Clinical trial NCT03895840
Conditions: Knee Osteoarthritis
Sponsor: University of Kansas Medical Center
Start date: 2018-03-19; Completion date: 2021-05-03
Enrollment: 70 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will be an open-label trial to determine the functional effects of bilateral IA injections of Zilretta into knee joints of 70 subjects with bilateral KL grade 2-4 symptomatic knee osteoarthritis (OA). Measurement and evaluation of outcomes at baseline, 6, 12 and 24 weeks will allow assessment of short and long-term effects, consistent with Osteoarthritis Research Society International (OARSI) and Outcome Measures in Rheumatology (OMERACT) recommendations.

Detailed description:
The primary aim of the proposed study is to demonstrate the effect of IA injection of Zilretta on physical performance measures in adults with bilateral knee OA. The primary study endpoint will be the change in OARSI recommended physical performance tests (30-second chair standing test, 40m fast-paced walking test, stair ascent) 12 weeks after treatment.

The secondary outcome will be the change in Knee Injury and Osteoarthritis Outcome Score (KOOS-PS) patient-reported physical function short form.

The tertiary outcomes will be the change in KOOS-Quality of life subscale (QoL) and Numerical Rating Scale (NRS) for pain. All outcomes will be assessed at 6- and 24-week follow-up as well to define the course and trajectory of effects.

Specific Aim 1: To determine the extent to which intra-articular (IA) injection of Zilretta in patients with bilateral knee OA improves physical performance (OARSI recommended physical performance measures).

Primary Hypothesis 1: Bilateral knee intra-articular injection of Zilretta results in improved physical performance detectable at 6 weeks, 12 weeks (primary), and 24 weeks.

Specific Aim 2: To determine the extent to which IA injection of Zilretta in patients with bilateral knee OA improves physical function (KOOS-PF).

Hypothesis 2: Bilateral knee IA injection of Zilretta results in improved patient-reported physical function (KOOS-PS) at 6 weeks,12 weeks (primary), and 24 weeks.

Specific Aim 3: To determine the extent to which bilateral knee IA injection of Zilretta in patients with bilateral knee OA improves quality of life (KOOS-QoL).

Hypothesis 3: Intra-articular (IA) bilateral knee injection of Zilretta in patients with bilateral knee osteoarthritis results in improved quality of life (KOOS-QoL) detectable at 6 weeks, 12 weeks (primary), and 24 weeks.

Arms: arm 1: 32 mg Zilretta in a 5ml diluent for each knee, per manufacturer guidelines
Interventions: intervention 1: Zilretta
Intervention descriptions: intervention 1: Zilretta (triamcinolone acetonide extended-release injectable suspension) is indicated as an intra-articular injection for the management of pain due to knee osteoarthritis.

Protocol documents:
Prot_SAP_000.pdf: 
 
KUMC – HRPP- 03/12/2015 
 
Page 1 of 14
 
 
 
University of Kansas Medical Center  
RESEARCH PROTOCOL INVOLVING HUMAN SUBJECTS TEMPLATE  
 
Version date: October 1, 2018 
Principal Investigator: Neil Segal, MD, MS 
Study Title: An open-label pilot study of the effect of intra-articular bilateral knee injections of Zilretta on OARSI 
recommended physical performance measures in adults with symptomatic knee osteoarthritis. 
Co-Investigator(s): Mayank Kothari, MBBS 
 
I. Purpose, Background, and Rationale 
A. Aim and Hypotheses  
This study will be an open-label trial to determine the functional effects of bilateral IA injections of Zilretta into 
knee joints of 70 subjects with bilateral KL grade 2-4 symptomatic knee osteoarthritis (OA). Measurement and 
evaluation of outcomes at baseline, 6, 12 and 24 weeks will allow assessment of short and long-term effects, 
consistent with Osteoarthritis Research Society International (OARSI) and Outcome Measures in 
Rheumatology (OMERACT) recommendations. 
The primary aim of the proposed study is to demonstrate the effect of IA injection of Zilretta on physical 
performance measures in adults with bilateral knee OA. We will test this primary study endpoint by assessing 
the change in OARSI recommended physical performance tests1 (30-second chair standing test, 40m fast-paced 
walking test, stair ascent) 6, 12 (primary) and 24 weeks after treatment. 
The secondary outcome will be the change in Knee Injury and Osteoarthritis Outcome Score (KOOS-PS) at 6, 
12 (main) and 24 weeks after treatment. This will be captured using the patient-reported physical function short 
form.  
The tertiary outcomes will be the change in KOOS-Quality of life subscale (QoL) and Numerical Rating Scale 
(NRS) for pain. While the primary outcomes will be defined at the 12-week follow-up, all outcomes will be 
assessed at the 6- and 24-week follow-up as well to define the course and trajectory of effects. 
We hypothesize that people with bilateral symptomatic knee OA will experience significant improvement in 
physical performance, physical function and quality of life for at least 12 weeks following treatment. Based on 
research done using Zilretta in patients with knee OA, we anticipate that it will have a greater magnitude and 
duration of analgesic effect along with significantly fewer adverse events when compared to the rates reported 
for standard of care therapy (i.e. immediate release corticosteroid injection).2  
  
Specific Aim 1: To determine the extent to which intra-articular (IA) injection of Zilretta in patients with 
bilateral knee OA improves physical performance (OARSI recommended physical performance measures). 
Primary Hypothesis 1: Bilateral knee intra-articular injection of Zilretta results in improved physical 
performance detectable at: a) 6 weeks, b) 12 weeks (primary), and c) 24 weeks.  
Specific Aim 2: To determine the extent to which IA injection of Zilretta in patients with bilateral knee OA 
improves physical function (KOOS-PF).  
Hypothesis 2: Bilateral knee IA injection of Zilretta results in improved patient-reported physical function 
(KOOS-PS) at: a) 6 weeks, b) 12 weeks, and c) 24 weeks. 
Specific Aim 3: To determine the extent to which bilateral knee IA injection of Zilretta in patients with bilateral 
knee OA improves quality of life (KOOS-QoL).  
Hypothesis 3: Intra-articular (IA) bilateral knee injection of Zilretta in patients with bilateral knee 
osteoarthritis results in improved quality of life (KOOS-QoL) detectable at: a) 6 weeks, b) 12 weeks, and 
c) 24 weeks. 
 
