Randomized Placebo-Controlled Single Blinded Study of Geniculate Artery Embolization for Knee Pain Secondary to Osteoarthritis
Phase: NA
Conditions: Osteo Arthritis Knee
Sponsor: University of North Carolina, Chapel Hill

 
Randomized Placebo-Controlled Single Blinded Study of Geniculate 
Artery Embolization for Knee Pain Secondary to Osteoarthritis 
 
NCT number NCT03362957 
Document Date August 16, 2018 
 

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Protocol Title: 
Randomized Placebo-Controlled Single 
Blinded Study of Geniculate Artery 
Embolization for Knee Pain Secondary 
to Osteoarthritis 
 
 
 
Sponsor: 
Ari Isaacson, MD (UNC-Chapel Hill, Radiology) 
Principal Investigators: 
Ari Isaacson, MD (UNC-Chapel Hill, Radiology) 
 
Rachel Piechowiak, DO (Vascular Institute of Virginia) 
 
 
Co-Investigator: 
Sandeep Bagla, MD (Vascular Institute of Virginia) 
 
William G. Hamilton, MD 
(Anderson Orthopedic 
Clinic) 
 
Biostatistician:  
Thad Benefield, MS (UNC-Chapel Hill, Radiology) 
 
 
Medical Device: 
Gel-Bead embolization spheres; OptiSphere 
embolization spheres 
 
IDE Number: 
G170229 
 
Version Date: 
8/16/18

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Table of Contents 
 
1 
Introduction 
1.1 
Study Conduct 
1.2 
Background 
1.3 
Medical Device 
1.3.1 Name of Investigational Device 
1.3.2 Intended Use of the Investigational Device 
1.3.3 Description of the Investigational Device 
1.4 
Preclinical Data 
1.5 
Clinical Data to Date 
2.0 
Study Objectives 
3 
Study Design 
3.1 
General Design 
3.2 
Primary Study Endpoints 
3.3 
Secondary Study Endpoints 
3.4 
Primary Safety Endpoints 
4 
Subject Selection and Withdrawal 
4.1 
General Characteristics of the Proposed Subject Population 
4.2 
Anticipated Number of Research Subjects 
4.3 
Inclusion Criteria 
4.4 
Exclusion Criteria 
4.5 
Subject Recruitment and Screening 
4.6 
Early Withdrawal of Subjects 
4.6.1 Criteria for removal from study 
4.6.2 Follow-up for Withdrawn Subjects 
5 
Study Treatment or Diagnostic Product Procedures 
5.1 
Description 
5.2 
Method for Assigning Subject to Treatment Groups 
5.3 
Subject Compliance Monitoring 
5.4 
Prior and Concomitant Therapy 
5.5 
Blinding of Study 
5.6 
Receiving, Storage, Dispensing and Return 
5.6.1 Receipt of Investigational Device Supplies 
5.6.2 Storage 
5.6.3 Dispensing 
5.6.4 Return or Destruction of Investigational Device 
6 
Study Procedures 
6.1 
Visit 1- Screening/Enrollment Visit 
6.2 
Visit 2- GAE or Sham Procedure 
6.3 
Visit 3- 1 day follow-up 
6.4 
Visit 4- 2 Week follow-up 
6.5 
Visit 5a and 5b- 1 month follow-up 
6.6 
Visit 6a and 6b- 3 month follow-up for blinded subjects 
6.7 
Visit 6c- GAE for unblinded subjects 
6.8 
Visit 7a and 7b- 6 month follow-up for blinded subjects 
6.9 
Visit 7c- 1 day follow up for unblinded subjects 
6.10 
Visit 8c – 2 week follow up for unblended subjects 

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6.11 
Visit 9c- 1 month follow-up for unblinded subjects 
6.12 
Visit 10c- 3 month follow-up for unblinded subjects 
6.13 
Visit 11c- 6 month follow-up for unblinded subjects 
6.14 
Visit 8a, 8b, or 12c– 12 month follow up for all subjects 
6.15 
Study Procedure Flow Chart 
7 
Safety and Effectiveness Assessments   
7.1 
Safety Assessments 
7.2 
Effectiveness Assessments 
8 
Statistical Plan 
8.1 
Sample Size Determination 
8.2 
Statistical Methods 
8.3 
Subject Population(s) for Analysis 
8.4 
Interim Analysis 
9 
Risk Analysis 
9.1 
Anticipated Risks 
9.2 
Risk Minimization 
9.3 
Adverse Event Definitions 
9.4 
Recording of Adverse Events 
9.5 
Causality and Severity Assessment 
9.6 
Reporting of Adverse Effects and Unanticipated Problems 
9.6.1 Reporting of Adverse Effects to the FDA 
9.6.2 Reporting Adverse Effects to the Responsible IRB 
9.7 
Stopping Rules 
9.8 
Medical Monitoring 
9.8.1 Data and Safety Monitoring Plan 
9.8.2 Data and Safety Monitoring Board 
10 
Data Handling and Record Keeping 
10.1 
Confidentiality 
10.2 
Source Documents 
10.3 
Case Report Forms 
10.4 
Record Retention 
10.5 
IRB Documentation 
11 
Study Monitoring, Auditing and Inspecting 
11.1 
Study Monitoring Plan 
11.1.1 Locations 
11.1.2 Study Staff Responsibilities and Training 
11.1.3 Quality Assurance and Quality Control 
11.1.4 Safety Monitoring 
11.1.5 Monitoring Activities 
11.1.6 Study Closure 
11.2 
Auditing and Inspecting 
12 
Ethics 
13.1 
Study Finances 
13.2 
Funding Source 
13.3 
Conflict of Interest 
13.4 
Subject Stipends or Travel Reimbursements 
14 
Publication Plan 
15 
Device IFU 

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1 Introduction 
1.1 Study Conduct 
This study will be conducted in compliance with the protocol approved by the 
Institutional Review Board, and according to Good Clinical Practice standards. 
No deviation from the protocol will be implemented without the prior review 
and approval of the IRB except where it may be necessary to eliminate an 
immediate hazard to a research subject. In such case, the deviation will be 
reported to the IRB according to its policies and procedures. 
 
1.2 Background 
 
Osteoarthritis (OA) is a common and major cause of pain and disability. An 
estimated 26.9 million adults in the US suffer from OA1 and nearly 50% of adults 
may develop symptomatic knee OA by age 852. Knee OA affects obese 
individuals at a higher rate with ⅔ of individuals developing symptomatic disease.  
The treatment for knee osteoarthritis is broad and includes: exercise and patient 
education; pharmacologic therapies, including oral, topical, and intra-articular 
medications; and surgical interventions, including total joint arthroplasty.  Minor 
symptoms can be managed with non-opioid pain medications such as 
acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), which are the 
mainstay of pain management for OA. Severe and end-stage osteoarthritis can be 
treated with total joint arthroplasty. Unfortunately, NSAIDs can be a cause of 
renal failure, exacerbation of asthma and most notably, gastrointestinal 
hemorrhage.  Number of deaths from NSAID-related gastrointestinal bleeding has 
been estimated at 165003. With the significant morbidity associated with 
treatment of OA, there is a need to develop a new, effective, minimally invasive 
and safe treatment for pain related to osteoarthritis of the knee. 
 
The principal symptom of OA pain is mediated by a number of factors. 
However, angiogenesis resulting in neovascularity, neural sensitization and 
inflammation has been described as a potential pathophysiological pathway of 
the deep joint pain described by many OA patients4, 5.  This increased 
vascularity in the setting of pain and OA has been the focus of recent 
endovascular investigation, with the proposed mechanism of embolization as a 
novel treatment. 
 
