Autologous Conditioned Plasma (ACP) Intra-articular (IA) Injections for Knee Osteoarthritis (OA)
Phase: NA
Conditions: Osteoarthritis
Sponsor: Arthrex, Inc.

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Protocol: 004 
Version Date: January 2017 
 
Autologous Conditioned Plasma (ACP) 
Intra-articular (IA) Injections for Knee Osteoarthritis 
(OA) 
 
Investigational Plan 
 
 
 
Study Sponsor  
 
ARTHREX INC 
1370 Creekside Boulevard 
Naples, Florida 34108 USA 
 
 
 
Statement of Compliance 
This study will be conducted in accordance with the International Conference on Harmonization 
guidelines for Good Clinical Practice (ICH), the Code of Federal Regulations (CFR) 812 Investigational 
Device Exemption, 21CFR50, Protection of Human Subjects, 21 CFR 56 Institutional Review Board, 21 
CFR 54 Financial Disclosure, and the investigational plan as outlined below. All personnel involved in 
the conduct of this study have completed human subject’s protection training. (i.e.: CITI, GCP) 
 
 

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LIST OF ABBREVIATIONS 
ACI 
Autologous Chondrocyte Implantation 
ACP 
Autologous Conditioned Plasma 
AE 
Adverse Event  
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulation 
CRA 
Clinical Research Associate 
EDC 
Electronic Data Collection 
FDA 
Food and Drug Administration 
GF 
Growth Factors  
HA 
Hyaluronic Acid 
IA 
Intra-Articular 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board  
NSAID 
Non-Steroidal Anti-Inflammatory 
OA 
Osteoarthritis  
OATS 
Osteochondral Autograft Transfer System 
PAR 
Protease-Activated  Receptor 
PRP 
Platelet Rich Plasma 
PE 
Physical Exam 
SAE 
Serious Adverse Event 
RBC 
Red Blood Count 
UADE 
Unanticipated Adverse Device Effect 
WOMAC 
Western Ontario an McMaster Universities 
WBC 
White Blood Count 
 
 
 

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Protocol Signature Page 
Protocol:  004 
Autologous Conditioned Plasma (ACP) Intra-articular (IA) Injections for Knee 
Osteoarthritis (OA): A Pivotal Trial  
I have read this protocol and agree to adhere to the requirements.  I will provide copies of 
this protocol and all pertinent information to the study personnel under my supervision.  I 
will discuss this material with them and ensure they are fully informed regarding the 
investigational device and the conduct of the study according to the ICH (GCP), 21CFR 
812 Investigational Device Exemptions, 21CFR50 Protection of Human Subjects, 
21CFR56 Institutional Review Board, 21CFR54 Financial Disclosure and applicable 
national and local regulations whichever provide the greater protection of the individual.  
I agree to collect and report all study data according to this protocol. 
 
 
_____________________________________________________________________________ 
 
Investigational Site Name 
 
______________________________________________________________________________ 
 
Primary Clinical Investigator – Print Name  
          Location (City, Country) 
 
______________________________________________________________________________ 
 
Primary Clinical Investigator Signature 
 
          Date (MM – DD – YYYY) 
 
______________________________________________________________________________  
 
Sub-Investigator Name –Print Name  
______________________________________________________________________________ 
 
Sub-Investigator Name / Signature 
 
                      Date (MM – DD – YYYY) 
 
______________________________________________________________________________  
 
Sub-Investigator Name –Print Name  
______________________________________________________________________________ 
Sub-Investigator Name / Signature 
 
                      Date (MM – DD – YYYY) 