 


 
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B. Background and Significance 
Osteoarthritis (OA) is the most common disabling disease in older adults, affecting over 27 million Americans, 
resulting in significantly impaired function and mobility and a societal economic burden. OA is a joint disorder 
characterized by structural pathology that involves the whole joint, including cartilage lesions, bone 
remodeling, osteophyte formation, and joint inflammation, among others, leading to symptoms and loss of 
normal joint function.  OA typically becomes symptomatic later in life, usually after age 50, though it may start 
earlier, such as when a joint injury has occurred or in familial forms. It is the most common form of arthritis 
worldwide, affecting an estimated 250 million people; about 80% of people over 65 having radiographic 
evidence of OA.   
OA is a leading cause of disability among elderly in the US. In recent estimates of global years lived with 
disability, musculoskeletal-related conditions ranked second, with low back pain, neck pain, and knee OA 
being the three most common conditions3. There is a high prevalence of knee OA globally4 and it ranked 
within the top 10 causes of disability and non-communicable diseases for global disability-adjusted life years 
worldwide (i.e., years of life lost and years lived with disability)3,5. The public health impact of OA is significant 
on both individuals and society due to the absence of a cure, making symptomatic treatment essential. 
The greatest challenge, affecting patients with OA of the hips and knees, is pain and stiffness in these joints, 
which often leads to significant disability requiring surgical intervention. In a longitudinal panel survey 
conducted by the US Census Bureau, arthritis or rheumatism was the most commonly reported cause of 
disability, and difficulties related to lower extremity functioning or activities were the most commonly reported 
limitations among all respondents. In particular, the most widely recognized limitation was in walking 3 city 
blocks, which influenced an estimated 22.5 million US adults, and difficulty with climbing stairs, influencing an 
estimated 21.7 million US adults6.  
Zilretta is an extended-release PLGA microsphere preparation of triamcinolone acetonide which is FDA 
approved for treatment of knee pain due to osteoarthritis. Zilretta (triamcinolone acetonide extended-release) 
is formulated using proprietary microsphere technology combining triamcinolone acetonide with a polylactic-
co-glycolic acid (PLGA) matrix. Zilretta received Fast Track Designation from the FDA. This designation is 
reserved for drugs in clinical development that is intended to treat a serious condition and addresses an unmet 
medical need. 
Preliminary Data: In previous clinical trials, Zilretta (triamcinolone acetonide extended-release) provided an 
extended and predictable release of triamcinolone acetonide as the biocompatible PLGA microspheres slowly 
degraded. A single IA dose of ZIlretta resulted in less systemically bioavailable triamcinolone acetonide when 
compared to a matched dose of triamcinolone acetonide crystalline suspension (TAcs)7 due to slower release 
and absorption into the systemic circulation. By providing prolonged local exposure to triamcinolone acetonide 
while minimizing systemic exposure, IA injection of Zilretta is expected to have sustained anti-inflammatory and 
analgesic efficacy while minimizing adverse effects8. A prior clinical trial provided evidence for analgesic efficacy 
for knee OA, with a significant reduction in average daily pain (ADP) sustained through 12-week follow-up9 
Therefore, the primary aim of the proposed study is to demonstrate the effects of IA injection of Zilretta on 
physical performance in adults with bilateral knee OA. We propose to determine the change in OARSI 
recommended10 physical performance measures (30-second chair stand time, 40m fast-paced walking 
time, stair ascent time) along with patient-reported physical function (KOOS-PS) and quality of life (KOOS-
QoL) at baseline and at intervals following bilateral knee injection of Zilretta. The expected deliverables of 
this research will be evidence regarding the effects of Zilretta on objective and patient-reported physical 
functional outcomes in patients with bilateral symptomatic knee OA. 
 
C. Rationale 
Disability due to knee OA is based on the inter-relationships of pathology (e.g. knee cartilage 
degeneration), impairments (e.g. pain), functional limitations (e.g. difficulties with standing from a chair, 
walking or using stairs), and disability (e.g. inability to participate in community). Biomedical research 
frequently focuses primarily on pathology and sometimes on impairments. However, there is an imperfect 
correlation between impairments and functional limitations. While the effect of Zilretta on pain has been 
explored, the effects on physical function and performance are incompletely understood. 
 
 
 


 
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II. Research Plan and Design 
 
A. Study Objectives: The goal of this study is to evaluate the efficacy of Zilretta for improving physical 
performance, physical function, and quality of life.  
B. Study Type and Design:  
This will be an open-label study to determine the functional effects of IA injection of Zilretta into bilateral knees 
of 70 subjects with KL grade 2-4 symptomatic knee OA. Measurement of OARSI recommended physical 
performance measures10, patient-reported physical function, quality of life and pain at baseline, 6, 12 and 24 
weeks will allow assessment of short and long-term effects, consistent with OARSI and OMERACT 
recommendations. Adverse events will be monitored. 
Each subject will participate for up to 24 weeks following the intra-articular Zilretta injection. Enrollment is 
expected to take approximately 6 months. Total study duration is expected to require at least 12 months. 
 