Particulate embolization of geniculate artery branches supplying hypervascular 
joint tissue, the same technique we are proposing to treat pain from OA, has 
been previously described as a safe treatment for hemorrhage after total knee 
arthroplasty in multiple reports 6, 7,8, 9. In 2008, three cases were reported using 
150-355 micrometer particles without any complications6. In 2013, a Japanese 
group reported the use of 1000-2000 micrometer particles in the treatment of 
five patients, again without complication9.  In 2015, an author group that 
includes one of the Co- PIs reported outcomes from 13 cases in which there 
were no major complications and two minor complications (transient cutaneous 
ischemia)8. Finally, in 2016 a fourth report of 14 embolizations was published in 

Page 5 of 32 
 
which there were no major complications and, again, two minor complications 
(transient cutaneous ischemia)7. 
Embolization of hypervascular joint tissue for the treatment of pain has been 
pioneered by Dr. Okuno and his colleagues, in Japan. They initially reported a 
case series in which they were able to reduce pain related to refractory 
tendinopathy and enthesopathy in multiple joints in 7 patients using an antibiotic 
particulate for embolization without major complication10.  Subsequently, the 
same team published its experience with transcatheter embolization of 
hypervascular tissue within the shoulder joint in 7 patients diagnosed with 
adhesive capsulitis. The procedure successfully resulted in pain reduction 
without any complications11. Finally, Okuno et al also published their results 
after synovial embolization in patients with painful OA. The procedure was 
performed on 14 patients and there were no major complications. There was 
significant pain reduction and decreased difficulty of movement at 4 months. 
Medication frequency also decreased after embolization12. Most recently, the 
same group published a larger cohort13 of 72 patients with follow-up with 
midterm follow-up. Geniculate artery embolization was technically successful in 
in all patients. It was clinically successful in 86.3% of patients at 6 months and 
79.8% at 3 years. MRI follow-up in patients demonstrated no osteonecrosis or 
other evidence of progression of degenerative changes.   
 
The current investigation team has led efforts pioneering embolization 
procedures in novel targets that have proved successful14,15,16,17,18,19.  We have 
also had experience in embolization of the knee, in particular with post-
arthroplasty hemorrhage8.  The principal investigator/sponsor is also an 
Investigator on a pilot study of GAE for knee pain, with a current Investigational 
Device Exemption (IDE) at UNC Chapel Hill. With our proven experience in 
embolization, and in particular the local-regional anatomy, we have set forth to 
pursue a US study evaluating embolization as a treatment for OA related knee 
pain versus placebo to demonstrate the actual effect of embolization on pain and 
disability. 
 
1.3 Medical Device 
 
1.3.1 Name of Investigational Device 
Gel-Bead embolization spheres; OptiSphere embolization spheres 
  
1.3.2 Intended Use of the Investigational Device 
Gel-Bead embolization spheres; OptiSphere embolization spheres will be used 
for geniculate artery embolization (GAE) in subjects with knee osteoarthritis. 
 
1.3.3 Description of the Investigational Device  
Gel-Bead embolization spheres; OptiSphere embolization spheres were found 
to be substantially equivalent and          cleared medical devices (Premarket 
Notification K133237) to prior technologies:  
 
• 
Emboshpere Microshperes (Biosphere Medical, Inc/Merit Medical Systems, 
Inc, K021397), and 

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• 
Gel-Block Embolization Pledgets (Vascular Solutions, Inc, K113266) 
 
 
Identified in the Code of Federal Regulations 21 Part 870- Subpart D-
Cardiovascular Prosthetic Devices. 
 
Classification Name: Artificial Embolization Device. Class II Medical Device 
Common Name: Vascular Embolization Device Subpart D-Prosthetic Devices; 
Sec. 870.3300 
 
Indication for Use: Gel-Bead embolization spheres; OptiSphere embolization spheres 
is intended for use in embolization of hypervascular tumors. 
 
The Gel-Bead embolization spheres; OptiSphere embolization spheres (Gel-Bead) 
consists of biodegradable gelatin spheres pre-filled in a 20ml syringe. The syringe 
contains 1 ml of spheres suspended in 5 ml of saline. Gel-Bead is offered in four 
size ranges: 100-300 um, 300-500 um, 500-700 um and 700-1000 um. The 
spheres are intended to be used with a delivery catheter with an inner diameter 
that is adequate for sphere delivery (not included). The finished product is 
sterilized by Gamma irradiation and is intended for single use only.  They come in 
a liquid suspension that is mixed with iodinated contrast before use. Once a 
catheter has been fluoroscopically guided into the target vessel, the embolization 
spheres are then injected, causing obstruction at the arteriole level until the 
desired degree of embolization has occurred. The embolization spheres used 
during the study will be unchanged. 
 
1.4 Preclinical Data 
Gel-Bead embolization spheres; OptiSphere embolization spheres have proven to 
be an effective embolization material with high biocompatibility in non-human 
studies. A GLP animal study was conducted on twelve mature miniature swine, 
with animals survived up to 12 weeks following implantation20. Eight animals 
were implanted with Gel-Bead and four animals implanted with a control 
(Embosphere). Gel-Bead spheres were consistently and reliably implanted in the 
selected target arteries of appropriate size and not in additional non-target tissues 
or regions. All instances of Gel-Bead delivery resulted in successful arterial 
occlusion at the time of implant, as confirmed by angiography. There were similar 
well-demarcated foci of infarction, indicative of successful embolization, 
observed in the target organs of both test article and control article animals. There 
were no clinically significant abnormalities identified in the clinical pathology 
blood results that negatively reflected on either the test or control devices. 
Examination of the tissues distant to the implantation sites did not identify any 
systemic abnormalities. Verification, animal study, and biocompatibility test 
results met the specified acceptance criteria and did not raise new safety or 
performance issues. Therefore, Gel-Bead is substantially equivalent to the 
predicate devices. 
 
1.5 Clinical Data to Date 
Gel-Bead embolization spheres; OptiSphere embolization spheres is substantially 
equivalent to predicate microsphere devices such as Embosphere. Embosphere 

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has have been safely used as an embolic agent to target 
hypervascular lesions throughout the body including uterine fibroids 21, 
benign prostatic hyperplasia22, meningioma23, and adenomyosis24.  The 
investigators have also performed GAE for knee hemarthrosis with technical and 
clinical success using Embosphere microspheres8. Recently, embolization spheres 
have been used safely and effectively for GAE to treat knee pain in the setting of 
osteoarthritis12. Gel-Bead embolization spheres; OptiSphere embolization spheres 
are FDA approved for the treatment of arteriovenous malformations and 
hypervascular tumors. 
 
2.0 Study Objectives 
The primary aim of this study is to determine if GAE will reduce the severity of 
pain as well as global disability (resulting from the combination of pain, 
stiffness and difficulty performing daily activities) caused by knee OA compared 
with placebo. The secondary aim is to determine if GAE can result in the 
decreased necessity for ongoing conservative OA therapies such as medication 
therapy and joint injections. 
 
3 Study Design 
3.1 General Design 
This will be a single-blinded randomized-controlled study of GAE versus 
placebo in a small population with knee pain secondary to arthritis to determine 
safety and efficacy.  After IRB approval of a written informed consent and over, 
approximately a 24 month duration, N=21 subjects will be recruited.  Only 
subjects ≥ 40 years will be screened for study recruitment.  Subjects will be 
randomized in a 2:1 ratio of GAE:Placebo and will be blinded from study 
treatment (see flow chart below).  The placebo procedure will be a diagnostic 
angiogram of the knee, without embolization. Appropriate measures will be 
taken to ensure patients and nursing staff caring for the patient are blinded to 
assignment. Each patient will be told at the time of recruitment that they may be 
randomly assigned to sham, but if after 1 month they have not had symptom 
improvement, their assigned procedure would be revealed and, if they had 
undergone a sham procedure, they will be allowed to proceed with embolization. 
This second procedure should be shorter than a complete angiogram and 
embolization, as the detailed angiogram will not need to be repeated, and 
therefore both arms will have similar total radiation dose. 
 