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Table of Contents 
Protocol Signature Page......................................................................................................................................................... 3 
Table of Contents ................................................................................................................................................................... 4 
1 Protocol Summary .............................................................................................................................................................. 7 
2 
Introduction ................................................................................................................................................................ 10 
2.1 
 Background 
10 
2.2 
 Treatment Options 
11 
2.3 
 Investigational Treatment 
12 
2.4 
 History of Development 
12 
2.5 
 ACP Definition and Biological Description 
12 
2.6 
 Dosing and Frequency 
13 
2.7  Alternative Practices and Procedures 
14 
3 
Study Design, Endpoints and Criteria ......................................................................................................................... 15 
3.1  Study Design 
15 
3.2 
Study Hypotheses and Endpoints 
15 
3.2.1 Primary Effectiveness Hypotheses for Pain: 
15 
3.2.2 Conditional Effectiveness Hypotheses for Function: 
15 
3.2.3 Primary and Conditional Endpoints: 
16 
3.2.4 Secondary Endpoints: 
16 
3.2.5 Safety Endpoint 
16 
3.3 
Study Population 
16 
3.4 
Study Subject Eligibility Criteria 
16 
3.5 
Kellgren Lawrence Grades of OA 
18 
3.6 
Stroke Test Grading System 
18 
3.7 
WOMAC 
18 
3.8 
Allowed Concomitant Medications and Prohibited Treatments 
18 
3.9 
Screen Failures 
18 
3.10 Withdrawal Criteria 
19 
3.11 Study Duration 
19 
3.11   Unscheduled Visits 
19 
3.12 Subject Compensation 
19 
4 
Risk Analysis ................................................................................................................................................................ 21 
4.1 
 Benefits 
21 
4.2 
 Risks and Mitigations 
21 
5 
Device Description ...................................................................................................................................................... 22 
5.1 
Device Description 
22 
5.2   Principle of Device Operation 
24 
5.3 
Analytical Study 
27 
6 
Study Procedures ........................................................................................................................................................ 29 
6.1  Subject Recruitment, Consent and Enrollment 
29 
6.2 
Study Visits 
30 
6.2.2.4 
Venipuncture and Blood collection 
31 
6.2.2.6 
Blinding Procedure 
31 

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7 
Adverse Events ........................................................................................................................................................... 34 
7.1 
Definitions 
34 
7.2  Adverse Event Documentation 
36 
7.3   Adverse Event and Unanticipated Adverse Device Effect Reporting 
37 
7.4   Device Complications 
37 
7.5 
 Safety Monitoring 
37 
8 
Statistical Method and Sample Size Calculation ........................................................................................................ 38 
8.1  Primary Effectiveness Hypothesis for Pain 
38 
8.2 
Conditional  Effectiveness Hypothesis for Function 
38 
8.3 
Statistical Methods for Testing Superiority 
39 
8.3.1 MMRM 
39 
8.4 
  Sample Size Analysis 
42 
8.4.1 Primary Superiority Test 
42 
8.4.2 Conditional Superiority Test 
43 
8.5    Secondary Endpoints 
43 
8.6   Concomitant Analgesics/Treatment 
43 
8.8 
Other Elements of Analysis Plan 
44 
8.8.4 Description of Effectiveness Outcome 
46 
8.8.5    Site Poolability 
46 
8.8.6   Treatment of Missing Data 
46 
8.7 
Subgroup Analyses 
47 
8.8 
 Safety Analysis 
47 
8.9 Adverse events counts over time 
47 
8.9.1 Adverse event detail listings 
47 
9 
 Study Administration ................................................................................................................................................. 48 
9.1 
Role of the Study Sponsor 
48 
9.2 
General Duties 
48 
9.3 
Subject Confidentiality 
48 
9.4 
Selection of Investigators 
49 
9.5 
Supplemental Applications 
49 
9.6 
Submitting Reports 
49 
9.7 
Maintaining Records 
49 
9.8 
Institutional Review Board (IRB) Approval 
50 
9.9 
Investigator Agreement and Financial Disclosure 
50 
9.10 Study Monitors and Visits 
50 
9.11 Investigational Site Qualification 
53 
9.12 Investigational Site Training 
53 
9.13 Investigator Responsibility for Study Conduct 
53 
9.14 Investigational Site Termination 
56 
9.15 Final Monitoring Visit 
56 
9.16 Protocol Amendments 
56 
9.17 Protocol Deviations 
56 
9.18 Publication 
57 
9.19  Audits / Inspections 
58 
Appendix 2-1 Schedule of Events ........................................................................................................................................ 59 
Appendix 2-2 Knee Exam: Stroke Test Grading ................................................................................................................... 61 
Appendix 2-3 ACP Venipuncture and Blood Collection Procedure: .................................................................................... 62 