C. Sample size, statistical methods, and power calculation 
In this open-label study, all subjects will receive a single IA Zilretta injection into each knee. Outcome measures 
will be collected at baseline, 6, 12 (primary) and 24 weeks post-treatment. A 24-week follow-up duration was 
selected to detect meaningful differences from standard of care (IA corticosteroids - TAcs) and long-term effects, 
while minimizing the variability that may occur further out from treatment. The overall type I error rate will be 
controlled with an alpha level of 0.0167 to account for three comparisons at the primary time point. 
 
Based on the respective MDC95 calculated from the standard error of the mean change for OARSI 
recommended physical performance1, the effect size for this minimal detectible change is 0.392. To detect an 
effect size at least this large, with an adjusted alpha of 0.0167 and 80% power, a sample size of 60 would be 
required. To accommodate up to 14% dropout, we plan to recruit 70 subjects.  
 
D. Subject Criteria (See Vulnerable Populations appendix, if applicable):  
Enrollment will be comprised of 70 subjects age 30 and over with symptomatic bilateral knee OA. There will be 
no exclusions based on sex or ethnic group. Potential subjects will be identified through hospital records, 
referrals from physicians in the surrounding community, mass mailings, and advertisements posted in area 
clinics and businesses. Any study-related advertisements will be approved by the IRB prior to use. Subjects 
will be recruited based upon inclusion and exclusion criteria detailed below.  
1. Inclusion Criteria 
• 
Men and women age 30 years or older with symptomatic bilateral knee OA. 
• 
Symptomatic Knee OA will be defined as the presence of a definite osteophyte or joint space 
narrowing (KL Grade ≥2) on posteroanterior (PA) fixed flexion knee radiographs in subjects limited by 
bilateral pain in each knee, rated on a Numerical Rating Scale as ≥ 4/10 on more than half of the days 
over the past month. Radiographic change must be visible at standard image size, irrespective of 
capability to detect more subtle changes through digital enhancement. 
• 
Bilateral knee symptoms for ≥ 3 months prior to screening. 
• 
Undergone at least one prior conservative osteoarthritis treatment (e.g. physical therapy, analgesics). 
• 
Body Mass Index ≤ 40 kg/m2. 
• 
Ambulatory. 
• 
Willing and able to comply with the study procedures and visit schedules and ability to follow verbal 
and written instructions. 
• 
Willing to abstain from the use of protocol-restricted medications during the study after signing 
Informed Consent (Refer to §II.5) and also willing to abstain from use of all analgesics other than 
acetaminophen 1 week prior to the beginning of treatment. 
 


 
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2. Exclusion Criteria 
• 
Current consumption of more than 14 alcoholic drinks per week. 
• 
Clinical signs and symptoms of active knee infection or crystal disease of either knee within 1 month of 
screening. 
• 
Diagnosed with rheumatoid arthritis, Reiter’s syndrome, psoriatic arthritis, gout, ankylosing spondylitis, 
or arthritis secondary to other inflammatory diseases; HIV, viral hepatitis; chondrocalcinosis, Paget’s 
disease, or villonodular synovitis. 
• 
Diagnosed with leukemia, known presence of metastatic malignant cells, or ongoing or planned 
chemotherapeutic treatment. 
• 
Diseases of the spine, hip or other lower extremity joints judged by the investigator to be contributing 
to the pain in either knee (i.e. sciatica, nerve pain, hip OA). Note: Patients with hip replacement in 
either hip may be enrolled provided there is sufficient pain relief after hip replacement that analgesics 
are not required 
• 
Untreated symptomatic injury of either knee (e.g., acute traumatic injury, anterior cruciate ligament 
injury, clinically symptomatic meniscus injury characterized by a mechanical issue such as locking or 
catching). 
• 
Uncontrolled diabetes. 
• 
Women who report pregnancy or childbearing potential and not using acceptable contraceptive 
measures (oral contraceptive, long acting reversible contraceptive therapy) (due to the potential for 
change in body mass and distribution to alter knee symptoms over the period of follow-up). 
• 
Presence of surgical hardware or other foreign body intended to treat arthritis or cartilage-related 
pathology in either knee. 
• 
Arthroscopy or open surgery of either knee within 6 months of screening. 
• 
Planned/anticipated surgery of either knee during the study period. 
• 
Use of systemic immunosuppressant within 6 weeks of screening. 
• 
Oral corticosteroids (investigational or marketed) within 2 weeks of screening. 
• 
IA corticosteroid (investigational or marketed) in either knee within 3 months of screening. 
• 
IV or IM corticosteroid (investigational or marketed) within 3 months of screening. 
• 
Any other IA drug/biologic use within 6 months of screening or 5 half-lives (whichever is longer) (e.g., 
hyaluronic acid, platelet-rich plasma (PRP) injection, stem cells, prolotherapy and amniotic fluid 
injection). 
• 
Any documented clinically significant degree of cognitive impairment or other condition, finding, or 
psychiatric illness at screening which, in the opinion of the investigator, could compromise subject 
safety. 
• 
Any condition other than OA of the knee which, in the opinion of the investigator, affects the ability to 
ambulate to a sufficient degree to interfere with the assessment of the safety and treatment effects of 
the study injection. 
• 
Participated in any investigational drug or device trial within 30 days prior to screening or concurrent 
participation in another research study that could complicate interpretation of the study findings. 
 