Clinical procedures and evaluations will consist of a preoperative screening 
assessment to determine if the potential study subject meets the inclusion and 
exclusion criteria, enrollment, surgical procedure for geniculate artery 
embolization, and follow-up visits at 24 hours, 2 weeks, 1, 3,  6, & 12 months.  
An MRI will be performed after the 1-month visit in those patients who 
underwent embolization to detect a change in synovial vascularity and to exclude 
complication. 
 
3.2 Primary Study Endpoints 
1. Overall efficacy of treatment as determined by a minimal clinically 
significant reduction in global Western Ontario and McMaster University 

Page 8 of 32 
 
Osteoarthritis Index (WOMAC) questionnaire scoring of 16% at 1 and 6 
month follow-up. 
2. Minimal clinically important decrease of 15% on the pain VAS at 1 or 6 
months follow-up. 
 
3.3 Secondary Study Endpoints 
1. Reduction of previously initiated OA medical therapy (e.g. NSAIDs) at 12 
months follow-up. 
 
3.4 Primary Safety Endpoints 
1. GAE without major complication. 
 
4 
Subject Selection and Withdrawal 
4.1 General Characteristics of the Proposed Subject Population 
Study subjects will be men and women with knee osteoarthritis resulting in knee 
pain that is refractory to conservative therapies, who are not planning to undergo 
surgery within 12 months. 
 
4.2 Anticipated Number of Research Subjects 
Enrollment into the investigation will be defined as providing informed 
consent for study participation per IRB policies. 
 
Twenty-one (21) subjects will be enrolled and all are anticipated to complete the 
study. 
 
4.3 Inclusion Criteria 
1. Moderate to severe knee pain (VAS > 50 mm), and 
2. Pain refractory to at least 3 months* of conservative therapies (anti-
inflammatory drugs, or physical therapy, or muscle strengthening, or intra-
articular injections), and 
3. Kellgren-Lawrence grade 1, 2 or 3 on radiograph of the knee. 
4. Age > 40 years. 
 
*3 months was chosen because this time interval is thought adequate for knee pain to 
be considered refractory to conservative care. 
 
4.4 Exclusion Criteria 
1. Current local infection, or 
2. Life expectancy less than 6 months, or 
3. Known advanced atherosclerosis, or 
4. Rheumatoid or infectious arthritis, or 
5. Prior knee replacement surgery, or 
6. Uncorrectable coagulopathy including INR > 2.5 or platelets < 30,000, or 
7. Iodine allergy resulting in anaphylaxis, or 
8. Renal dysfunction as defined by serum creatinine >1.6 dl/mg or eGFR <60 
obtained within the past 30 days. 
 
4.5 Subject Recruitment and Screening 
Subjects will be recruited from orthopedic and interventional radiology clinics in 

Page 9 of 32 
 
the Northern Virginia Area or the Vascular Interventional Radiology Clinic at 
UNC-Chapel Hill. 
 
4.6 Early Withdrawal of Subjects 
          4.7.1   Criteria for Removal from Study 
 
         Subjects will be withdrawn from the study if 
a. a major complication occurs that prevents completion of GAE or the 
ability to complete the follow up visits, or 
b. at any point at their discretion. 
 
         4.7.2 Follow-up for Withdrawn Subjects 
If a subject withdraws from the study, any recorded data will still be 
included in the analysis. Subjects will only be replaced if they withdrew 
prior to undergoing GAE. 
 
5 Study Treatment or Diagnostic Product Procedures 
5.1 Description 
 
Subjects will not initiate any new pain therapy or escalate current therapy for 1 
month prior to GAE. They will be given an intravenous dose of antibiotics on the 
day of the procedure and continue with oral antibiotics for seven days after the 
procedure.  The subjects will be given the choice of receiving intravenous 
anxiolytic and analgesic medication during procedure or proceeding with local 
anesthetic only. 
 
Arterial access site will be prepped and draped using sterile technique. 
Ultrasound-guided access may be used and arterial access will be obtained. An 
intra-arterial sheath will be placed. Through this sheath a guiding catheter will be 
used to perform lower extremity angiography on the targeted side. Using the 
guiding catheter and a microcatheter, the geniculate arteries supplying 
hypervascular synovial tissue in the region of the knee joint will be catheterized.  
This will allow the operators to know exactly what tissues will be receiving the 
Gel-Bead embolization spheres; OptiSphere embolization spheres. Gel-Bead 
embolization spheres; OptiSphere embolization spheres ranging from 100-500 
microns*, selected at the operator’s discretion based upon size of target vessels, 
will then be injected under fluoroscopic guidance to prevent reflux and non-target 
embolization. Injection will continue until an end point of at least ‘near stasis’ 
(slowed antegrade flow of contrast). Multiple geniculate arteries may be 
embolized until neovascularity is no longer seen. A repeat lower extremity 
angiogram will then be performed to evaluate for success of embolization and to 
exclude complication. The catheter and sheath will then be removed and 
hemostasis will be achieved with manual compression or a vascular closure 
device. The subject subsequently will be discharged home the same day 
(<23hours) unless a complication arises that requires inpatient admission for 
management of the complication.  Subjects may be discharged on pain 
medications as needed for post-operative care (<14 days). 
 
*The range in size of particles will allow the operators to discern the safest, most 
effective size for the vessels targeted. For example, if the catheter can be 

Page 10 of 32 
 
advanced all the way in to the branch supplying only the synovium, smaller 
particles can be safely used to induce ischemia in the target tissue. If the catheter 
cannot be advanced due to tortuous or small caliber vessels, a larger sized 
particle may be selected. This will allow for proximal embolization without distal 
penetration into the cutaneous branches, thereby allowing continued blood flow 
to the skin through collateral pathways (Fig 1-2). This concept is utilized 
routinely within embolization procedures are commonly performed. 
 
 
 
 
Fig 1. Geniculate artery angiogram after total knee arthroplasty demonstrating 
“contrast blush” denoting hypervascular synovium (bold arrow). Separate arterial 
branches are seen supplying the joint tissue (arrow) and skin (dotted arrow). At this 
point an attempt would be made to place a microcatheter in the synovial branch. If 
impossible due to the size of the target vessel, embolization would be performed from 
this catheter location using larger particles to preserve distal collateral supply to the 
skin. 
 
 
 
 
 

Page 11 of 32 
 
 
 
Fig 2. Lateral angiogram of the knee with selective catheterization of the 
synovial branch of the geniculate artery. In this circumstance, smaller sized 
embolic particles would be appropriate because cutaneous branches are not 
seen.  
 
It is anticipated that less than 5 milliliters of Gel-Bead embolization 
spheres; OptiSphere embolization spheres will be required for 
embolization. Gel-Bead embolization spheres; OptiSphere 
embolization spheres currently have FDA approval for embolization of 
hypervascular tumors. 
 
5.2 Method for Assigning Subject to Treatment Groups  
Subjects who meet all criteria for study entry and have signed written informed 
consent will be randomized in a 2:1 allocation of treatment (geniculate artery 
embolization) versus placebo (angiogram). Patients will be blinded to the study 
procedure. Each patient will be told at the time of recruitment that they may be 

Page 12 of 32 
 
randomly assigned to GAE or sham. If after 1 month if they have not had 
symptom improvement, their assigned procedure would be revealed only if they 
had undergone a sham procedure. They will then be allowed to proceed with 
embolization in Arm C if they elect to proceed. This second procedure should be 
shorter than a complete angiogram and embolization, as the detailed angiogram 
will not need to be repeated. See table 1 (study schema).  A 2:1 ratio was selected 
so that patients would be more likely to enroll in the study.   
 
5.3 Subject Compliance Monitoring 
Study coordinators and physicians will inquire of the subjects to determine if they 
have escalated any current or initiated any new conservative therapies during the 
follow-up period. 
 