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Appendix 2-4 Intra-Articular Injection Procedure: Visits 2, 3 & 4 ....................................................................................... 70 
Appendix 2-5 Blinding Procedure ........................................................................................................................................ 72 
Appendix 2-6 Case Report Forms ........................................................................................................................................ 74 
Appendix 2-7 References ..................................................................................................................................................... 96 

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1 Protocol Summary 
Title: 
Autologous Conditioned Plasma (ACP) Intra-Articular (IA) 
Injections for Knee Osteoarthritis (OA):  
Study Design: 
This study is a prospective, multicenter (up to 5 sites), randomized, 
double blind, two-arm study. Ninety (90) patients will be 
randomized to receive a three single weekly intra-articular (IA) 
injection of either ACP (n=60) or Phosphate buffered saline 
(n=30). To evaluate the effectiveness of ACP (three weekly doses 
IA of 3-6 ml of ACP injected into the knee from baseline through 6 
months) to treat Knee OA. Subjects will remain blinded to 
treatment throughout the study.  
 
 All patients will have a screening visit and three treatment visits 
one week apart (visit 2/Week 0, visit 3/Week 1, and Visit 4/Week 
2), followed by four  follow-up visits; Visit 5/2 months (60 days), 
Visit 6/3 months (90 days) and Visit 7/6 months 180 days) after the 
1st treatment visit.   
 
Patients will have a follow-up visit at Visit 8/12 month (365 days) 
after the 1st treatment visit. 
 Note: Once the last patient has 
reached their 6 month (180 days) Visit, an analysis of the primary 
endpoint will be performed based on 6-month outcomes. 
 
All subjects will continue to be followed out to 12 month (365 
days) post-treatment. When the last patient reaches the 6-month 
time point, all available data will be reported to FDA. 
 
Investigational Arm: 
ACP Treatment: Three IA injections of 3-6 mL ACP at  
 
 
 
 
 
1-week intervals. 
Control Arm:  
 
Three Normal Saline IA injections of 3-6 mL at 1-week  
 
 
 
 
 
 
 
intervals. 
Primary Endpoint: 
 Change in WOMAC Pain score from baseline to 6 months.  
Primary Hypotheses:  
ACP treatment is superior to control in terms of mean change from  
 
 
baseline to 6 months (180 days) in the WOMAC Pain score.  
  
Study Success Criterion:  
This study will be achieve its study success criterion if it is 
demonstrated that the mean improvement in WOMAC Pain score 
from baseline to 6 months (180 days) is significantly larger for 
ACP treatment compared to saline control with a 1-sided p ≤ 
0.025. 
 

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Conditional Endpoint: 
If superiority in WOMAC Pain score improvement is established, 
the study is designed to provide additional evidence of superiority 
in terms on improvements in WOMAC Function score from 
baseline to 6 months (180 days).  
Conditional Hypotheses:   ACP treatment is superior to control in terms of mean change from 
baseline to 6 months (180 days) in the WOMAC Function score.  
No multiplicity adjustment is necessary when testing the 
conditional hypothesis. 
Secondary Endpoint:  
The following will be evaluated as secondary endpoints in descriptive    
 
 
 
analyses: WOMAC Total (Pain, Function, Stiffness) Scores 2 (60 
days), 3 (90 days) and 12 month (365 days) and changes to these time 
points. WOMAC Stiffness Score at Month 6 (180 days) and changes 
to Month 6.  
 
 
 
 
 
  
 
 
 
 
 
Safety Endpoints: 
 
Adverse events will be compared between ACP treatment and the  
 
 
 
 
control in terms of both per patient incidence and total. 
 