3. Withdrawal/Termination criteria:  
 
Subjects may discontinue the study at any time. The investigator may discontinue a subject at any time for 
subject safety or noncompliance. Subjects who are discontinued for safety will be referred to their primary 
care physician for follow-up. 
 


 
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The Investigator/Coordinator will complete a study exit form in the CRF for any subject who prematurely 
discontinues from the study. If discontinuation was the result of an AE, the AE also will be recorded in the 
CRF. 
 
4. Allowable Medications/Nonpharmacological Therapies  
 
The following medications and nonpharmacological therapies may be taken or used throughout the study:  
• 
Aspirin for cardio-protection at a maximum stable dose provided the dose was stabilized over 3 months 
prior to study entry. 
• 
Physical therapy/bracing for the knee joint if the program was initiated and consistent prior to study 
entry. 
• 
Acetaminophen may be taken (up to 3000 mg per day) as rescue medication, if needed. Rescue 
medication is used only to treat worsening pain, whether or not that pain is associated with knee (e.g, 
may be used to treat headache, acute injury, etc.) and is not used for prophylaxis.  
• 
Use of acetaminophen must be discontinued 48 hours prior to the procedure visit and each follow-up 
visit. 
 
5. Restricted Medications/Nonpharmacological Therapies  
 
Volunteers will be advised that participation in the study will require them to abstain from certain medications 
and therapies. The following medications and nonpharmacological therapies should not be taken or used 
beginning immediately upon enrollment (after signing informed consent) until subject reaches the end of the 
study:  
• 
Oral non-steroidal anti-inflammatory drugs (unless on a chronic stable dose for ≥3 months prior to 
enrollment). 
• 
Topical analgesics applied to the skin over the knee (e.g., NSAID’s, capsaicin, lidocaine, heat patches).  
• 
Orally administered systemic corticosteroids. 
• 
Other Intra-articular injection into the knee joint. 
• 
Centrally acting pain medications (e.g., pregabalin, gabapentin, duloxetine, milnacipran) (unless on a 
chronic stable dose for ≥3 months prior to enrollment). 
 
E. Specific methods and techniques used throughout the study  
 
Investigational Product 
 
Zilretta kits will be received from Flexion Therapeutics and stored in a refrigerator between 2-8 degrees 
Celsius upon receipt. An ‘Investigational Drug Accountability Record’ will be used to record the product use 
for each subject. The kit label number, date of receipt, dates of dispense and preparation, and the date of 
destruction of the remaining product will be tracked and logged.  
   
Treatment Procedure:  
Zilretta (triamcinolone acetonide extended-release injectable suspension) is indicated as an intra-articular 
injection for the management of pain due to knee OA. To prepare the injectate, we will dilute 32 mg Zilretta in 
a 5 ml diluent for each knee, per manufacturer instructions. After application of sterile chlorhexidine and topical  
lidocaine (optional) for skin anesthesia, we will locate the superior recess of each knee joint, aspirate excess 
joint fluid and then inject the 5ml injectate into each knee joint capsule (bilateral injections).   
 
Primary Outcome  
OARSI recommended physical performance measures 
OARSI (Osteoarthritis Research Society International) recommended physical performance measures1 are a 
consensus-derived set that test physical function, which is complementary to patient-reported measures for 


 
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use in people diagnosed with knee osteoarthritis or following knee replacement. They are recommended for 
use prospectively as outcome measures in research, and also in clinical practice to make treatment decisions 
based on the results11. 
 
1. 30-second chair standing test  
The 30-second chair standing test evaluates the maximum number of repetitions that a subject can stand 
from a seated position in a 30 second period1.  From the sitting position, the subject will stand up 
completely up so hips and knees are fully extended, then completely back in the seated position. This will 
be repeated for 30 seconds and we will record the total number of chair stands (up and down equals one 
stand). The tester will stand close to the side of the chair for safety and also ensure that the subject comes 
to a full standing and sitting position during the test. 
The study coordinator or designee will enter the data collected into the CRF after completion of the test. 
 
2. 40m fast-paced walking test 
The 40-meter fast-paced walking test is a test that is timed over 4 x 10m (33 ft) paths for a total of 40 m 
(132 ft)1. We will mark out a 10 m (33 ft) walkway with bright colored tape at each end. A cone will be 
placed approximately 2 meters before the start mark and 2 meters beyond the finish mark of the 10m 
walkway. Enough space will be left to turn safely around at each end.  
A practice trial of 1-2 turns will be done before testing to help subjects to understand the procedure. We 
will begin timing subjects after giving the signal to start at the start line and stop the timer once the subject 
crosses back over the start line after completing the course. When the subject crosses the 10m mark, 
timing will be paused while the subject turns around the cone and then it will be resumed once they cross 
the 10m mark again. The same will be repeated for the following turns and timing will be stopped once the 
subject crosses the start line for the final time. The duration of one trial will be recorded to the nearest 
100th of a second. Time of one test trial will be recorded and expressed as speed (m/s) by dividing 
distance (40m) by total time. Regular walking aid will be allowed and its use will be recorded. 
For subjects in whom safety is of concern, the tester will follow slightly behind and off to one side of the 
subject, while taking care not to pace or impede them. If there is no excess concern for safety, the tester 
will follow well to the side so as to view the crossing at the 10m walkway at both ends. The study 
coordinator or designee will enter the data into the CRF. 
 