5.4 Prior and Concomitant Therapy 
The subjects will be required to have been on conservative therapy for OA for at 
least three months prior to undergoing GAE. They will be allowed to continue 
previously initiated therapies throughout the study period, but if new or escalated 
therapies are required past the post-operative period (14 days), the treatment will 
be considered a failure. 
 
5.5 Blinding of Study 
Following randomization, efforts will be made to blind the subject to the study 
procedure. Patients will not be informed to their treatment or placebo arm. As the 
procedures of a diagnostic angiogram and embolization are similar (femoral 
artery access, angiogram, post-operative care), the subject will inherently not 
know if he/she received the treatment or placebo. The post-operative staff caring 
for the patient will not be informed as to the treatment the patient received.  
Datasets for each arm will be presented for analysis by statistician labeled as 
treatment arm (i.e. A, B or C).  
 
5.6 Receiving, Storage, Dispensing and Return 
 
5.6.1 Receipt of Investigational Device Supplies 
Medtronic will provide, at no charge, up to six (6) boxes (5 vials/box) of 
Gel-Bead Microspheres for the Study (“Devices”).  Gel-Bead 
embolization spheres; OptiSphere embolization spheres will be stored 
within the Interventional Radiology Department in a separate area.  
Embolic devices will be labeled ‘for investigational use only’ and will be 
reserved for use in the clinical trial. 
 
5.6.2 Storage 
Gel-Bead embolization spheres; OptiSphere embolization spheres 
must be stored in a cool, dark, dry place in their original packing. 
 
5.6.3 Dispensing 
No study specific dispensing techniques will be used. 
 
5.6.4 Return or Destruction of Investigational Device 
The Institution and Sponsor-Investigator shall, return any such Product to 

Page 13 of 32 
 
Company promptly if requested by the Company upon the completion or 
termination of the Study for which such Product was being utilized, or 
promptly dispose of or destroy, as the Company may reasonably direct, all 
of its remaining stocks of Product. All Devices supplied by Medtronic to 
Institution for the Study shall be used by Institution only as specified in 
the Protocol and the Clinical Trial Agreement. No other use of the 
Devices is authorized.   
 
Disposable syringes, which spherical particulate is stored in, will be 
discarded as medical waste and packaging will be kept in a secure location 
until the study is completed. Packages will be disposed of upon 
completion of the study. 
 
Lot numbers of the device used will be recorded in the CRFs for the study 
procedure. 
 
6 Study Procedures 
6.1 Screening Visit (Visit 1) 
Potential enrollees will first be identified and will undergo a standard knee OA 
work-up to include history and physical exam with emphasis on specific site of 
knee tenderness. The Western Ontario and McMaster University Osteoarthritis 
Index (WOMAC) questionnaire will be administered to assess difficulty as a 
result of pain, stiffness and overall decreased function secondary to knee pain in 
the past week.  
Current pain will also be assessed using a visual analog scale (VAS). A knee 
radiograph will be obtained and evaluated using the Kellgren-Lawrence grading 
scale. A baseline knee MRI will also be acquired to evaluate for concomitant 
pathology as part of routine orthopedic evaluation.  If the patient previously had 
an MRI for clinical care that can be obtained from his/her medical record and 
used for the purposes of this study.   
 
If a patient qualifies to be a subject in the study based on the inclusion and 
exclusion criteria listed in section 4.3 and 4.4, the local study coordinator, 
investigator or designee will provide the candidate with a copy of the approved 
informed consent. Written informed consent will be obtained if appropriate. If the 
patient wishes to take more time to review the study before enrolling, he/she may 
complete the consent process at the beginning of the next visit, prior to the study 
GAE procedure. Those candidates who are disqualified from study entry will be 
logged into the Screening Log with a reason for no study entry.  A copy of the 
consent will be provided to the subject and the original filed in the study files. 
 
Patients will be randomized at this point according to the schema created prior to 
the commencement of the study.  
 
6.2 Visit 2 GAE or Sham Procedure 
GAE or sham procedure will be performed as described in part 5.1 above within 4 
weeks of Visit 1.  Subjects will be given a pager number to reach a physician (24 
hours a day) to report any adverse symptoms and receive medical advice. The 

Page 14 of 32 
 
sham procedure patients will be provided with the same information and follow-
up instructions. 
 
If a patient does not undergo the procedure within the specified visit window, 
then the WOMAC and VAS questionnaires should be repeated prior to the 
procedure. 
 
6.3 Visit 3 -1 Day Follow-up 
Subjects will be seen in clinic or contacted by phone or by teleconference, per 
the subject’s preference, the day following GAE or sham procedure (+3 days). 
As most complications of the procedure will be evident within this time period, 
this visit is to evaluate for early AE’s. If an AE is suspected based on change in 
pain scores or functionality, an appropriate work-up will be performed which 
may include MRI. 
 
6.4 Visit 4 – 2 Week Follow-Up 
Patients will be called after 2 weeks to assess any adverse events, such as 
persistent pain. 
 
6.5 Visit 5a and 5b - 1 Month Follow-Up 
Subjects will be seen in clinic or contacted by phone or by teleconference, per the 
subject’s preference, 30 +/- 7 days following GAE or sham procedure. The 
WOMAC questionnaire and VAS pain score will be completed and subjects will 
be evaluated for possible adverse events. An MRI of the treated knee will be 
acquired for those subjects who underwent GAE*.  Subjects will also provide an 
update about the necessity/frequency of pre-established conservative therapies. 
 
For those subjects who do not report improvement in symptoms or worsening, 
and are in the placebo arm, they will be unblinded and offered to undergo the 
geniculate artery embolization (Arm C) and then followed at similar follow-up 
intervals to 12 months (24 hours, 2 weeks, 1 month, 3 months, 6 months, and 12 
months).  
 
*MRI is only scheduled at one month in order to evaluate for non-target ischemic 
injury. These types of injuries will become apparent as early as 24 hours after 
embolization. Infarcted tissue will still be detectable at one month. Based on our 
experience with embolization in other areas, it is thought extremely unlikely that 
new ischemic injury related to the procedure will develop after the one-month 
follow-up. Additionally, findings that would be detected on later scans may be 
unrelated to the procedure and confound the data. 
 
6.6 Visit 6a and 6b - 3 Month Follow-Up for blinded subjects  
Subjects will be seen in clinic or contacted by phone or by teleconference, per 
the subject’s preference, 90 +/- 10 days following GAE or sham procedure. The 
WOMAC questionnaire and VAS pain score will be completed and subjects will 
be evaluated for possible adverse events. Subjects will also provide an update 
about the necessity/frequency of pre-established conservative therapies. If an 
AE is suspected based on change in pain scores or functionality, an appropriate 

Page 15 of 32 
 
work-up will be performed which may include MRI.   
 
6.7 Visit 6c -  GAE for unblinded subjects   
GAE will be performed (as described in part 5.2 above) within 4 weeks of visit 4.  
Subjects will be given a pager number to reach a physician, 24 hours a day, to 
report any adverse symptoms and receive medical advice.   
 
6.8 Visit 7a and 7b - 6 Month Follow-Up for blinded subjects 
 
Subjects will be seen in clinic or contacted by phone or by teleconference, per the 
subject’s preference, 180 +/- 10 days following GAE or sham procedure. The 
WOMAC questionnaire and VAS pain score will be completed and subjects will 
be evaluated for possible adverse events. Subjects will also provide an update 
about the necessity/frequency of pre-established conservative therapies. If an 
AE is suspected based on change in pain scores or functionality, an appropriate 
work-up will be performed which may include MRI.   
 
