the imputed VAS are 
restricted to values ranging from 0-100. If the MI procedure is unable to successfully impute values 
within that range, the constraints will be applied after imputation, such that any values less than 0 will 
be set to 0, and any values greater than 100 will be set to 100. Following imputation, the objective will 
be evaluated using MI analysis method in SAS.  
In addition, percentage of change in VAS will be calculated using change in VAS divided by VAS at 
Baseline. A negative percentage of change in VAS is a percentage of reduction in VAS, thus an 
improvement. The percentage of change in VAS will be summarized using descriptive statistics, (e.g., 
median and inter-quartile range, etc.). If a subject has VAS equal to 0 at both the Baseline and the 6-
Month Visit, the percentage of change will be 0%. If a subject has VAS equal to 0 at the Baseline visit, 
and non-zero at the 6-Month Visit, this subject will be excluded from summary of percentage of change 
in VAS. 
If more than 10% of the 6-Month Visits within the Per-protocol Analysis Set are conducted remotely, an  
additional sensitivity analysis of the Per-protocol Analysis Set will be performed as described in Section 
7.4.1. Changes in VAS will be characterized without statistical testing for this analysis. 
7.9.3 
Secondary Objective #2 – NOSE at the 6-Month Visit 
To characterize the change in opioid-related side effects scores (NOSE) from Baseline to the 6-Month 
Visit. 
7.9.3.1 Hypothesis 
There is no formal hypothesis. The objective is to estimate the change in NOSE from Baseline to the 6-
Month Visit.  
7.9.3.2 Experimental Design 
The measurement of opioid-related side effect using NOSE is described in Section 5.2.1.2. The total 
NOSE score is the sum of each score from the 10 opioid-related side effects normalized by the number 
of scores provided. The change in NOSE is calculated using total NOSE score at the 6-Month Visit minus 
the total NOSE score at Baseline. A negative change is an improvement.  
7.9.3.3 Analysis Methods 
The change in NOSE as well as the total NOSE score at Baseline and the 6-Month Visit will be 
summarized using descriptive statistics (e.g., mean, standard deviations, etc.). The analysis will use all 
the implanted subjects who maintain morphine monotherapy and provide data at both Baseline and the 
6-Month Visits. 
Two sensitivity analyses will be performed, one will include subjects who provide data (completers) and 
one will include all implanted subjects. The sensitivity analysis of all implanted subjects will be 


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performed using MI method for missing data at the Baseline and the 6-Month Visits.  For missing NOSE 
at the scheduled 6-Month Visit, if an Unscheduled Visit occurred within the 6-Month Visit window, and 
NOSE is collected at the Unscheduled Visit, the NOSE from the Unscheduled Visit will be used in the 
analysis of the 6-Month Visit. Otherwise, the missing NOSE will be imputed using MI. Prior to the use of 
MI, the distributions of the continuous variables will be assessed for normality and the need for 
transformation if they are not normally distributed. The model variables in MI may include the following 
when deemed appropriate: study site, subject age, gender, primary diagnosis, NOSE at Baseline, 1-
Month Visit, 3-Month Visit. The fully conditional specification method with 10 burn-in iterations within 
SAS and 10 repetitions (M = 10) will be used for imputation. Constraints will be set so that the imputed 
NOSE are restricted to values ranging from 0-100. If the MI procedure is unable to successfully impute 
values within that range, the constraints will be applied after imputation, such that any values less than 
0 will be set to 0, and any values greater than 100 will be set to 100. Following imputation, the objective 
will be evaluated using MI analysis method. 
In addition, percentage of change in NOSE will be calculated using change in NOSE divided by the total 
NOSE score at Baseline. A negative percentage of change in NOSE is a percentage of reduction in NOSE, 
thus an improvement. The percentage of change in NOSE will be summarized using descriptive statistics, 
(e.g., median and inter-quartile range, etc.). If a subject has NOSE equal to 0 at both the Baseline and 
the 6-Month Visit, the percentage of change will be 0%. If a subject has NOSE equal to 0 at the Baseline 
visit, and non-zero at the 6-Month Visit, this subject will be excluded from summary of percentage of 
change in NOSE. 
NOSE score for each individual opioid-related side effect at Baseline and 6-Month Visit will be 
summarized using descriptive statistics (e.g., mean, standard deviations, etc.).  
If more than 10% of the 6-Month Visits within the Per-protocol Analysis Set are conducted remotely, an 
additional sensitivity analysis of the Per-protocol Analysis Set will be performed as described in Section 
7.4.1. 
7.9.4 
Secondary Objective #3 – Systemic Opioids Elimination through the 
6-Month Visit 
To characterize the proportion of subjects who eliminate systemic opioids through the 6-Month Visit.  
7.9.4.1 Hypothesis 
There is no formal hypothesis. The objective is to estimate the proportion of subjects who eliminate 
systemic opioids through the 6-Month Visit.   
7.9.4.2 Experimental Design 
The test for systemic opioids and illicit drug use will be collected at all scheduled study visits except for 
the Implant Visit and Post-op Visit. If a subject has a negative test for systemic opioid use, this subject 
will be considered as having eliminated systemic opioids at the scheduled study visit.  
7.9.4.3 Analysis Methods 
The proportion of subjects who eliminate systemic opioids and its exact binomial two-sided 95% CI will 
be reported at the 6-Month Visit as well as for those having eliminated systemic opioids from therapy 
initiation through the 6-Month Visit. The primary analysis method will use all the implanted subjects 
who maintain morphine monotherapy and provide data at the 6-Month Visit for the analysis at the 6-