3. Stair negotiation  
Stair negotiation is also a common activity limitation and rehabilitation goal in people with symptomatic 
knee OA. We will time the subjects ascending and descending a flight of 9 stairs as quickly as they can 
accomplish in a safe manner. We will conduct the nine-step stair test in the staircase adjoining our 
research space (individual step height of 17 cm).  
Timing will begin on the signal to start and terminate when the subject returns with both feet to the ground 
level. Total time to ascend and descend steps for 1 test trial will be recorded to the nearest 100th of a 
second. 
Use of a handrail and walking aid will be permitted if required1. The study coordinator or designee will 
enter the data into the CRF. 
          
Secondary Outcome                                                                                                                           
Patient-reported physical function (KOOS-PS).  
In addition to the performance-based primary outcome measures, KOOS-PS, a self-reported measure of 
mobility will be included.  
KOOS-Physical Function (KOOS-PS) Short Form is a parsimonious measure of physical function derived 
from the KOOS12. The KOOS-Physical Function Short Form also has good internal consistency and high 


 
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test-retest reliability. 
A working group tasked with constructing a composite measure of OA severity sponsored by the 
Osteoarthritis Research Society International (OARSI) and Outcome Measures in Rheumatology 
(OMERACT) developed the KOOS-PS. Respondents are asked to indicate the degree of difficulty 
experienced in the last week due to a knee problem in 7 tasks: Rising from Bed, Putting on socks/stockings, 
Rising from sitting, Bending to the floor, Twisting/pivoting on the injured knee, Kneeling, and Squatting. 
Responses are measured on a Likert scale ranging from ‘None’ to ‘Extreme’.  
 
Tertiary Outcomes  
KOOS QoL 
KOOS-QoL is a self-reported measure13 (4 questions) of quality of life, which is part of the five patient-
relevant subscales of KOOS. A Likert scale is used and all four questions have five possible answer 
options scored from 0 (No Problems) to 4 (Extreme Problems). Each of the five scores is calculated as the 
sum of the items included. Scores are transformed to a 0-100 scale, with zero representing extreme knee 
problems and 100 representing no knee problems as is common in orthopedic assessment scales and 
generic measures. Scores between 0 and 100 represent the percentage of total possible score achieved.  
 
Numerical Rating Scale (NRS) for Pain 
 
The Numeric Rating Scale for Pain (NRS for Pain) is a measure of pain intensity. The investigator or 
designee will verbally introduce the 11-point scale to the research subject to rate pain in each knee.  The 
investigator or designee will ask the following questions,  
• 
 “On a scale of 0 to 10, with 0 being no pain at all and 10 being the worst pain imaginable, how would 
you rate your knee pain IN THE PAST 7 DAYS?” 
 
The subject will complete the NRS for Pain worksheet after receiving instructions from the study 
coordinator. The NRS for Pain will be completed by the subject at baseline evaluation and at each follow-
up visit (6,12 and 24 weeks). The study coordinator or designee will enter the data into the CRF. 
 
The table below details the schedule of study assessments and procedures, for each visit. 
 
 


 
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        *Each visit must be within ±5 days of the scheduled visit; ‡ may be combined with screening visit. 
 
F. Risk/benefit assessment 
The reference safety information for Zilretta for this study is the Zilretta USPI.  
 
1. Physical risk:  
Zilretta (triamcinolone acetonide extended-release injectable suspension) is indicated as an intra-articular 
injection for the management of pain due to knee OA. The most commonly reported adverse reactions 
(incidence ≥1%) in clinical studies included sinusitis (2%), cough (2%), contusions (2%) and joint swelling 
(3%). For additional details, please see Package Insert (http://www.zilrettalabel.com/PI.pdf). The website 
for Zilretta additionally lists: joint pain, headache, back pain, sore throat and runny nose, and bruising as 
common side effects of receiving a Zilretta injection. 
 
The following is a list of other adverse events that can occur following injection of corticosteroids, although 
not reported following Zilretta.   
 
• 
Hypersensitivity Reactions: Rare instances of anaphylaxis, including serious cases, have 
occurred in patients with hypersensitivity to corticosteroids. Serious cases of anaphylaxis, 
including death, have been reported in individuals receiving triamcinolone acetonide injection, 
regardless of the route of administration. 
• 
Joint Damage: Intra-articular administration may result in damage to joint tissues. 
• 
Increased Risk of Infections: Infection with any pathogen in any location of the body may be 
Assessment 
Visit 1 
Screening 
Visit 2  
Day 1- 
Zilretta 
Treatment‡ 
Visit 3  
6-Week 
Follow-up 
Visit 4  
12-Week 
Follow-up 
Visit 5  
24-Week 
Follow-up  
Informed Consent 
X 
 
Eligibility 
X 
X‡ 
 
Medical history 
X 
X‡ 
 
Radiograph (if not 
previously done) 
X 
 
 
Concomitant 
medications 
X 
X‡ 
X 
X 
X 
Prior/Concurrent 
Therapy 
X 
Study Treatment 
X 
 
BMI Assessment 
X 
 
 
Physical Exam 
 
X 
X 
X 
X 
KOOS-PS & QoL 
Questionnaire 
 
X 
X 
X 
X 
NRS for Pain 
X 
X‡ 
X 
X 
X 
Physical Performance 
Measures 
 
X 
X 
X 
AE/SAE Assessment 
X 
X 
X 
X 


 
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associated with corticosteroids. Corticosteroids may increase the susceptibility to new infection 
and decrease resistance and the ability to localize infection. A marked increase in pain 
accompanied by local swelling, restriction of joint motion, fever, and malaise are suggestive of 
septic arthritis. 
• 
Alterations in Endocrine Function: Corticosteroids can produce reversible hypothalamic-
pituitary-adrenal axis suppression, with potential for adrenal insufficiency after withdrawal of 
treatment, which may persist for months.  
• 
Cardiovascular and Renal Effects: Corticosteroids can cause blood pressure elevation, salt, 
and water retention, and an increase potassium excretion.  
• 
Increased Intraocular Pressure: Corticosteroid use may be associated with increased 
intraocular pressure.  
• 
Gastrointestinal Perforation: Corticosteroid administration may increase the risk of 
gastrointestinal perforation in a patient with certain GI disorders and fresh intestinal anastomoses.  
• 
Alterations in Bone Density: Corticosteroids decrease bone formation and increase bone 
resorption.  
 