6.9 Visit 7c - 1 day follow-up for unblinded subjects 
Subjects will be seen in clinic or contacted by phone or by teleconference, per 
the subject’s preference, the day following GAE (+3 days). As most 
complications of the procedure will be evident within this time period, this visit 
is to evaluate for early AE’s. If an AE is suspected based on change in pain 
scores or functionality, an appropriate work-up will be performed which may 
include MRI. 
 
6.10 Visit 8c – 2 Week Follow-Up for unblinded subjects (arm C only) 
Patients will be called after 2 weeks to assess any adverse events, such as 
persistent pain. 
 
6.11 Visit 9c-1 month follow-up for unblinded subjects     
Subjects will be seen in clinic 30 +/- 7 days following GAE. The WOMAC 
questionnaire and VAS pain score will be completed and subjects will be 
evaluated for possible adverse events. An MRI of the treated knee will be 
acquired.  Subjects will also provide an update about the necessity/frequency of 
pre-established conservative therapies. 
 
6.12 Visit 10c- 3 month follow-up for unblinded subjects    
Subjects will be seen in clinic or contacted by phone or by teleconference, per 
the subject’s preference, 90 +/- 10 days following GAE. The WOMAC 
questionnaire and VAS pain score will be completed and subjects will be 
evaluated for possible adverse events. Subjects will also provide an update 
about the necessity/frequency of pre-established conservative therapies. If an 
AE is suspected based on change in pain scores or functionality, an appropriate 
work-up will be performed which may include MRI.   
 
6.13 Visit 11c - 6 month follow-up for unblinded subjects    
Subjects will be seen in clinic or contacted by phone or by teleconference per, the 
subject’s preference, 180 +/- 10 days following GAE. The WOMAC 

Page 16 of 32 
 
questionnaire and VAS pain score will be completed and subjects will be 
evaluated for possible adverse events. Subjects will also provide an update about 
the necessity/frequency of pre-established conservative therapies. If an AE is 
suspected based on change in pain scores or functionality, an appropriate work-up 
will be performed which may include MRI.    
 
6.14 Visit 8a, 8b, or 12c– 12 month follow-up for all subjects 
Subjects will be seen in clinic or contacted by phone or by teleconference per, the 
subject’s preference, 180 +/- 10 days following GAE. The WOMAC 
questionnaire and VAS pain score will be completed and subjects will be 
evaluated for possible adverse events. Subjects will also provide an update about 
the necessity/frequency of pre-established conservative therapies. If an AE is 
suspected based on change in pain scores or functionality, an appropriate work-up 
will be performed which may include MRI.    
 
 

Page 17 of 32 
 
 
6.15 Study Procedure Flow Chart 
 
 
 
 

Page 18 of 33 
 
7 Safety and Effectiveness Assessments 
7.1 Safety Assessments 
Subjects will be observed for several hours after GAE to monitor for immediate 
complications to include bleeding, infection and acute ischemia of the lower 
extremity. The subjects will be given a phone number that they can call to reach 
the principal investigator or designee if they believe they have developed a 
complication of the procedure. If at any point during the study period (including 
between scheduled follow-up visits) a subject reports symptoms that suggest an 
AE, an appropriate work-up will be initiated by the investigators to evaluate the 
etiology of the symptoms. This may include physical exam, laboratory tests and 
imaging (including MRI if appropriate). 
 
7.2 Effectiveness Assessments 
Technical success will be defined as devascularization of hypervascular synovium 
at the affected knee. This will be determined during the procedure. Clinical 
success will be defined as a 16% reduction of the baseline global WOMAC score 
at 1 or 6 month follow-up (primary outcome) and a 15% reduction of the baseline 
pain VAS score at 6 or 1 month follow-up (primary outcome). 
 
8 Statistical Plan 
8.1 Sample Size Determination 
 
Using baseline WOMAC means and standard deviations of 12.2 and 1.9, 
respectively, from the Okuno study, we will have at least 69.1 % power to 
detect a clinically relevant difference of 16% for WOMAC for a one-sided 
alternative hypothesis.   Actual power will be greater than this 69.1% lower 
bound since our analysis strategy uses data from multiple time points to 
formulate individual growth trajectories.   
 
Using baseline VAS means and ranges of 72 and (54-100), respectively, we 
used the method of devised by S.P. Hozo, B. Djulbegovic, and I. Hozo to 
derive an estimate of the baseline standard deviation as 13.3.  Given these 
parameters, we will have at least 51.7 % power to detect a clinically relevant 
difference of 15% for VAS for a one-sided alternative hypothesis.   Actual 
power will be greater than this 51.7% lower bound since our analysis strategy 
uses data from multiple time points to formulate individual growth trajectories.   
   
Power calculations used GPower, version 3.1.9.2. 
 
8.2 Statistical Methods 
 
The primary study endpoints, WOMAC and VAS scores, will be collected at 
baseline, 1 month follow-up, 3 month follow-up, and 6 month follow-up.  Mean 
WOMAC and VAS scores will be reported at baseline, 1 month follow-up, 3 
month follow-up, and 6 month follow-up, along with associated confidence 
intervals.    
 

Page 19 of 33 
 
We will address the primary study endpoints by modeling each clinical outcome 
using random coefficient modeling.   The clinical outcomes will be modeled as a 
linear function of time.   We will allow a random intercept and slope that is 
dependent on treatment, so that each patient will have their own trajectory of pain 
over time.   No additional covariates will be included in the model.  We will 
employ a compound symmetric R-side covariance structure to account for 
dependencies arising from observations from the same patient.  Random 
coefficient models are robust to missing values only require data to be MAR (and 
not the stronger assumption of MCAR), so that presence of missing values will 
not invalidate our conclusions.   
 
We will compute predicted means, as well as the estimated difference in predicted 
means, at 6 months for both WOMAC and VAS; these will be derived from the 
population-averaged trajectories (i.e. fixed effects).  We will test the H0:  µsham, 6 
months - µGAE, 6 months = 0 versus the one-sided alternative hypothesis Ha:  µsham, 6 
months - µGAE, 6 months > 0 using a Wald test. Both primary study endpoints will be 
evaluated by considering significance of the p-value (p < 0.05) along with the 
percentage predicted mean difference with respect to the clinically relevant 
differences (16% for WOMAC and 15% for VAS).  Both these factors will be 
taken in tandem as evidence to suggest GAE treatment efficacy.  Primary 
endpoints will be assessed only at one time point, so that adjustment for multiple 
comparisons is not necessary since the evaluation of the primary endpoints for 
WOMAC and VAS each consists of only one statistical test. 
Non-significance of the p-value for this test will be considered inconclusive 
evidence against the null hypothesis.  Variance components, including the 
intraclass correlation coefficient, will also be reported for each model.   All 
analyses will use SAS version 9.4 (SAS Institute, Inc., Cary, NC). 
  
We will identify extreme primary endpoint values by computing studentized 
residuals and then conduct sensitivity analyses by deleting these outliers from the 
analysis datasets.  We will repeat the above statistical tests and use results of the 
sensitivity analyses to corroborate conclusions reached in the primary analyses.   
 
We will address the secondary study endpoint of reduction of OA by comparing 
frequency of OA medical therapy between the sham group, the crossover group, 
and the GAE group at 12 months.    We will employ a chi-squared test to test the 
H0: frequency of OA medical therapy is equal for between the sham group, the 
crossover group, and the GAE group versus the one-sided alternative hypothesis.   
A p-value of < 0.05 will be taken as evidence to suggest that the frequency of OA 
medical therapy is not equal between the groups.  Non-significance of the p-value 
for this test will be considered inconclusive evidence against the null hypothesis.     
 