Timeline: 
 
 
First Subject In: 
 
 
7/2016 
 
 
 
 
Last Enrollment (90 subjects): 
7/2017 
 
 
 
 
12 month follow-up:   
 
7/2018 
 
 
 
 
 
Study Population: 
Male and female patients between the ages of 18 and 70 years old, 
with at least 6 weeks of symptomatic OA of the tibio-femoral or 
patella-femoral compartment of the target knee, as evidenced by 
radiographs and continued pain. 
Inclusion Criteria:  General: 
1. The subject is  18 to 70 years of age. 
2. The subject presents with complaints of continued pain of 
            target knee for at least 6 weeks. 
3. The subject has documented radiographic evidence of OA in the 
tibio-femoral or patella-femoral compartment of the target knee 
(Kellgren-Lawrence Grades II-III), using radiographs performed 
within 24 weeks of screening.  
4. The subject has a WOMAC pain score of at least 8 out of 20 and at 
least moderate pain (a score of 2) for at least 2 questions on 
activities.  
 
 
Exclusion Criteria:  
General: 
1. Grade I and IV on the target  knee Kellgren-Lawrence grading 
scale  

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2. Subject has clinically 3+ effusion of the target knee (stroke test 
grading system). 
3. Subject has significant (> 10⁰) valgus or varus deformities as 
evidenced by standard of care X-ray.  
4. Subject has had systemic or IA injection of corticosteroids in any 
joint within three months prior to screening.  
5. Viscosupplementation in any joint in the past six months. 
6. Subject which, in the investigator’s opinion, has an increased risk 
for post procedure bleeding (e.g., bleeding disorder or taking 
anticoagulants except low-dose aspirin). 
7. Subject had prior open surgery on the target knee within 12 months 
or knee arthroscopy within 6 months   
8. Subject has inflammatory disease of either knee other than OA.  
9. Subject which, in the investigator’s opinion, has underlying 
medical conditions that could interfere with the evaluation of the 
outcome.  
10. Subject with positive pregnancy test, or breast feeding. 
11. Subject with plans to participate in other clinical trial involving 
medical or surgical intervention in the next 12 months. 
12. Subject with any condition (including cognitive impairment) that, 
in the opinion of the investigator, might interfere with the 
evaluation of the study objectives. 
13. Subject has rheumatoid arthritis or gout 
14. Subject has history or a current infection at the affected joint. 
15. Subject with plans to undergo any elective orthopedic surgery in 
the next 12 months. 
16. Subject requires pain management therapy (with the exception of 
acetaminophen) not related to the target knee. 

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2  Introduction 
2.1 
Background 
Arthritis is a very prevalent disease all over the world, and the United States is no 
exception. Between 2010 and 2012, 52.5 million adults in the US ages 18 and 
over (which is 22.7% of the total adult population in the US) were diagnosed with 
some form of arthritis. Out of the total adult population in the US, 49.7% of those 
ages 65 or over had an arthritis diagnosis.1  Furthermore, by 2030, the number of 
adults in the US with doctor-diagnosed arthritis is expected to rise to almost 67 
million people.2  
The prevalence of doctor-diagnosed arthritis by race and gender between 2010 
and 2012 was: 35.7 million whites, 7.5 million Hispanic adults, 6.2 million  
blacks, 2.6 million Asians and 420,000 adults of other races.  Additionally, 
between 2010 and 2012, the prevalence of doctor-diagnosed arthritis out of the 
total US population was 26% for adult women and 19.1% for adult men. Lastly, 
the prevalence of doctor-diagnosed arthritis from 2010-2012 in the total US 
population was 7.3% for ages 18-44 and 30.3% for ages 45-64.1  
Knee OA is a condition where articular cartilage at the knee is worn away, 
leading to severe pain for the patient.  This pain can lead to decreased mobility 
and inability to function. Therefore, as the population gets older and lives longer, 
the number of people with OA will increase significantly.   
OA can be classified as either primary or secondary.  Primary OA is usually 
diagnosed when an underlying cause cannot be found.3  Secondary OA, however, 
indicates there is some underlying cause, such as an endocrine or metabolic 
disorder, trauma, malformation, or some genetic cause.4 The clinical 
manifestation of OA is the destruction of cartilage, and this can be affected by the 
synovial membrane, the subchondral bone, and the meniscus.  Prior to the 
destruction of cartilage, the balance of anabolic cytokines such as TGF-β1, bone 
morphogenic protein-7 (BMP-7), and IGF-1, and catabolic cytokines such as IL-
1β and TNF-α in the joint space is disturbed.5  When OA becomes a significant 
issue, it is usually found that the catabolic cytokines play a much larger role in 
creating cartilage degradation.   
Many groups have investigated what risk factors could be predictive for OA, such 
as age, weight, gender, and genetics.6-8 However, there is no major consensus on 
which risk factor is the best indicator of OA, if at all.  Due to its uncertain disease 
etiology and progression, as well as the pain it causes, the need for an effective 
OA treatment that allows patients to go back to normal function as quickly as 
possible is important.   