2. Psychological risk: Corticosteroids may cause adverse psychiatric reactions. Although this has not 
been reported following Zilretta injection, we will advise patients to immediately report any behavior or 
mood disturbances. 
3. Social risk: N/A 
4. Economic risk:  N/A 
5. Potential benefit of participating in the study: Participation in this study may produce possible 
benefits for the individual subjects such as improved pain, stiffness or function in your knee joint.   
G. Location where study will be performed: The study will be performed at the University of Kansas Medical 
Center, Sudler 1st Floor (primarily Rooms 1023-1024).  All data forms and records will be kept on site at the 
University of Kansas Medical Center in locked drawers and password-protected computers in a locked office. 
Only members of the research team will have access to the data. 
H. Collaboration (with another institution, if applicable): N/A 
I. 
Single IRB Review for a Multi-site study (if applicable):  N/A 
 
J. Community-Based Participatory Research (if applicable): N/A 
 
K. Personnel who will conduct the study, including: 
1. Indicate, by title, who will be present during study procedure(s):  
a. Dr. Neil Segal, Principal Investigator 
b. Dr. Mayank Kothari, Sub-Investigator 
2. Primary responsibility for the following activities, for example:  
a. Determining eligibility: Segal/Kothari/Deas 
b. Obtaining informed consent: Deas/Segal 
c. Providing on-going information to the study sponsor and the IRB: Deas/Segal 
d. Maintaining subject's research records: Deas/Segal 
e. Completing physical examination: Segal 
f. Measuring height, weight: Kothari/Deas/Segal 
g. Drawing / collecting laboratory specimens: N/A 


 
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h. Performing / conducting tests, procedures, interventions, questionnaires: Segal/Deas 
i. Completing study data forms: Deas/Segal/Kothari 
j. Managing study database: Deas/Kothari 
 
L. Assessment of Subject Safety and Development of a Data and Safety Monitoring Plan 
Compliance reports which include telephone screening forms for eligibility, radiographs, medication 
amenability and safety logs will be reviewed by the Principal Investigator on a weekly basis. Reports containing 
the proportion of subjects completing the intervention or prematurely terminating participation will be generated 
monthly. 
Adverse event information will be collected at each visit and during all contacts with subjects.  If an adverse 
event is reported to study staff, data including the type of event, onset/end dates, duration, and outcome will 
be collected and reported to the Principal Investigator. All adverse event information will be assessed by the 
Principal Investigator for severity, seriousness, and relationship to Zilretta, per the definitions below.   
The Investigator is required to follow SAEs until resolution or withdrawal of consent. Resolution is defined as: 
• 
A return to baseline for a pre-existing condition; or 
• 
Resolved with or without residual effects; or 
• 
The Investigator does not expect any further improvement or worsening of the event. 
 
Reporting Serious Adverse Events: 
An event that is serious must be recorded on the AE worksheet and requires expeditious handling to comply 
with regulatory requirements.  Any adverse event classified as “serious” by the Investigator must be reported 
to the IRB within 24 hours of becoming aware of its occurrence. All serious adverse events in patients treated 
with Zilretta must also be reported to Flexion within 3 calendar days. The Investigator should attempt to 
collect as much information about the adverse event as needed to get a complete medical understanding and 
forward that information to Flexion as it becomes available.  
 
 All serious adverse events which are considered causally related to Zilretta (see definitions below) must be 
assessed for whether it is expected per the USPI. An unexpected event means that it is not described within 
the reference safety information (the Zilretta USPI) as associated with Zilretta. If an event is assessed as 
serious, related to Zilretta, and unexpected, it must be reported to the FDA according to 21CFR314.80   
 
Safety Definitions: 
 Adverse Event (AE): An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product, any clinically significant abnormality found 
on an ECG, laboratory test, or physical examination, or any worsening (i.e., any clinical significant adverse 
change in frequency and/or intensity) of a preexisting condition, which is temporally associated with the use 
of the medicinal (investigational) product 
Serious Adverse Event (SAE): An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death, 
• 
Is life-threatening, (“Life-threatening” refers to an event in which the patient was at substantial risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe.)   
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 


 
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• 
Note:  Adverse events requiring hospitalizations that are less than 24 hours in duration do 
not meet this criterion. A scheduled hospitalization for an elective procedure or a pre-
existing condition that has not worsened during participation in the study does not meet 
this criterion.  
• 
Results in permanent or significant disability/incapacity; a substantial disruption of the patient’s ability 
to carry out normal life functions. 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event: event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed in the definition above. 
 
Severity: the intensity of the adverse event. This is not the same as “serious,” which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to a patient’s life or 
functioning. The severity of AEs will be assessed according to the following definitions:   
• 
Mild:  the AE is noticeable to the patient and/or the Investigator, but does not interfere with routine 
activity. 
• 
Moderate:  the AE interferes with routine activity, but responds to symptomatic therapy or rest. 
• 
Severe:  the AE significantly limits the patient’s ability to perform routine activities despite symptomatic 
therapy. 
 