Reduction in AE will be evaluated with a multilevel logistic regression model.  
The outcome of adverse events will be regressed on treatment status.   We will 
employ a compound symmetric R-side covariance structure to account for 
dependencies arising from observations from the same patient. The H0: frequency 
of AE is equal for between the sham group and the GAE group will be assessed 
versus the two-sided alternative hypothesis with a statistical test of the treatment 

Page 20 of 33 
 
parameter different than 0, with a p-value of < 0.05 taken as evidence to suggest 
that the frequency of OA medical therapy is not equal between the groups.  Non-
significance of the p-value for this test will be considered inconclusive evidence 
against the null hypothesis.    
 
8.3 Subject Population(s) for Analysis 
A patient will be considered an evaluable study subject evaluable for 
data analysis per the following criteria, a written informed consent was 
obtained, he/she meets the inclusion and exclusion criteria, and received 
the GAE or sham study procedure.  All subjects with 12 month follow-
up data will be included for analysis even if some follow up data is 
incomplete. Every attempt will be made to ensure that there is as little 
missing data as possible including reminder phone calls and follow-up 
phone calls, if a subject misses a visit. 
 
9 Risk Analysis 
 
9.1 Anticipated Risks 
Previous studies of lower extremity geniculate artery embolization for arthritis 
related pain have reported only one complication of moderate puncture site 
related hematoma (1/13), however this was a small population12. A recent 
study of GAE for recurrent hemarthrosis completed by one of the co-Is 
(Bagla) included 2/13 subjects who developed transient cutaneous ischemia 
that resolved within three weeks without intervention8. Additional risks that 
are anticipated but occur infrequently after any arterial intervention include 
infection, pain, pseudoaneurysm formation, arterial dissection and distal non-
target embolization resulting in ischemia or necrosis. Detailed risk analysis is 
below: 
 
Risk or Side Effect 
Source of Risk 
or Side Effect 
 
Possible 
Less 
Possible 
 
Rare 
Events 
Potential 
Risks 
Associated 
Study 
Enrollment 
& Study 
Procedures 
Discomfort 
Blood draw for lab 
test, ultrasound or 
MRI 
X 
Thrombophlebitis, bruising, 
bleeding, blood clot, Pre- 
syncope or Syncope (i.e. 
Fainting) 
Blood draw for lab 
tests 
X 
Anxiety or Claustrophobia 
MRI scan 
X 
Psychological Discomfort 
Clinical 
Trial 
X 
Infection 
Blood draw for lab 
tests 
X 
Allergic Reaction 
MRI 
contrast 
X 

Page 21 of 33 
 
Gadolinium contrast adverse 
reaction (i.e. Nephrogenic 
Systemic Fibrosis or severe 
skin reaction from contrast 
agent only reported in 
patients with kidney 
MRI 
Contrast 
injection 
X 
Confidentiality breach 
from Medical Records 
Medical Record 
Keeping 
X 
Groin/Anesthetic 
Injection/Neurologic Injury/ 
Pressure during 
arterial access 
X 
 
Discomfort/Pain 
after catheter 
removed at the 
leg/femoral 
artery site 
X 
Risks of 
the GAE 
Procedure 
and Post- 
operative 
care 
Radiation Exposure Injury 
GAE/Sham 
procedure 
X 
Kidney Dysfunction 
Contrast 
injected 
X 
Joint Infection 
GAE Procedure 
X 
Adverse or Allergic Reaction 
Intravenous 
contrast agent or 
medications 
administered as 
part of procedure 
or follow-up care 
X 
Tissue damage to Skin, 
Muscle, Skin or other 
structure in legs (Non-target 
Embolization) 
GAE/Sham 
procedure 
X 
Minor Bruising or Bleeding 
GAE/Sham 
procedure 
X 
Bleeding requiring 
Transfusion or surgery 
GAE/Sham 
procedure 
X 
Synovitis related symptoms 
including pain, stiffness or 
limited joint mobility 
GAE procedure 
X 
Post Embolization 
Syndrome, including 
fever, malaise, headache, 
and myalgia (body aches) 
GAE procedure 
X 
Internal bleeding, 
such as 
Gastrointestinal  
bleeding 
Medications 
taken after the 
procedure 
(i.e. 
Ibuprofen) 
X 
Infection 
Catheter site in 
the leg/groin 
X 
Arterial injury/trauma, 
laceration, 
bruising/pseudoaneury
Procedure/ 
Closure 
device 
(clip) 
on 
the 
X 
Pulmonary embolism (clot in 
lung), Thrombophlebitis 
(clot in artery or vein) 
GAE/Sham 
procedure and 
immobility 
X 

Page 22 of 33 
 
Myocardial Infarction 
(Heart attack) 
GAE/Sham 
procedure including 
moderate 
sedation/sedative 
X 
Stroke 
GAE/Sham 
procedure including 
moderate 
sedation/sedative 
X 
Disability 
GAE/Sham 
procedure including 
moderate 
sedation/sedative 
X 
Death 
GAE/Sham 
procedure including 
moderate 
sedation/sedative 
X 
 
9.2 Risk Minimization 
The GAE procedure will be performed by board-certified interventional radiologists 
who have expertise in endovascular techniques, particularly in selective 
catheterization and transcatheter embolization techniques. Analgesia during the 
procedures will be provided through the use of conscious sedation if required. The 
risks of conscious sedation will be minimized by continuous monitoring of heart rate, 
blood pressure, oxygen saturation, and cardiac rhythm.  The dose area product 
projected for the procedure is thought to be less than 30 gray/cm2 which is about 2-4 
years of background radiation and significantly less than that of a cardiac 
catheterization. Radiation exposure will be minimized to subjects under the principal 
of ‘as low as reasonably achievable’ (ALARA). 
 
Sterile instruments with a sterile technique will be used to minimize infection risk at 
the arterial access site.  Pre-operative antibiotic(s) will be administered to reduce 
risk of other infections, such as urinary tract. The arterial access site discomfort will 
be minimized by administration of local anesthesia into the overlying skin and 
adjacent tissues. Catheter access into the appropriate artery may be performed using 
ultrasound-guided arterial puncture to prevent inadvertent vessel puncture with 
subsequent bleeding. Real-time fluoroscopic monitoring of all catheter/wire 
manipulations will be used to prevent vascular injury. 
 
The subject will be monitored for the risk of an allergic response to iodinated 
contrast. To minimize the risk of renal dysfunction there will be use of non-ionic 
contrast agents, and appropriate pre-procedure hydration, when necessary.  Subjects 
who report an allergic reaction to iodinated contrast will be pre-medicated as per 
routine allergy prophylaxis per standard of care. 
 
9.3 Adverse Event Definitions 
Adverse effect. Any untoward medical occurrence in a clinical study of an 
investigational device; regardless of the causal relationship of the problem 
with the device or, if applicable, other study treatment or diagnostic 
product(s). 
 

Page 23 of 33 
 
Associated with the investigational device or, if applicable, other study 
treatment or diagnostic product(s).  There is a reasonable possibility that the 
adverse effect may have been caused by the investigational device or, if 
applicable, the other study treatment or diagnostic product(s). 
 
Disability.  A substantial disruption of a person’s ability to conduct normal life 
functions. 
Life-threatening adverse effect.  Any adverse effect that places the subject, in 
the view of the investigator-sponsor, at immediate risk of death from the effect 
as it occurred (i.e., does not include an adverse effect that, had it actually 
occurred in a more severe form, might have caused death). 
 
Serious adverse effect. Any adverse effect that results in any of the following 
outcomes: death, a life-threatening adverse effect, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. 
● Hospitalization shall include any initial admission (even if less than 24 
hours) to a healthcare facility as a result of a precipitating clinical adverse 
effect; to include transfer within the hospital to an intensive care unit.  
Hospitalization or prolongation of hospitalization in the absence of a 
precipitating, clinical adverse effect (e.g., for a preexisting condition not 
associated with a new adverse effect or with a worsening of the 
preexisting condition; admission for a protocol-specified procedure) is 
not, in itself, a serious adverse effect. 
 