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2.2 
Treatment Options 
The current non-surgical standard of care for OA is treatment with substances that 
provide pain relief.  The most common type of injection is corticosteroids such as 
triamcinolone, methylprednisolone, and betamethasone, which are designed to 
dissolve slowly to provide pain relief.  As shown in clinical studies, 
corticosteroids can provide long-term pain relief equal to or better than placebo 
(saline) for up to 24 weeks.9  The effect of corticosteroids in OA is evident in a 
study that showed a decrease in the amount of macrophages and lymphocytes in 
the synovial tissue, with an increase in new fibroblasts and collagen.10,11  
However, another study found that even though macrophages are reduced, this 
does not come with a decrease in MMPs.10,12   
Since knee synovial fluid contains HA, many companies have also pursued 
viscosupplementation or injection of gels such as HA into the knee.  HA is 
isolated from chicken combs or produced from bacteria, and this HA is injected 
into the joint for pain relief.  Exogenous HA can reduce pain through several 
different mechanisms – by inhibiting inflammatory mediators such as IL-1β, 
binding to neuropeptides that shield pain receptors, stimulating production of new 
endogenous HA, and decreasing production of MMPs which can destroy 
cartilage.13  HA with differing molecular weights (from 500-730 kDa to 6000 
kDa) have been produced, and all have had success in clinical studies to receive 
FDA approval in the United States.  In pooled comparisons between HA and 
placebo for OA, results indicated that there were significant differences in pain 
and physical function between 1 to 4 weeks, but that these measurements were 
similar by 14 weeks.13  Studies that measured HA vs. corticosteroid injections 
found a significant difference in pain relief for the corticosteroids compared to 
HA from 0 to 4 weeks, but that HA had a significant improvement in pain relief 
compared to corticosteroids from 5 to 13 weeks.13 
Even though corticosteroids and HA have been successful in treating OA, there 
has been a movement towards treating OA with natural or autogenous substances. 
PRP is a mixture of platelets at a higher concentration than whole blood, mixed 
with blood plasma, and red and white blood cells in some cases.  When injected, 
the platelets in PRP become activated and release GFs and cytokines which 
modify the healing process of the damaged or modified tissues.  Using this 
autologous therapy, there are no concerns with allergic or immunogenic responses 
to the patient, unlike the possibility with allogeneic, xenogeneic, or alloplastic 
substances.   
Since PRP is being proposed as a therapy for OA, the effect of platelets on pain 
reduction needs to be explored.  When platelets are activated, in addition to 
releasing GFs, they release serotonin and histamine, known activators in the 
nocioceptive and inflammatory processes, respectively.  However, when activated 
by thrombin, these cytokines do not appear to have major effects on either process 
to increase pain.14  Therefore, it is not believed that PRP itself contributes to pain.  
Protease-activated receptor-4 (PAR4) is a newly discovered receptor released 