Causal Relationship: A medically-qualified Investigator must assess the relationship of any AE (including 
SAEs) to the use of the investigational product, as related or not related, based on clinical judgment and 
using all available information, and may include consideration of possible alternative causes of the AE, 
including the disease under treatment, pre-existing conditions, concomitant use of other drugs, and presence 
of environmental or genetic factors, the temporal association between drug exposure and onset of the AE, 
and whether the manifestations of the AE are consistent with known actions or toxicity of the investigational 
product. The causal relationship between the study medication and the AE will be assessed using one of the 
following categories: 
• 
Not Related: An AE is not associated with study medication if:  
o 
Temporal relationship is lacking (e.g., the event did not occur within a reasonable time frame 
following administration of the study medication); or  
o 
Other causative factors more likely explain the event (e.g., a pre-existing condition, other 
concomitant treatments). 
• 
Related: An AE is attributed to the study medication if:  
o 
There is a positive temporal relationship (e.g., the event occurred within a reasonable time frame 
following administration of study medication); and 
o 
The AE is more likely explained by the investigational product than by another cause (i.e., the AE 
shows a pattern consistent with previous knowledge of the investigational product or the class of 
the investigational product).  
 
Data and Safety Monitoring Plan 
The data will be reviewed by the study team and the Principal Investigator. The reviewed data include eligibility, 
data reconcilation and safety logs. There will also be reports containing the proportion of subjects completing the 
intervention or prematurely terminating participation . This will be done on a monthly basis. 
 


 
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III. Subject Participation 
A. Recruitment: 
Potential study subjects will be recruited from the clinics of the principal investigator and referring physicians, 
and using local advertising. Any study-related advertisements will be approved by the governing IRB prior to 
use.  Subjects will be recruited based upon inclusion and exclusion criteria detailed above. Subjects will be 
compensated for their time and effort at follow-up visits. 
Each subject will participate for up to 24 weeks. Enrollment is expected to take up to 6 months.  Total study 
duration is expected to be at least 12 months. 
B. Screening Interview/questionnaire:  
Potential subjects who express interest in the study will be pre-screened by telephone. A script will be used to 
determine eligibility for the first screening clinic visit by study staff. Please reference Appendix A. 
C. Informed consent process and timing of obtaining consent 
Potential subjects who pass the initial screening criteria (telephone screen) will be asked to schedule a 
screening visit to provide written consent and possibly undergo screening procedures during a screening visit. 
Subjects will be informed that the study is voluntary and choosing not to participate will not affect their current 
treatment. They may request the opportunity to review the consent form with their physician and/or family 
members.  Moreover, they will be fully informed of the purpose of the study and of the possible risks involved 
before providing their consent. Written, informed consent will be obtained and documented by an investigator 
or a study coordinator prior to initiation of study procedures.  All subjects will be provided with a copy of the 
signed consent form. 
D. Alternatives to Participation: The alternative to study participation is choosing not to participate and to 
continue with their current treatment plan. 
E. Costs to Subjects: There will be no cost to subjects to participate in the study and no insurance will be billed 
as a part of the study procedures. 
F. How new information will be conveyed to the study subject and how it will be documented: If any new 
information is to be provided to the study subject the informed consent form (ICF) will be amended and 
approved by the IRB.  Each subject will then be reconsented using the newest revision of the ICF. 
G. Payment, including a prorated plan for payment:  
Subjects will be provided $20 at Visit #2, $20 at Visit #3, $30 at Visit #4, and $30 at the final Visit #5 (up to $100 
per subject) as compensation for their time. They additionally will be provided with parking validation for in-
person visits. Moreover, subjects will be provided with encouragement during the study period, especially prior 
to and after each study visit by letting them know that their contributions are appreciated.     
 
H. Payment for a research-related injury:  
If the subject is injured because of study participation, there will be no compensation for physical or non-
physical injuries. No compensation will be available for any extra expenses that may be the result of research-
related physical injuries including additional hospital bills, lost wages, travel expenses, etc.  No compensation 
will be available for any non-physical injuries that may occur because of research participation, such as legal 
problems, problems with your finances or job, or damage to your reputation. 
 
IV. Data Collection and Protection 
A. Data Management and Security:  
OARSI recommended10 physical performance measures (30-second chair stand time, 40m fast-paced walking 
time, stair ascent time) along with patient-reported physical function (KOOS-PS), quality of life (KOOS-QoL) 
and NRS pain data will be collected at baseline and 6, 12 and 24 weeks post-treatment. All data collected will 
remain confidential and accessible only to the research team. This data will be collected using a paper-based 


 
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CRF that will be transferred into two databases. These two databases contain the same collection points so 
reconciliation can be done to detect data entry errors. 
Data regarding subject demographics, knee radiographs, OARSI recommended physical performance 
measures, and KOOS subscale responses and NRS pain will be gathered from subjects and numerically coded 
in sequential order with no patient identifiers.  A master list with patient information and assigned study IDs will 
be stored in a separate password-protected file available only to the Principal Investigator and the Research 
Coordinator. Analyses will be performed on coded files. Physical files (e.g. questionnaires) will be stored in 
locked file cabinets in the offices of the Principal Investigator.   
 