Unexpected adverse effect.  Any adverse effect, the frequency, specificity or 
severity of which is not consistent with the risk information described in the 
clinical study protocol(s) or elsewhere in the current IDE application, as 
amended. 
 
Unanticipated adverse device effect.  Any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or IDE application 
(including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. 
 
9.4 Recording of Adverse Events 
Research subjects will be questioned about adverse effects in person or by 
telephone the day following the procedure. In addition, they will be given a 
pager number to reach a physician on call, 24 hours a day, to report adverse 
effects and receive medical advice. The subjects will also be questioned about 
possible adverse effects at each follow-up visit. 
 
 
All observed or volunteered adverse effects (serious or non-serious) and 
abnormal test findings, regardless of treatment group, if applicable, or suspected 
causal relationship to the investigational device or, if applicable, other study 

Page 24 of 33 
 
treatment or diagnostic product(s) will be recorded in the subjects’ case 
histories.  For all adverse effects, sufficient information will be pursued and/or 
obtained so as to permit 1) an adequate determination of the outcome of the 
effect (i.e., whether the effect should be classified as a serious adverse effect) 
and; 2) an assessment of the causal relationship between the adverse effect and 
the investigational device or, if applicable, the other study treatment or 
diagnostic product(s). 
 
Adverse effects or abnormal test findings felt to be associated with the 
investigational device or, if applicable, other study treatment or diagnostic 
product(s) will be followed until the effect (or its sequelae) or the abnormal test 
finding resolves or stabilizes at a level acceptable to the investigator-sponsor. 
 
An abnormal test finding will be classified as an adverse effect if one or more 
of the following criteria are met: 
 
● The test finding is accompanied by clinical symptoms 
● The test finding necessitates additional diagnostic evaluation(s) or 
medical/surgical intervention; including significant additional 
concomitant drug treatment or other therapy 
          o   Note: simply repeating a test finding, in the absence of  any 
of the other listed criteria, does not constitute an adverse 
effect. 
• The test finding leads to a change in study protocol or 
discontinuation of subject participation in the clinical research 
study 
● The test finding is considered an adverse effect by the Sponsor-
Investigator. 
 
9.5 Causality and severity assessment 
The investigator-sponsor will promptly review documented adverse effects and 
abnormal test findings to determine 1) if the abnormal test finding should be 
classified as an adverse effect; 2) if there is a reasonable possibility that the 
adverse effect was caused by the investigational device or, if applicable, other 
study treatment or diagnostic product(s); and 3) if the adverse effect meets the 
criteria for a serious adverse effect. 
 
If the investigator-sponsor’s final determination of causality is “unknown and of 
questionable relationship to the investigational device or, if applicable, other 
study treatment or diagnostic product(s)”, the adverse effect will be classified as 
associated with the use of the investigational device or study treatment or 
diagnostic drug product(s) for reporting purposes.  If the investigator-sponsor’s 
final determination of causality is “unknown but not related to the 
investigational device or, if applicable, other study treatment or diagnostic 
product(s)”, this determination and the rationale for the determination will be 
documented in the respective subject’s case history. 
 
9.6 Reporting of Adverse Effects and Unanticipated Problems 

Page 25 of 33 
 
9.6.1 Reporting of adverse reactions to the FDA 
The investigator-sponsor will submit a completed FDA Form 3500Ato the FDA’s 
Center for Devices and Radiological Health for any observed or volunteered 
adverse effect that is determined to be an unanticipated adverse device effect. A 
copy of this completed form will be provided to all participating sub-
investigators. 
 
The completed FDA Form 3500Awill be submitted to the FDA as soon as 
possible and in no event, later than 10 working days after the investigator-
sponsor first receives notice of the adverse effect. 
 
If the results of the sponsor-investigator’s follow-up evaluation show that an 
adverse effect that was initially determined to not constitute an unanticipated 
adverse device effect does, in fact, meet the requirements for reporting; the 
investigator-sponsor will submit a completed FDA Form 3500A as soon as 
possible, but in no event later than 10 working days, after the determination was 
made. 
 
For each submitted FDA Form 3500A, the sponsor-investigator will identify 
all previously submitted reports that that addressed a similar adverse effect 
experience and will provide an analysis of the significance of newly reported 
adverse effect in light of the previous, similar report(s). 
 
Subsequent to the initial submission of a completed FDA Form 3500A, 
the investigator-sponsor will submit additional information concerning 
the reported adverse effect as requested by the FDA. 
 
9.6.2 
Reporting Adverse Events to the Responsible IRB 
In accordance with applicable policies of UNC-Chapel Hill and Vascular 
Institute of Virginia, the investigator will report, to the IRB, any observed or 
volunteered adverse effect that is determined to be (1) unexpected; (2) related or 
possibly related to the research; and (3) involves increased or greater risk of 
harm to participant(s) or others than was previously known or approved by the 
IRB. Adverse effect reports will be submitted to the IRB in accordance with the 
IRB policies and procedures. 
 
9.7 Stopping Rules 
The study will be stopped if there is greater than one major complication (Grade 
D, E or F) as defined by the Society of Interventional Radiology Classification 
System for Complications by Outcome (29). 
 
9.8 Medical Monitoring 
9.8.1 Data and Safety Monitoring Plan 
Data and Safety Monitoring will be performed by a licensed physician who 
is not a study investigator. 
 
Study Monitor will be: 
 

Page 26 of 33 
 
Keith Smith, MD, PhD 
UNC Department of Radiology  
2016 Old Clinic Bldg 
CB #7510 
Chapel Hill, NC 275199-7510 
 
 
The CRFs and any relevant source documents will be sent to the Study 
Monitor (as above) who will review them after treatment is complete for 
subjects 1, 5, 10 and 21. 
 
Complications will be assessed by the co-PIs, categorized into major and 
minor categories and recorded on the CRF. CRFs and appropriate source 
documents will be made available to this individual for bi-monthly (every 2 
months) review to ensure completeness of data collection. Any discrepancies 
will be immediately addressed by the co-PIs.  All adverse events will be 
recorded and then summarized for inclusion in the final manuscript. 
Data monitoring will be performed by Study Monitor listed above. CRFs and 
appropriate source documents will be made available to this individual for bi-
monthly review to ensure completeness of data collection. Any discrepancies 
will be immediately addressed by the co-PIs. 
 
9.8.2 
Data and Safety Monitoring Board  
Because this is a small study with only 21 subjects, no DSMB will be used for 
this study.  Data and safety monitoring will be conducted by an individual (Study 
Monitor) who is not an investigator on this study (see above). 
 
10 
Data Handling and Record Keeping 
10.1 
Confidentiality 
Information about study subjects will be kept confidential and managed 
according to the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). Consistent with these regulations a 
signed authorization will be obtained that informs each subject of the following: 
● What protected health information (PHI) will be collected from 
subjects in this study 
●  Who will have access to that information and why 
●  Who will use or disclose that information 
● The rights of a research subject to revoke their authorization for 
use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected 
prior to the revocation of subject authorization.  For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 
 
10.2 Source Documents 

Page 27 of 33 
 
Source data are all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation 
of the trial.  Source data are contained in source documents.  Examples of these 
original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate 
and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, 
and at medical-technical departments involved in the clinical trial. 
 
10.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for 
the study.  All data requested on the CRF must be recorded.  All missing data 
must be explained.  If a space on the CRF is left blank because the procedure 
was not done or the question was not asked, write “N/D”.  If the item is not 
applicable to the individual case, write “N/A”.  All entries should be printed 
legibly in black ink.  If any entry error has been made, to correct such an error, 
draw a single straight line through the incorrect entry and enter the correct data 
above it.  All such changes must be initialed and dated.  DO NOT ERASE OR 
WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print 
the clarification above the item, then initial and date it. 
 