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from platelets when activated by thrombin or trypsin; it is very analgesic and has 
anti-nocioceptive properties.15  This receptor is a candidate for the proposed 
decrease in pain when PRP is injected.    
2.3 
Investigational Treatment 
PRP is an autologous treatment in which blood is drawn from a patient and is 
spun down to produce a separation of platelets and plasma from WBCs and 
RBCs.  The platelets and plasma are then recovered after centrifugation and re-
injected into the patient’s body at or near the site of injury or damage.  This 
technique has seen increased use in Orthopaedic and sports medicine in the past 
10 years.   
2.4 
History of Development  
 
The concept of PRP was developed in the blood banking field.  A newspaper 
article from January 9, 1961 stated that, at the time, PRP could increase the 
supply of donated human platelets and plasma in blood banks by up to 30 times 
over current supply. 16 The American Red Cross set the definition of PRP as at 
least 5.5 x 1010 platelets per 50 mL of plasma.  Since the average platelet 
concentration in humans is between 150000-450000 platelets per µL, this leads to 
a definition of PRP concentration as 2X to 7X over baseline.17  This fits the 
definition of PRP as being any concentration of platelets over baseline whole 
blood.   
When PRP is clotted, it is an autologous version of allogeneic fibrin glue or fibrin 
sealant,18 which has a history of use since the 1900s,19,20 primarily for haemostasis 
during surgeries.  However, PRP did not receive recognition clinically until the 
mid-1990s, mostly in dentistry.  The seminal paper in the field was published in 
1998 by Dr. Robert Marx.21  He used PRP, at a 3X concentration over baseline, in 
combination with cellular marrow grafts from the ilium.  A significant increase in 
new bone was seen in the cellular marrow with PRP group vs. marrow alone at 6 
months.  Other studies since the Marx paper have focused on the use of PRP in 
dentistry.22,23  Many other clinical studies have focused on the use of PRP for 
various orthopedic and sports medicine applications.24-26 
2.5 
ACP Definition and Biological Description 
In December 2008, Arthrex received 510K clearance (#BK070069) for the ACP 
double syringe system. The system is used to facilitate the safe and rapid 
preparation of autologous PRP from a small sample of blood at the patient’s point 
of care. The indication is that the PRP can be mixed with autograft and allograft 
bone prior to application to an orthopedic surgical site as deemed necessary by the 
clinical use requirements. Arthrex Inc. is seeking to expand this indication for the 
use of PRP to be injected into the knee for the treatment of OA.  This study is 
designed to investigate the safety and effectiveness of ACP in treating pain in 
subjects with primary OA of the knee.   

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There are many biological factors in ACP which combine to create an optimal 
healing environment for OA.  Table 1 below highlights the prominent GFs and 
cytokines involved in the OA healing process.  Many studies have shown the 
importance of these GFs and cytokines, both in the pathogenesis and possible 
resolution of OA.5,27-29  These growth factors and cytokines are found in PRP, and 
specifically in ACP.30,31 
 
Factor 
Name 
Effects/Activities 
PDGF-AB 
Platelet-derived growth factor 
AB 
Cell proliferation and 
mitogenesis 
TGF-β1 
Transforming growth factor-
beta1 
Extracellular matrix (ECM) 
synthesis, cell proliferation 
VEGF 
Vascular endothelial growth 
factor 
Angiogenesis, cartilage 
metabolism 
IL-10 
Interleukin-10 
Prevention of IL-1β and TNF-α 
activity 
IL-1ra 
Interleukin-1 receptor 
antagonist 
Prevention of IL-1β and TNF-α 
activity 
IL-1β 
Interleukin-1 beta 
Cartilage degradation and 
inflammation 
TNF-α 
Tumor necrosis factor-alpha 
Cartilage degradation and 
inflammation 
2.6 
Dosing and Frequency 
The volume of ACP after the whole blood is centrifuged will vary between individuals.  
In this study, the rationale for a dosage between 3-8 mL with an injection frequency of 
once a week for 3 weeks is based on previous studies, as listed in the table below.  These 
studies used either a plasma-based PRP system similar in platelet and WBC concentration 
to ACP, or actual ACP which is also a plasma-based PRP system.  The other studies, 
however, use buffy coat-based PRP systems with a higher WBC concentration than ACP.  
They have longer times in between injections due to the extra inflammation caused by the 
additional WBCs in the buffy coat-based PRPs.   
 