B. Sample / Specimen Collection: N/A 
C. Tissue Banking Considerations: N/A  
D. Procedures to protect subject confidentiality:  
Data regarding subject’s demographic, knee radiographs, OARSI recommended physical performance 
measures, and KOOS subscale responses and NRS pain data will be obtained directly from subjects. All data 
will be coded with no information that could identify a subject. A master list with patient information and assigned 
study ID’s will be stored in a password-protected file available only to the Principal Investigator and the 
Research Coordinator. Analyses will be performed on coded files. Physical files (e.g. questionnaires) will be 
stored in locked file cabinets in the office of the Principal Investigator.  
 
E. Quality Assurance / Monitoring 
Study staff will have proper qualifications for data entry and will receive training in data entry procedures to 
ensure data entered is of highest quality.  Data will be entered by researchers into two separate databases 
developed for this study.  Each database will contain the same collection points and then be reconciled to clean 
the data for analysis and outcome reports to the Principal Investigator.  Data will be backed-up daily. 
 
V.    Data Analysis and Reporting 
A. Statistical and Data Analysis:   
The primary analysis will regard the change in the 3 OARSI-recommended physical performance measures 
between baseline and 12 weeks following injections. The three pre/post change scores will be assessed with 
one-sample t-test for matched pairs, using an alpha level of (.05/3) to determine statistical significant change. 
Differences between baseline and other timepoints and secondary/tertiary outcome measures will be assessed 
with repeated measures analyses, with time as a repeated factor to account for multiple comparisons over time. 
A soft-lock of the database will occur after the 6- and 12-week time points.   The analyses of secondary and 
tertiary outcomes will involve the analyses of longitudinal data, collected at baseline, 6 weeks, 12 weeks, and 
24 weeks. These response variables will be modeled using the framework of longitudinal mixed models.  Each 
model will be based on two main effects: a random subject effect, and a fixed time effect consisting of four 
levels (baseline, 3 follow-up time points). The distribution of the secondary and tertiary outcome measures will 
be examined and transformation to a normal distribution will be performed if needed. We will use the Akaike 
information criterion to determine an appropriate variance/covariance structure.  Each of the hypotheses of 
interest will be tested by examining appropriate contrasts and estimable linear forms in the overall mean and 
the main effects for time. Analyses will be conducted using SAS (Version 9.1.2).  PROC MIXED will be used to 
fit the longitudinal models. 
 
B. Outcome: We expect statistically significant and clinically meaningful improvement in physical performance, 
physical function, pain and quality of life 12 weeks following bilateral treatment with Zilretta.  
C. Study results to subjects: The study will be registered on www.clinicaltrials.gov and results posted upon 
completion of the study. 


 
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D. Publication Plan: Results will be submitted for presentation at an appropriate conference and for publication 
in an appropriate journal for the topic of study. 
VI. 
Bibliography / References / Literature Cited  
 
1. 
Dobson F, Hinman RS, Roos EM, et al. OARSI recommended performance-based tests to assess physical function 
in people diagnosed with hip or knee osteoarthritis. Osteoarthritis Cartilage 2013;21:1042-52. 
2. 
Maricar N, Callaghan MJ, Felson DT, O'Neill TW. Predictors of response to intra-articular steroid injections in knee 
osteoarthritis--a systematic review. Rheumatology (Oxford) 2013;52:1022-32. 
3. 
Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 
1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2197-223. 
4. 
Centers for Disease C, Prevention. Prevalence of disabilities and associated health conditions among adults--
United States, 1999. MMWR Morb Mortal Wkly Rep 2001;50:120-5. 
5. 
Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and 
injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163-96. 
6. 
Centers for Disease C, Prevention. Prevalence and most common causes of disability among adults--United States, 
2005. MMWR Morb Mortal Wkly Rep 2009;58:421-6. 
7. 
Byers-Kraus V, Aazami HA, Mehra P, et al. Synovial and systemic pharmacokinetics of triamcinolone acetonide 
following intra-articular injection of an extended release formulation (FX006) or standard crystalline suspension in 
patients with knee osteoarthritis. Osteoarthritis and Cartilage;25:S431. 
8. 
Bodick N, Lufkin J, Willwerth C, et al. An intra-articular, extended-release formulation of triamcinolone acetonide 
prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial. J Bone 
Joint Surg Am 2015;97:877-88. 
9. 
Conaghan P, Strand V, Hunter D, et al. An intra-articular, extended release formulation of triamcinolone (FX006) 
affords clinically relevant improvements in pain and function of knee osteoarthritis: post-hoc pooled analyses of 3 
randomized controlled trials. Osteoarthritis and Cartilage;25:S432-S3. 
10. McAlindon TE, Driban JB, Henrotin Y, et al. OARSI Clinical Trials Recommendations: Design, conduct, and 
reporting of clinical trials for knee osteoarthritis. Osteoarthritis Cartilage 2015;23:747-60. 
11. Dobson F, Hinman RS, Hall M, et al. Reliability and measurement error of the Osteoarthritis Research Society 
International (OARSI) recommended performance-based tests of physical function in people with hip and knee 
osteoarthritis. Osteoarthritis and Cartilage;25:1792-6. 
12. Davis AM, Perruccio AV, Canizares M, et al. Comparative, validity and responsiveness of the HOOS-PS and KOOS-
PS to the WOMAC physical function subscale in total joint replacement for osteoarthritis. Osteoarthritis Cartilage 
2009;17:843-7. 
13. Gandek B, Ware JE, Jr. Validity and Responsiveness of the Knee Injury and Osteoarthritis Outcome Score: A 
Comparative Study Among Total Knee Replacement Patients. Arthritis Care Res (Hoboken) 2017;69:817-25. 
 
APPENDIX I: VULNERABLE POPULATIONS 
 
I. 
Recruitment will not include any vulnerable population.