Safety and Efficacy of Genicular Artery Embolization for the Treatment of Symptomatic Knee Osteoarthritis
Phase: NA
Conditions: Knee Osteoarthritis, Degenerative Joint Disease of Knee
Sponsor: Siddharth Padia, MD

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NCT03491397 
 
Protocol Title:   
Feasibility of genicular artery embolization 
(GAE) for the treatment of pain associated with 
symptomatic knee osteoarthritis 
 
IDE Number: 
G180048 
 
 
 
Sponsor/Investigator: 
Siddharth A. Padia, MD 
 
University of California, Los Angeles 
1245 16th St. 
 
Suite 100 
 
Santa Monica, CA 90404 
 
(310) 319-3352 
 
 
 
Date of Protocol: 
March 13, 2020 
 
Protocol Version: 
1.10 

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TABLE OF CONTENTS 
 
SECTION 
NUMBER 
SECTION 
PAGE 
NUMBER 
1 
Introduction 
3 
2 
Study Objectives 
6 
3 
Eligibility Criteria 
7 
4 
Study Design 
8 
5 
Treatment and Assessments 
9 
6 
Withdrawal of Patients 
10 
7 
Adverse Events 
11 
8 
Symptom Assessments 
14 
9 
Statistical Analysis 
16 
10 
Records, Confidentiality and Data Monitoring 
17 
11 
Quality Control and Assurance 
17 
12 
Good Clinical Practice 
17 
13 
Ethical Considerations 
17 
14 
Patient Information and Informed Consent 
17 
15 
Patient Confidentiality 
17 
16 
Retention of Study Data 
17 
17 
References 
18 
Appendix A 
Schedule of Events 
19 
Appendix B 
Study Flow Chart 
20 
Appendix C 
Technical Protocol for Genicular Artery Embolization 
21 
Appendix D 
WOMAC Scale 
22 
Appendix E 
VAS Pain scale 
24 
Appendix F 
Embozene Instructions For Use 
25 
Appendix G 
PRO and PGIC 
26 
 
 
 
 

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1. Introduction 
Background: osteoarthritis 
Osteoarthritis (OA) is the most common degenerative joint disease and a leading cause of chronic 
pain and physical disability in older individuals. The lifetime risks of developing symptomatic knee 
OA are estimated at 40% in men and 47% in women (1).  
 
The hallmark symptom of OA is pain. This is the symptom that drives individuals to seek medical 
attention and contributes to functional limitation and reduced quality of life (2); the alleviation of 
pain is the main motivation for treatment, including nonpharmacologic, pharmacologic, and 
surgical approaches. End-stage knee OA is successfully treated with joint replacement surgery, but 
effective management of mild to moderate radiographic knee OA refractory to conservative 
treatment can be difficult.  
 
Although OA was viewed as a “wear-and-tear” disease for many decades, it is now generally 
accepted to be a low- grade inflammatory disease of synovial joints and a biomechanical whole-
organ disease (3). Angiogenesis is believed to contribute to the genesis of inflammation and 
particularly to its maintenance (4). The new increased vascular network provides inflammatory 
cells access to the synovium and other joint tissues and promotes additional hyperplasia and 
inflammation in other vessels, leading to bone and cartilage destruction (4). In addition, studies on 
OA have shown that angiogenesis may contribute to chronic pain by enabling the growth of new 
unmyelinated sensory nerves along their path (5).  
 
Selective genicular artery embolization (GAE) is an innovative, minimally invasive procedure that 
involves catheterization of the genicular artery and partial occlusion of this vessel (embolization) 
with particles. Preliminary data from feasibility studies in humans have been completed and show 
an excellent safety profile and efficacy (6, 7). The desired effect is to decrease vascularity, leading to 
a reduced inflammatory response. The purpose of this investigation is to confirm the safety and 
efficacy of GAE in adults with knee OA. 
 
Background: embolization 
The concept and practice of therapeutic arterial embolization is over 50 years old. Embolization has 
traditionally been used to treat acute hemorrhage (e.g. embolization of the gastroduodenal artery 
for gastrointestinal hemorrhage). Over the past twenty years, the practice of embolization has 
evolved to treat patients with both benign and malignant tumors. For example, liver cancer is now 
routinely treated via embolization of the hepatic artery (8). Benign symptomatic uterine fibroids 
are typically treated with particle embolization of the uterine arteries in the pelvis (9). Uterine 
fibroid embolization now has level I evidence as a treatment option by the American College of 
Obstetricians and Gynecologists for patients with symptomatic uterine fibroids (10). 
 
Embolization of arteries in the musculoskeletal system is typically performed in the setting of 
trauma in order to stop ongoing hemorrhage or for pre-operative embolization of hypervascular 
tumors. Treatment of bleeding arteries was quickly recognized as one potential therapeutic 
application of arterial embolization in the knee. Several reports of genicular artery embolization for 
the treatment of hemarthrosis after knee surgery have shown to result in significant symptomatic 
clinical improvement (11, 12). 
 