Copies of completed CRFs with subject IDs will be scanned and sent to the lead 
study coordinator at UNC for verification through the study database.  Data 
should be entered in the study database within 5 business days to ensure timely 
entry. 
 
The coordinator at each site will complete the first CRF together with one of the 
Co-PIs to verify that it is completed correctly. Then, we will verify a randomly 
selected 25% of all source docs at the conclusion of data collection.  
Randomization will occur on a visit level and not per patient.  The randomization 
for this verification will be generated using a random number generator in Excel. 
A concealed randomization look-up table will be generated in collaboration with 
the biostatistician and installed in the REDCap database. Assignments remain 
concealed to the staff until the moment the participant is enrolled online in the 
REDCap database. 
 
10.4 
Record Retention 
It is the investigators’ responsibility to retain study essential documents during 
the investigation and for a period of 2 years after the latter of the following two 
dates: The date on which the investigation is terminated or completed, or the 
date that the records are no longer required for purposes of supporting a 
premarket approval application or a notice of completion of a product 
development protocol. These documents should be retained for a longer period 
if required by an agreement with the sponsor.  In such an instance, it is the 
responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained. 

Page 28 of 33 
 
 
Research records and original signed consent forms are to be retained by 
principal investigator for at least 6 years if the form includes authorization for 
use of private health information.   Investigators may need to retain these 
documents for a longer period if required by an agreement with a sponsor or per 
other applicable regulatory requirements.  The 6 year minimum retention of 
authorizations complies with the privacy regulation requirements. 
 
10.5 
IRB Documentation 
The co-principal investigators and research coordinator will be responsible for 
maintaining IRB correspondence. IRB approved forms maintained, as part of the 
study will include the subject consent form and the HIPAA authorization form. 
 
11 Study Monitoring, Auditing and Inspecting 
11.1 Study Monitoring Plan 
11.1.1 Locations 
Initial enrollment will occur at either an orthopedic clinic or in an 
interventional radiology clinic in the Northern Virginia area or at UNC-
Chapel Hill. The procedures will be performed in Vascular Institute of 
Virginia Interventional Radiology or UNC-Chapel Hill procedural suites. 
Follow-up visits will occur at Vascular Institute of Virginia, UNC-
Chapel Hill, or via phone or teleconference. 
 
11.1.2 Study Staff Responsibilities and Training 
CITI Training: 
The investigators and all staff involved in the study will have completed 
their required CITI training in the protection of human research subjects 
and Good Clinical Practice training. Alternate training modules, as 
requested by local IRB, may also suffice. 
 
Drs. Isaacson, Piechowiak, and Bagla (fellowship trained interventional 
radiologists with subspecialty board certification) will be the only primary 
operators for each of the GAE’s. Drs. Isaacson, Piechowiak, and Bagla 
have performed more than 600 arterial embolization procedures. 
  
Any of the investigators may conduct follow-up visits as determined by 
the subjects’ and investigators’ availability. 
 
All subjects will be coded by an alphanumeric identifier (letters [initials] 
and site number) and subject identity will be kept confidential. Subjects 
will be apprised during the informed consent review that they have the 
right to voluntarily withdraw from the study at any time for any reason, 
and that his decision will not affect his medical care, but for attrition 
analysis subjects will be asked their reason for withdrawal . 
 
11.1.3 Quality Assurance and Quality Control 
The research coordinator will monitor the study files on a monthly basis 
to ensure the appropriate regulatory and IRB documentations are on file 
and up to date. The research coordinator will also be responsible for 

Page 29 of 33 
 
ensuring proper study documentation in order to verify compliance with 
Institutional policy, IRB, FDA and GCP guidelines in the following 
areas: Informed consent, Protocol, Source Documents and Electronic 
Case Report Forms. 
 
11.1.4 Safety Monitoring 
The research coordinator will complete the appropriate report form and 
logs; assist the PI to prepare reports and notify the IRB, FDA, and/or 
safety monitor of all Unanticipated Problems/SAE’s. 
 
The research coordinator and co-principal investigators will confirm that 
all Adverse effects (AE) are correctly entered into the AE log by the 
coordinator; be available to answer any questions that the coordinators 
may have concerning AEs; notify the IRB and FDA of all Unanticipated 
Problems/SAEs and AEs as appropriate. All assessments of AEs will be 
made by a licensed medical professional who is an investigator on the 
research. 
 
The research coordinator will confirm that the AEs are correctly entered 
into the AE log. The Study Monitor will confirm that the adverse events 
are consistent with the source documents and are reported to the 
appropriate regulatory bodies, as required. 
 
11.1.5 Monitoring Activities 
A safety monitor who is not a study investigator (see section 9.9.1) will 
conduct safety monitoring after treatment is complete for subjects 1, 5, 10, 
and 21. Adverse events will be documented and reported as described 
above. 
 
The following issues will be addressed quarterly or more frequently as 
necessary: 
• Verify receipt of all documents and supplies needed to conduct study 
• Informed consent obtained for each participant 
• CRF completion 
• Investigational product accountability 
• Check and review of the regulatory binder and all essential documents 
• Clinical supply inventory 
• SAE reporting 
• Enrollment issues and targets 
• Protocol amendment and their approval by the IRB 
• Significant protocol deviations 
• Personnel changes 
• Updated regulatory documentation 
• Any other issue as deemed important to the conduct of the study 
 
11.1.6 Study Closure 
Upon study closure a final evaluation of the data will ensure that all forms 
are present and complete. Data will be maintained in a secure location for 

Page 30 of 33 
 
the appropriate duration as described in section 10.5. At the conclusion of 
this term, all forms will be shredded and destroyed.  All subjects will be 
contacted via phone to thank them for their participation and to discuss the 
study findings as well possible additional treatment options. 
 
11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by 
the Research Quality Assurance Office, IRB, the sponsor, and government 
regulatory bodies, of all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data etc.).  The 
investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
12 
Ethics 
This study will be conducted in compliance with the protocol approved by the 
Institutional Review Board, the relevant federal regulations, and IRB policies 
and procedures and according to Good Clinical Practice standards. No deviation 
from the protocol will be implemented without the prior review and approval of 
the IRB except where it may be necessary to eliminate an immediate hazard to a 
research subject. In such case, the deviation will be reported to the IRB 
according to its policies and procedures. 
 
All subjects for this study will be provided a consent form describing this study 
and providing sufficient information for subjects to make an informed decision 
about their participation in this study.  This consent form will be submitted with 
the protocol for review and approval by the IRB for the study.  The formal 
consent of all subjects will be sought using the IRB-approved consent form. 
Before a subject undergoes any study procedure, an informed consent discussion 
will be conducted and written informed consent obtained with a consent form 
signed by the subject or legally acceptable surrogate if applicable. An 
investigator-designated research professional will obtain written informed 
consent from subjects. All subjects will be given a signed copy of the informed 
consent form. 
 
13 
Study Finances 
13.1 Funding Source 
The study is funded by a grant from Medtronic Sofamor Danek USA, Inc. 
 
13.2 Conflict of Interest 
Any investigator who has a conflict of interest (COI) with this study as defined 
by the policies of the UNC IRB will have the conflict reviewed by a properly 
constituted Conflict of Interest Review Committee with a committee-sanctioned 
conflict management plan that has been reviewed and approved by the IRB prior 
to participation in this study.  All investigators will follow the UNC conflict of 
interest policy.  
 
13.3 Subject Stipends or Travel Reimbursements 
  Subjects will not be remunerated for study participation. 

Page 31 of 33 
 
 
14 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided by the sponsor for the purposes of 
performing the study, will be published or passed on to any third party without 
the consent of the study sponsor. Any investigator involved with this study will 
be obligated to provide the sponsor with complete test results and all data 
derived from the study. 
 
15 Device Instructions For Use (IFU) 
      Study Device-Gel-Bead Microsphere; OptiSphere embolization spheres   
 
 
 
 
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