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Month Visit. The implanted subjects who maintain morphine monotherapy and have no more than one 
missing test through the 6-Month Visit (out of the IT Therapy Initiation, 1-Month, and 3-Month Visits) 
will be included in the analysis of eliminate systemic opioids through the 6-Month Visit. Assume the 
estimated proportion is 80%, with a sample size of 50 subjects, the exact two-sided 95% CI would be 
66.3-90.0%, with a confidence width of 23.7%.  The widest 95% CI would be at 28.9% for an estimated 
proportion of 50% (95% CI 35.5-64.5%). 
Two sensitivity analyses for both at and through 6-Month Visit will be performed, one will include 
subjects who provide data (completers) and one will include all implanted subjects. The sensitivity 
analysis in all implanted subjects’ analysis will display the full range on the potential impact of missing 
data by running an analysis assuming all missing values had eliminated systemic opioids to none of the 
missing values having eliminated systemic opioids. 
In addition, an analysis following the primary analysis methods but excluding subjects who were not 
taking systemic opioids at baseline will be performed. The subjects who were not taking systemic 
opioids at baseline is defined as reporting MME = 0 at baseline. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
  
 
 


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7.10 Safety Evaluation  
The safety evaluation will characterize all systemic opioid weaning-related, device-related, IT drug-
related, and procedure-related adverse events (AEs), all serious adverse events (SAEs) (regardless of 
relatedness), and device deficiencies (DD) for all subjects from enrollment until the subject exits. 
Adverse events and device deficiencies will be coded and summarized using the most recent version of 
Medical Dictionary for Regulatory Affairs (MedDRA). 
The adverse events will also be categorized by relationship to systemic opioid weaning-related, device-
related, IT drug-related, and procedure-related adverse events. The CEC adjudicated relatedness will be 
used for summary tables in the final report. Any differences between CEC adjudication and investigator 
reporting will be noted in the final report.  
Adverse events will be presented in summary tables displaying the number of serious events, the 
number of events, and the number and percentage of subjects with one or more events. A summary of 
all adverse events by System Organ Class (SOC) and Preferred Term (PT) will also be provided.  
Device deficiencies will be presented in summary tables displaying the number of deficiencies, and the 
number and percentage of subjects with device deficiencies.  
7.11 Changes to Planned Analysis  
The main analysis for the primary objective was originally planned to be evaluated after all subjects had 
reached the 6-Month Visit. The primary analysis was changed to analyze all per-protocol subjects with a 
6-Month Visit through the snapshot date in November 2021 (Primary Objective Analysis Set, which will 
be a subset of the Per-Protocol Analysis Set). The primary objective is a characterization of the clinical 
success rate; it is a descriptive analysis with no hypothesis testing. Therefore, this change will affect the 
precision around the estimated clinical success rate for the main analysis but will otherwise minimally 
impact the objective. Additionally, all subjects within the Per-Protocol Analysis Set who eventually 
complete the 6-Month Visit will be evaluated as a sensitivity analysis for the primary objective to assess 
the robustness of the results. 
8. 
Validation Requirements 
Statistical programming code that affects the result of the main analysis for the primary objective shall 
be validated using Level I validation, which is defined as the peer reviewer independently programs 
output and then compares the output with that generated by the original Statistical Programmer.  
Statistical programming code that affects the result of the main analysis for the secondary objectives 
shall be validated using at least Level II validation, which is defined as the peer reviewer reviews the 
code, and where appropriate, performs manual calculations or simple programming checks to verify the 
output. The CIP deviation summary shall be validated using at least Level III validation and the high-level 
adverse event summary shall be validated using at least Level II validation. 
In addition, the main statistical analyses that are planned for publication and have not been previously 
validated should be validated with at least Level II validation.  


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9. 
References  
1. Binsfeld H, Szczepanski L, Waechter S, Richarz U, Sabatowski R.  A randomized study to demonstrate 
noninferiority of once-daily OROS® hydromorphone with twice-daily sustained-release oxycodone 
for moderate to severe chronic noncancer pain, Pain Pract. 2010;10(5):404–415. 
 
 
4. NOSE: Smith HS, Kirsh KL. Documentation and potential tools in long-term opioid therapy for pain. 
Anesthesiol Clin. 2007 Dec;25(4):809-23, vii.