 
 
 

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Rationale 
The knee receives its blood supply from the genicular arteries, branches from the superficial 
femoral and popliteal arteries. Deliberate partial blockage of the genicular arteries (embolization) 
leads to reduction of the inflammatory response, with potential improvement in pain. 
Recently, Okuno and colleagues reported their experience with genicular artery embolization for 
patients with mild-to-moderate knee osteoarthritis. In their pilot study, 14 patients underwent 
embolization (7). No major adverse events were reported. There was a dramatic and rapid 
reduction in symptom and pain scores of patients. 
 
In 2017, the same authors reported their results of genicular artery embolization performed on 95 
knees in 72 patients (6). All patients had pain that was resistant to conservative treatment, such as 
oral nonsteroidal ant-inflammatory drugs, oral opioid agents, physical therapy, stretching, muscle 
strengthening, or intraarticular injection of hyaluronic acid. The distribution of local tenderness 
(indicating the presence of inflammation) was evaluated in all cases immediately before 
transcatheter arterial embolization and subdivided into eight areas to determine the key arteries to 
be treated. After selective catheterization of the appropriate genicular artery, imipenem/cilastatin 
sodium was used as the embolic material in 88 knees in 65 patients. Patients who had 
contraindications to imipenem/cilastatin (ie, a history of hypersensitivity or allergy to antibiotic 
agents or treatment with valproic acid) were treated with 75-μm Embozene microspheres instead 
(7 knees in seven patients).  
 
Mean Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores 
decreased significantly from 12.1 at baseline to 6.2 at 1 month, 4.4 at 4 months, 3.7 at 6 months, 3.0 
at 12 months, and 2.6 at 24 months after the first transcatheter arterial embolization procedure (all 
P < .001). The intent-to-treat clinical success rate at 6 months of follow-up was 86.3% (95% CI, 
78%–92%). The mean total WOMAC score also decreased significantly from 43 at baseline to 24, 
14.8, 11.2, 8.2, and 6.2 at 1, 4, 6, 12, and 24 months, respectively (all P < .001). The mean VAS score 
significantly decreased from 72 at baseline to 38, 29, 19, 13, and 14 at 1, 4, 6, 12, and 24 months, 
respectively (all P < .001). Patients reported a decrease in the dose of medication used and 
frequency of other treatments after the procedure. 
 
No serious adverse events were noted. Minor complications occurred, such as moderate 
subcutaneous hemorrhage at the puncture site and transient cutaneous color change on the treated 
knee, all of which resolved without treatment.  
 
While these single center results show a great deal of promise, the vast majority of patients 
underwent embolization with imipenem/cilastatin, which is not readily available in the United 
States. Seven patients underwent embolization with small calibrated microspheres (75-μm 
Embozene, Boston Scientific). While equivalent success rates were shown between the two 
embolics, the low number of patients treated with Embozene microspheres precludes a true 
comparative analysis.  
 
Embozene particles are FDA approved for the embolization of hypervascular tumors and 
arteriovenous malformations. Several studies have shown excellent safety and efficacy with regards 
to tumor control and objective response in liver cancer (13, 14). It has been used extensively for the 
treatment of symptomatic uterine fibroids, where Embozene embolization of the uterine arteries 
results in necrosis of uterine fibroids and cessation of abnormal vaginal bleeding (9). Other proven 
uses include embolization of arteriovenous malformations and fistulas (15). 
 

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Genicular artery embolization appears to be safe and effective for the treatment of knee 
osteoarthritis based on a single center study. Its mechanism of action in decreasing knee 
hypervascularity and inflammation appears consistent with other studies. Embozene particles are 
FDA-approved for the treatment of hypervascular tumors, and have shown promise in this arena. 
Based on these principles, a study of the safety and efficacy of Embozene particles for genicular 
artery embolization is warranted. 
 
 
 
 
 
 
 

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2. Study Objectives 
2.1 Primary Objective 
The primary objective of this investigation is to assess safety of genicular artery embolization 
(GAE) for knee osteoarthritis (OA) using Embozene particles.  
 
 
2.2 Secondary Objectives 
The secondary objectives of this investigation are to assess efficacy using the following 
outcomes, compared to baseline values when appropriate: 
• 
Improvement in pain 
• 
Improvement in WOMAC score 
• 
Change in radiographic imaging 
 
 
 

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3. Eligibility Criteria 
3.1 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria in order to be eligible for this study: 
• 
Provided informed consent 
• 
Age ≥ 40 years and less than 80 years 
• 
Life expectancy greater than 12 months 
• 
Ineligibility for or refusal of surgical management 
• 
Moderate-severe knee pain as determined by visual analog scale > 4 
• 
Osteoarthritis based on xray. Kellgren-Lawrence score > 1 based on radiograph 
completed within 6 months of procedure date. 
• 
Local knee tenderness 
• 
Resistant/failed conservative treatment (e.g. NSAIDS/physical therapy/steroid joint 
injection) for at least 3 months. 
 
 
 
3.2 Exclusion Criteria 
Subjects that meet any of the following exclusion criteria will not be eligible for this study: 
• 
Mild knee pain as determined by visual analog scale < 4 
• 
Chronic renal insufficiency (serum creatinine >2 mg/dL) 
• 
Uncorrectable bleeding diathesis 
o INR >1.6 
o Platelets <50,000 
• 
Significant arterial atherosclerosis that would limit selective angiography 
• 
Allergy to iodinated contrast agents that is not responsive to steroid management 
• 
Active Infection or malignancy 
• 
Appropriate candidate for knee replacement surgery determined by clinical and 
physical examination 
• 
Recent (within 3 months) or active cigarette use 
• 
Prior knee arthroplasty surgery in the subject knee 
• 
Active pregnancy 
 
 
 
 

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4. Study Design 
This is a single-center, prospective, single arm investigational study to evaluate the safety of 
genicular artery embolization (GAE) for treatment of symptomatic knee osteoarthritis (OA). In 
addition, the improvement as part of efficacy will be reported.  All subjects will have either failed or 
be intolerant to conservative management, and be ineligible for or refuse surgical intervention.  
Subjects will be considered enrolled in the study once they have provided informed consent and 
have been determined to meet all eligibility criteria.  A total of 40 subjects will be enrolled in the 
single treatment arm of the study and will be followed for 12 months. The subjects will be stratified 
according to arthritis severity based on imaging, with 20 subjects allocated to mild-moderate 
arthritis based on x-ray (Kellgren-Lawrence x-ray grade 1-2), and with 20 subjects allocated to 
severe arthritis based on x-ray (Kellgren-Lawrence x-ray grade 3-4). The stratification will not be 
randomized, but each category will be limited to 20 patients.   
 
The study will involve a screening period in which patient eligibility is determined.  Once eligibility 
is confirmed, subjects will undergo GAE with Embozene microspheres (100 micron). Following 
treatment, subjects will return for follow-up visits at 1 week (± 4 days), 1 month (± 2 weeks), 3 
months (± 2 weeks), 6 months (± 2 weeks), and 12 months (± 2 weeks) post-procedure.  At these 
visits, subjects will complete the Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) score, and a visual analog scale (VAS) score, undergo a directed physical examination, 
and report any new adverse events (AEs).  At 3 months of follow-up, subjects will also undergo 
knee MRI. At 12 months of follow-up, subjects will also undergo knee x-ray. At the 12 month follow-
up, subjects will also complete a patient-reported outcomes (PRO) and patient global impression of 
change (PGIC) questionnaire. 
 
 
The primary objective of the study will be to assess safety via minor and major adverse events. 
Secondary objective will be improvement of OA symptoms as assessed by the WOMAC and VAS 
scores at each follow-up visit. Subjects will continue to be followed according to the institutional 
standard of care after they complete the 12-month study visit. 
 
 
 

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5. Treatments and Assessments 
Subjects will be treated with a genicular artery embolization (GAE) procedure performed with 
Embozene Microspheres.  The microspheres will be delivered in a saline-contrast medium solution 
and will be delivered to the arteries supplying the areas of the subject’s pain. A complete 
description of the technical protocol to be followed is provided in Appendix C. 
 
After GAE, follow-up visits will take place at 1 week (± 4 days), 1 month (± 2 weeks), 3 months (± 2 
weeks), 6 months (± 2 weeks), and 12 months (± 2 weeks) from the date of treatment. Subjects who 
cannot present in person to the clinic at the 3, 6 or 12 month visit due to travel restrictions from the 
COVID-19 virus will conduct the follow-up visit over the phone. A schedule of study events and 
study flow chart are presented in Appendices A and B, respectively. 
 
 
5.1  Visit 1: Screening/Baseline (within 8 weeks of GAE) 
Subjects that meet all eligibility criteria listed in Section 3 above are eligible for participation in 
this study. 
 
Prior to enrollment, each patient will have the following assessments performed:  
• 
Obtain written informed consent 
• 
Medical history, including demographics 
• 
Physical examination including vital signs 
• 
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC, version 3.1) 
questionnaire 
• 
Visual analog scale (VAS) score 
• 
Laboratory evaluation: serum complete blood count and basic metabolic panel 
• 
Knee MRI without contrast. If patients cannot undergo MRI (e.g. pacemaker, significant 
claustrophobia), then CT of the knee without contrast will be performed. If a knee MRI 
or CT has already been performed within 6 months of Visit 1, that will be accepted.   
• 
Knee x-ray (within 6 months of Visit 1) 
• 
Evaluation for moderate sedation 
 
 
5.2  Visit 2: Genicular Artery Embolization  
The following data will be collected during each GAE procedure:  
• 
Technical success of GAE, defined as successful catheterization and embolization 
• 
Procedure time, duration of hospitalization, duration of catheterization, fluoroscopy 
dose, volume of embolic delivered, arteries embolized. 
 
5.3  Visits 3-7: Post GAE Follow-Up 
Subjects will have the following assessments performed:  
• 
Physical examination including vital signs 
• 
WOMAC and VAS questionnaires (at visits 4-7) 
• 
Review of adverse events 
• 
Knee MRI (at visit 5: 3 month follow-up). If patients cannot undergo MRI (e.g. 
pacemaker, significant claustrophobia), then CT of the knee without contrast will be 
performed. 
• 
Knee x-ray (at visit 7: 12 month follow-up) 
 
 

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6. Withdrawal of Subjects 
Subjects will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The Investigator also has the right to withdraw 
patients from the study for any of the following reasons:  
• 
Adverse Event 
• 
Concurrent medical condition 
• 
Patient unwillingness to comply with study requirements 
• 
Patient death 
• 
Other Investigator decision 
 
If a patient is withdrawn or discontinued from the study, the reason for withdrawal will be 
recorded in the source documents and on the End of Study case report form (CRF).  All patients 
withdrawn from the study will be encouraged to complete, if possible, all clinical evaluations 
scheduled for the 12-month follow-up visit.  All adverse events will be followed as described in 
Section 7.  Patients who are withdrawn from the study for any reason will not be replaced.  The 
Principle Investigator may terminate the study at any time. 
 

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7. Adverse Events 
7.1 Definitions 
Adverse Event: An adverse event (AE) is any untoward medical occurrence in a patient 
regardless of any causal relationship with a study treatment or procedure.  An AE can therefore 
be any unfavorable or unintended sign, symptom, or disease temporally associated with the use 
of a medicine or a procedure, whether or not considered related to the product or procedure.  A 
non-serious AE is any untoward medical occurrence that does not meet any of the criteria for a 
serious adverse event as defined below. 
 
Laboratory data will be collected as described in this protocol.  Clinical syndromes associated 
with laboratory abnormalities are to be recorded as appropriate. 
 
Patients will be instructed to report AE that they experience to the Investigator or Study 
Coordinator at each visit.  AEs occurring during the trial and the protocol-defined 12-month 
follow-up period will be reported on the AE case report form (CRF).  The Investigator will 
record AE terms according to Medical Dictionary for Regulatory Activities (MedDRA) lowest 
level terms.  Whenever possible, a specific disease or syndrome will be reported rather than the 
associated signs and symptoms.  Independent signs and symptoms will be reported as separate 
AEs. 
 
All AEs will be assessed for severity, relationship to the study treatment, treatment required 
and outcome/resolution.  This information will be reported on the AE CRF. 
 
Serious Adverse Event: A serious adverse event (SAE) is any AE, occurring at any dose and 
regardless of causality, that:  
• 
Results in death 
• 
Is life-threatening, such that the patient was at immediate risk of death from the event 
as it occurred 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; note that 
hospital admissions and/or surgical operations scheduled to occur during the study 
period but planned prior to study entry are not considered AEs if the illness or disease 
was diagnosed before the patient was enrolled in the study (provided that the patient’s 
condition does not deteriorate in an unexpected manner during the study) 
• 
Results in persistent or significant disability or incapacity, such that the patient 
experiences a substantial disruption of their ability to perform normal functions 
• 
Is an important medical event as determined by the Investigator.  An important medical 
event is an event that may not result in death, be life-threatening or require 
hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, it may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
Under this protocol, scheduled hospitalizations or elective surgical procedures will not be 
considered SAEs. Complications associated with surgical procedures or study treatments 
resulting in one of the outcomes above are considered SAEs. 
 
 
7.2 Adverse Event Reporting 
The Investigators are responsible for monitoring the safety of patients who have been enrolled 
in the study.  All AEs considered to be related to the procedure or study device will be followed 

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until the event resolves or has reached a fatal outcome.  AEs will be evaluated for severity using 
the standardized terms “mild,” “moderate” and “severe.” 
 
The Investigators will document all AEs occurring during the study, commencing with the date 
of the GAE treatment and including the protocol-defined 12-month follow-up period.  AEs and 
SAEs that occur following the signature of informed consent but prior to treatment will not be 
captured or reported. 
 
 
7.3 Serious Adverse Event Reporting 
Any unanticipated SAE, including death due to any cause that occurs during the study treatment 
or initial 12-month follow-up period, related to the procedure or study device, will be reported 
to the FDA within 3 days of the site learning of the event.   
Unrelated SAEs will be reported at the FDA IDE annual report. The SAE must be completely 
described on the AE CRF as well as the Serious Adverse Event Form. 
 
All safety concerns should be reported to:  
 
Siddharth Padia, MD 
1245 16th St. 
Suite 100 
Santa Monica, CA 90404 
spadia@mednet.ucla.edu 
310-319-3352 
 
7.4 Potential adverse events 
 
Commonly observed 
 
Blood draw:  
• 
Temporary pain from the needle stick 
• 
Bruising or swelling at the site 
 
MRI: 
• 
Feeling of claustrophobia 
 
Angiogram:  
• 
Temporary pain at the insertion site 
 
Genicular artery embolization:  
• 
Temporary discoloration of the skin (less than 2 weeks) 
• 
Temporary soreness in the knee (less than 2 weeks) 
 
Less likely 
 
Blood draw:  
• 
Fainting 
 
Angiogram:  

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• 
Allergic reaction to contrast dye 
• 
Reaction to sedative medications (for example: nausea, itching) 
 
Rare but serious 
 
Blood draw:  
• 
Infection 
 
MRI: 
• 
Potential heating or movement of any metal in the body 
 
Angiogram:  
• 
Possible risk of a blood clot in the artery 
• 
Bleeding around the catheter insertion site  
• 
Damage to the artery itself.  
• 
Risk of ionizing radiation (typically less than a CT scan) 
 
Genicular artery embolization:  
• 
Infection 
• 
Prolonged severe pain 
• 
Injury to the knee (osteonecrosis) 
• 
Allergic reaction to Embozene Microspheres 
• 
Sequela of non-target embolization (skin necrosis, toe necrosis). 
 
Warnings/complications on the Embozene Microsphere IFU include: 
 
• 
Undesirable reflux or passage of Embozene into normal arteries adjacent to the target or 
through the lesion into other arteries or arterial beds.  
• 
Embolization of the wrong artery or migration of the microspheres to other parts of the 
body, which may necessitate further treatment. 
• 
Hematoma, or bruising, at the incision site for arterial access. 
• 
Arterial aneurysm or thrombosis at the incision site for arterial access. 
• 
Deep vein thrombosis, or clotting of a deep vein in patient’s leg. 
• 
Pulmonary embolization 
• 
Ischemia at an undesirable location 
• 
Capillary bed saturation and tissue damage. 
• 
Ischemic stroke or ischemic infarction 
• 
Vessel or lesion rupture and hemorrhage 
• 
Neurological deficit including cranial nerve palsies.  
• 
Vasospasm 
• 
Recanalization 
• 
Foreign body reactions necessitating medical intervention 
• 
Infection necessitating medical intervention 
• 
Clot formation at the tip of the catheter and subsequent dislodgement 
• 
Allergic reaction 
• 
Risks of radiation from angiography and fluoroscopy used to visualize the blood vessels 
during embolization, which may include a radiation burn and risks to future fertility.  
• 
Death 

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Many of these risks may not apply, since these risks are from embolizing areas in the lungs or 
brain.  
 
Every effort will be made to minimize risks of the procedure. Since the embolization is being 
performed in a branch off of the femoral or popliteal artery in the knee, many of the risks listed 
on the IFU do not apply to the intended use in the protocol. For example, “migration of the 
microspheres to other parts of the body” cannot occur since the procedure is being done in an 
extremity, unlike a liver embolization for liver tumors where collateral vessels are present. The 
use is for arterial embolization, and deep vein thrombosis or pulmonary embolism only occurs 
in the setting of Embozene embolization of a vascular malformation, where there is an inherent 
abnormal communication between arteries and veins. Ischemic stroke or neurological deficit 
should only occur if embolization is being performed in the head or neck, and since the 
embolization is being performed in the knee, this risk does not apply. The risks of radiation 
from this procedure is exceedingly low, since angiography is only being performed on the 
extremity. Therefore, vital solid (eyes, thyroid) and reproductive organs (ovaries, testicles) are 
not in the field of view. Angiography of the extremity tends to involve extremely low amounts of 
radiation due to the lack of fat and muscle (compared to the abdomen) needed to penetrate for 
the x-rays. Finally, death from the use of this device has only been reported in embolization of 
high-risk regions, such as the lungs or brain. Since the procedure is being performed in the 
knee, there is no risk of death in this study. 
 
An MRI (or CT) of the knee will be performed during follow up, for the purposes of detecting 
any sequela of non-target embolization, or other unexpected abnormality. It is likely that there 
will be no changes in the MRI or CT appearance compared to baseline. 
 
 
 
8. Symptom Assessment 
8.1 Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC, version 3.1) 
 
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is a widely 
used, set of standardized questionnaires used by health professionals to evaluate the condition 
of patients with osteoarthritis of the knee and hip, including pain, stiffness, and physical 
functioning of the joints. It can be self-administered and was developed at Western Ontario and 
McMaster Universities in 1982. 
 
The WOMAC measures five items for pain (score range 0–20), two for stiffness (score range 0–
8), and 17 for functional limitation (score range 0–68). Physical functioning questions cover 
everyday activities such as stair use, standing up from a sitting or lying position, standing, 
bending, walking, getting in and out of a car, shopping, putting on or taking off socks, lying in 
bed, getting in or out of a bath, sitting, and heavy and light household duties. 
 
A WOMAC test takes about 12 minutes, and is among the most widely used assessments in 
arthritis research. 
 
A copy of the WOMAC (version 3.1) is provided in Appendix D. 
 
 
8.2 Visual analog scale (VAS) 

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The VAS is a validated commonly used pain score. A copy of the VAS score is provided in 
Appendix E. 
 
8.3 Patient-reported outcomes (PRO) and patient global impression of change (PGIC)  
The patient-reported outcomes (PRO) and patient global impression of change (PGIC) 
questionnaire is provided in Appendix G. 
 
 

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9. Statistical Analysis 
 
Safety Analyses 
Cumulative rates of AEs will be estimated and 95% CIs will be reported. AEs will be analyzed as 
a composite of all AEs, composites based on major AE types or severity and as individual AE 
types. The rates will be compared qualitatively to values reported in the literature of other 
studies of GAE and knee arthroplasty. An interim safety analysis will be performed after the 
first 10 patients are treated. 
 
With 40 patients expected with the stratification of moderate and severe arthritis, we can 
achieve approximate 83% power to test the difference of 10% of the upper bound of a 95% CI 
for an AE rate of <0.01% (no such events seen) vs 10%. At this sample size, for AE rates of 0% 
to 50%, the difference between the upper bound of the 95% CI and the estimate AE rate ranges 
from 7.1% to 14.8%. These calculations were based on exact binomial CIs, assuming no loss to 
follow up. 
 
 
Efficacy Analyses 
The primary is the change in WOMAC before GAE to 12 months after GAE. All statistical tests 
and confidence intervals (CIs) will be two-sided with a nominal significance level of p < 0.05 
(95% confidence). A linear mixed model (LMM) will be used to test for the mean change in 
WOMAC while adjusting for potential site-effects. The baseline and 12 month observations will 
be included in the model. The dependent variable will be the changes in WOMAC and the 
independent variables will be the WOMAC at baseline, baseline severity (moderate/severe 
arthritis), indicators of time (fixed effect Δ) and random intercepts for patient and site. The 
parameter Δ corresponds to the mean change in WOMAC. A Wald-type test of Δ = 0 and 95% CI 
of Δ will be calculated.  
 
Secondary analyses will also include analyzing changes from baseline to other timepoints and 
between post-treatment timepoints using the same methods. The Kaplan-Meier curves will be 
used to analyze the time until WOMAC improvement is first observed (i.e. time to 
improvement). The Turnbull method will be used to estimate these curves while accounting for 
interval censoring (the clinical improvement event is only known to have occurred between the 
current and prior visit). 
 
 
 
 
 

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10. Records, Confidentiality and Data Monitoring 
Each patient will be identified by a study ID number only in the trial records.  Study data will be 
recorded on pre-printed case report forms (CRFs).  Monitoring of study data recorded on source 
documents and reported on study CRFs will be conducted for all patients to ensure accuracy and 
completeness. All data will be stored on a HIPAA compliant online resource. 
 
11. Quality Control and Assurance 
Complete and accurate data collection and reporting will be the responsibility of the Principle 
Investigator. 
 
12. Good Clinical Practice 
This investigation will be conducted in accordance with the International Conference on 
Harmonization (ICH) E6 for Good Clinical Practice (GCP): Consolidated Guidance and all 
appropriate regulatory requirements.  The Investigator will be thoroughly familiar with the 
appropriate use of the treatment procedure as described in the protocol.  Essential clinical 
documents will be maintained to demonstrate the validity of the study and the integrity of the data 
collected.  Master files will be established by the site personnel at the beginning of the study, 
maintained for the duration of the trial and retained according to all appropriate regulations. 
 
13. Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki.  The Institutional Review Board (IRB) will review all appropriate study documentation, 
including the protocol, informed consent and any advertisements that will be used for the study in 
order to safeguard the rights, safety and wellbeing of the patients.  The study will only be conducted 
once IRB approval has been obtained.   The Investigator will provide safety updates, annual 
progress reports and any revisions to these documents to the IRB as required by regulations. 
 
14. Patient Information and Informed Consent 
After the study has been fully explained to each patient in their preferred language, written 
informed consent (also in the patient’s preferred language) will be obtained from each patient prior 
to any study-specific procedures being performed.  The IRB will approve the informed consent form 
prior to use.  The method of obtaining and documenting the informed consent and the contents of 
the consent will comply with ICH-GCP and all other applicable regulatory requirements. 
 
15. Patient Confidentiality 
In order to maintain patient privacy, all case report forms (CRFs), study reports and 
communications will identify the patient by their assigned study ID only.  The patient’s 
confidentiality will be maintained and will not be made publically available to the extent permitted 
by the applicable laws and regulations. 
 
16. Retention of Study Data 
University of California Los Angeles (UCLA) Medical Center will retain the written and/or electronic 
medical records, reports and data relating to the study in a secure location for a period of ten (10) 
years.  UCLA Medical Center will prepare and maintain accurate written records of and data from 
the study. 
 
 
 
 
 

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17. References 
 
1. 
Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, et al. The global burden of hip and 
knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014 
Jul;73(7):1323-30. PubMed PMID: 24553908.  
2. 
Dominick KL, Ahern FM, Gold CH, Heller DA. Health-related quality of life and health service 
use among older adults with osteoarthritis. Arthritis Rheum. 2004 Jun;51(3):326-31. PubMed 
PMID: 15188315. 
3. 
Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not 
osteoarthrosis!). Osteoarthritis Cartilage. 2013 Jan;21(1):16-21. PubMed PMID: 23194896.  
4. 
Pap T, Distler O. Linking angiogenesis to bone destruction in arthritis. Arthritis Rheum. 
2005 May;52(5):1346-8. PubMed PMID: 15880805.  
5. 
Ashraf S, Wibberley H, Mapp PI, Hill R, Wilson D, Walsh DA. Increased vascular penetration 
and nerve growth in the meniscus: a potential source of pain in osteoarthritis. Ann Rheum Dis. 2011 
Mar;70(3):523-9. PubMed PMID: 21081524. 
6. 
Okuno Y, Korchi AM, Shinjo T, Kato S, Kaneko T. Midterm Clinical Outcomes and MR Imaging 
Changes after Transcatheter Arterial Embolization as a Treatment for Mild to Moderate 
Radiographic Knee Osteoarthritis Resistant to Conservative Treatment. J Vasc Interv Radiol. 2017 
Jul;28(7):995-1002. PubMed PMID: 28365171.  
7. 
Okuno Y, Korchi AM, Shinjo T, Kato S. Transcatheter arterial embolization as a treatment for 
medial knee pain in patients with mild to moderate osteoarthritis. Cardiovasc Intervent Radiol. 
2015 Apr;38(2):336-43. PubMed PMID: 24993956.  
8. 
Gbolahan OB, Schacht MA, Beckley EW, LaRoche TP, O'Neil BH, Pyko M. Locoregional and 
systemic therapy for hepatocellular carcinoma. J Gastrointest Oncol. 2017 Apr;8(2):215-28. 
PubMed PMID: 28480062.  
9. 
Stampfl U, Radeleff B, Sommer C, Stampfl S, Dahlke A, Bellemann N, et al. Midterm results of 
uterine artery embolization using narrow-size calibrated embozene microspheres. Cardiovasc 
Intervent Radiol. 2011 Apr;34(2):295-305. PubMed PMID: 20953610.  
10. 
Gynecologists ACoOa. ACOG practice bulletin. Alternatives to hysterectomy in the 
management of leiomyomas. Obstet Gynecol. 2008 Aug;112(2 Pt 1):387-400. PubMed PMID: 
18669742.  
11. 
Weidner ZD, Hamilton WG, Smirniotopoulos J, Bagla S. Recurrent Hemarthrosis Following 
Knee Arthroplasty Treated with Arterial Embolization. J Arthroplasty. 2015 Nov;30(11):2004-7. 
PubMed PMID: 26092252.  
12. 
Waldenberger P, Chemelli A, Hennerbichler A, Wick M, Freund MC, Jaschke W, et al. 
Transarterial embolization for the management of hemarthrosis of the knee. Eur J Radiol. 2012 
Oct;81(10):2737-40. PubMed PMID: 22154590.  
13. 
Bonomo G, Pedicini V, Monfardini L, Della Vigna P, Poretti D, Orgera G, et al. Bland 
embolization in patients with unresectable hepatocellular carcinoma using precise, tightly size-
calibrated, anti-inflammatory microparticles: first clinical experience and one-year follow-up. 
Cardiovasc Intervent Radiol. 2010 Jun;33(3):552-9. PubMed PMID: 19957182.  
14. 
Greco G, Cascella T, Facciorusso A, Nani R, Lanocita R, Morosi C, et al. Transarterial 
chemoembolization using 40 µm drug eluting beads for hepatocellular carcinoma. World J Radiol. 
2017 May;9(5):245-52. PubMed PMID: 28634515. PMCID: PMC5441456.  
15. 
Hlavica M, Ineichen BV, Fathi AR, Remonda L, Diepers M. Parasagittal Dural Arteriovenous 
Fistula Treated With Embozene Microspheres. J Endovasc Ther. 2015 Dec;22(6):952-5. PubMed 
PMID: 26337189.  

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Appendix A: Schedule of Study Events 
 
 
 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
 
Visit 5 
 
Visit 6 
 
Visit 7 
Screening 
(within 8 weeks 
of Day 1) 
 
Treatment 
(Day 1) 
Week 1 
(day 4-10) 
Month 1 
(4 weeks 
± 2 weeks) 
Month 3 
(12 weeks 
± 2 weeks) 
Month 6 
(24 weeks 
±2 weeks) 
Month 12 
(52 weeks 
± 2 weeks) 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility criteria 
assessment 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concurrent Medical 
Conditions 
X 
 
 
 
 
 
 
Physical Examination  
X 
 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
Laboratory Evaluations1 
X 
 
 
 
 
 
 
WOMAC 
X 
 
 
X 
X 
X 
X 
VAS 
X 
 
 
X 
X 
X 
X 
PRO and PGIC 
 
 
 
 
 
 
X 
Knee x-ray2 
X 
 
 
 
 
 
X 
Knee MRI3 
X 
 
 
 
X 
 
 
GAE 
 
X 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
 
X 
X 
X 
X 
Protocol violations 
X 
X 
X 
X 
X 
X 
X 
 
1 Laboratory evaluations include complete blood count and serum chemistry 
2 Screening knee X-Ray can be performed within 6 months before Visit 1. 
3 Screening knee MRI can be performed within 6 months before Visit 1. If patients cannot undergo MRI (e.g. 
pacemaker, significant claustrophobia), then CT of the knee without contrast will be performed. 
 
 
 

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Appendix B: Study Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING/BASELINE 
Physical Exam, Labs, xray, MRI, 
WOMAC and VAS questionnaires, 
consent 
GENICULAR ARTERY EMBOLIZATION 
Within 8 weeks of screening/baseline visit 
1 Week Follow-Up 
Physical Exam, AE 
assessment 
3 Month Follow-Up 
Physical Exam, WOMAC and 
VAS, MRI, AE assessment 
6 Month Follow-Up 
Physical Exam, WOMAC and 
VAS, AE assessment 
12 Month Follow-Up 
Physical Exam, WOMAC and 
VAS, x-ray, AE assessment 
1 Month Follow-Up 
Physical Exam, WOMAC and 
VAS, AE assessment 

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Appendix C: Technical Protocol for Genicular Artery Embolization  
 
• 
Immediately prior to the procedure, appropriate knee will be marked. Discern areas of focal 
point tenderness (up to 3 locations) and place radio-opaque BB marker. 
• 
Administer prophylactic IV antibiotics, based on institution standard of care. Choice of 
antibiotic and sedation will be at the discretion of the interventional radiologist. 
• 
Local anesthesia should be administered for a transfemoral approach on the side with the best 
arterial pulse, preferably on the same side as the affected knee. 
• 
Access of the common femoral artery with a 21-gauge needle, with exchange to a 3-5 French 
sheath 
• 
Angiogram of the superficial femoral artery (thigh) 
• 
Catheterization of the distal superficial femoral artery, with repeat angiogram.  
• 
Intraprocedural rotational c-arm CT of the knee with concurrent contrast injection in the 
distal superficial femoral artery 
• 
Selective catheterization of the specific genicular arteries that are supplying the areas of the 
patient’s pain, with repeat angiogram.  
• 
If hypervascularity is seen, embolization is performed with 100 micron Embozene particles, 
suspended in a diluted solution of contrast and saline. 
• 
Procedural endpoint is lack of distal hypervascularity, with preservation of normal arterial 
flow. Arterial stasis should not be achieved.  
• 
Perform follow up angiography after each vessel is embolized to evaluate genicular 
devascularization and to identify any remaining collateral blood supply to the knee.  
• 
Once the embolization procedure is complete, follow institution’s standard of care for catheter 
and introducer removal and closure of femoral puncture. This will typically be done with 
manual compression. 
• 
It is suggested that patients be discharged with and oral non-opioid analgesic, 4-6 hours after 
the procedure. 
 
 
 
 
 

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Appendix D: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC, 
version 3.1) 
 
 
Instructions: Please rate the activities in each category according to the following 
scale of difficulty: 0 = None, 1 = Slight, 2 = Moderate, 3 = Very, 4 = Extremely 
Circle one number for each activity 
Pain  
 
 
1. Walking  
 
 
 
0  
1  
2  
3  
4 
2. Stair Climbing 
 
 
 0  
1  
2  
3  
4 
3. Nocturnal  
 
 
 
0  
1  
2  
3  
4 
4. Rest   
 
 
 
0  
1  
2  
3  
4 
5. Weight bearing  
 
 
0  
1  
2  
3  
4 
Stiffness  
 
1. Morning stiffness  
 
 
0  
1  
2  
3  
4 
2. Stiffness occurring later in the day  
0  
1  
2  
3  
4 
Physical Function  
1. Descending stairs  
 
 
0  
1  
2  
3  
4 
2. Ascending stairs  
 
 
0  
1  
2  
3  
4 
3. Rising from sitting  
 
 
0  
1  
2  
3  
4 
4. Standing  
 
 
 
0  
1  
2  
3  
4 
5. Bending to floor  
 
 
0  
1  
2  
3  
4 
6. Walking on flat surface  
 
0  
1  
2  
3  
4 
7. Getting in / out of car  
 
0  
1  
2  
3  
4 
8. Going shopping  
 
 
0  
1  
2  
3  
4 
9. Putting on socks  
 
 
0  
1  
2  
3  
4 
10. Lying in bed  
 
 
0  
1  
2  
3  
4 
11. Taking off socks  
 
 
0  
1  
2  
3  
4 
12. Rising from bed  
 
 
0  
1  
2  
3  
4 
13. Getting in/out of bath  
 
0  
1  
2  
3  
4 

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14. Sitting  
 
 
 
0  
1  
2  
3  
4 
15. Getting on/off toilet  
 
0  
1  
2  
3  
4 
16. Heavy domestic duties  
 
0  
1  
2  
3  
4 
17. Light domestic duties  
 
0  
1  
2  
3  
4 
Pain Score (1-5): _____ 
Total Score: ______  
 
 
 
 
 

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Appendix E: Visual analog pain score 
 
 
 
 
 
 

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Appendix F: Embozene Instructions For Use (IFU) 
 
See attached document. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix G: PRO and PGIC Questionnaire 
 
1. Since the procedure, how would you describe the change (if any) in activity limitations, symptoms, 
emotions, and overall quality of life related to your knee arthritis? 
 
1. No change (or condition has gotten worse) 
 
2. Almost the same, hardly any change at all 
 
3. A little better, but no noticeable change 
 
4. Somewhat better, but the change has not made any real difference 
 
5. Moderately better, and a slight but noticeable change 
 
6. Better, and a definite improvement that has made a real and worthwhile difference 
 
7. A great deal better, and a considerable improvement that has made all the difference 
 
2. If you could go back in time, knowing what you know now - would you have the procedure 
done again? 
 
 
1. Yes 
 
 
 
2. No