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Study – Author 
Year 
PRP 
Volume 
Dosage 
Frequency 
Purpose 
“IA injection of an autologous 
PRGF for the treatment of knee 
OA: a retrospective cohort study” 
– Sanchez et al32 
2008 
6-8 mL 
3 weekly 
injections 
OA IA 
injection 
“Comparison between HA and 
PRP, IA infiltration in treatment of 
gonarthrosis” – Cerza et al 
(unpublished)33 
2011 
5.5 mL 
4 weekly 
injections 
OA IA 
injection 
“PRP: IA knee injections produced 
favorable results on degenerative 
cartilage lesions” – Kon et al34 
2010 
5 mL 
3 
injections 
every 21 
days 
OA IA 
injection 
“Injection of PRP in patients with 
primary and secondary knee OA” – 
Sampson et al35 
2010 
~6 mL 
3 
injections 
every 4 
weeks 
OA IA 
injection 
“PRP IA knee injections for the 
treatment of degenerative 
cartilage lesions and OA” – Filardo 
& Kon et al36 
2011 
5 mL 
3 
injections 
every 21 
days 
OA IA 
injection 
“PRP IA injection vs. 
viscosupplementation as 
treatments for cartilage 
pathology: from early 
degeneration to OA” – Kon  & 
Mandelbaum et al37 
2011 
5 mL 
3 
injections 
every 2 
weeks 
OA IA 
injection 
2.7  
Alternative Practices and Procedures 
Alternative practice and procedures include nonsteroidal anti-inflammatory drugs 
(NSAIDS), intra-articular injection of corticosteroids; avoidance of activities that cause 
joint pain; exercise; physical therapy; weight loss; and removal of excess fluid from the 
knee. For patients who have failed the above treatments, surgical interventions such as 
arthroscopic surgery and total knee replacement are also alternative treatments.   
 
 

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3 Study Design, Endpoints and Criteria 
3.1  
Study Design 
 
This study is primarily investigating the effectiveness ACP IA in 
patients with OA of the knee in reducing pain. 
 
This study is a prospective, multicenter, double blind, clinical 
study with up to 5 sites, approximately 90 subjects who are 
candidates for IA ACP treatments for knee OA. Ninety (90) 
subjects will be randomized to receive three single weekly intra-
articular (IA) injection of either ACP (n=60) or Phosphate buffered 
saline (n=30).   
To evaluate the effectiveness of three weekly doses IA of 3-6 ml of 
ACP injected into the knee from baseline through 6 months (180 
days). 
 
 All patients will have a screening visit and three treatment visits 
one week apart (Visit 2 / Week 0, Visit 3 / Week 1, and Visit 4/ 
Week 2), followed by three follow-up visits; Visit 5/  2 months (60 
days) Visit 6/ 3 months (90 days)  and Visit 7/ 6 month (180 days) 
after the 1st treatment visit.   
Patients will have an additional follow-up Study visit at Visit 8/ 12 
month (365 days ) after the 1st treatment visit. Note: Once the last 
patient has reached their 6 month Visit (180 days), an analysis of 
the co-primary endpoints will be performed based on 6-month (180 
days) outcomes.  Subjects will remain blinded to treatment 
throughout the study. 
 
 
 
 
 
 
 
3.2      Study Hypotheses and Endpoints 
3.2.1 Primary Effectiveness Hypotheses for Pain:  
ACP treatment is superior to control in terms of mean change from baseline to 6 
month (180 days) in the WOMAC Pain score. 
3.2.2 Conditional Effectiveness Hypotheses for Function:  
The study is designed to permit an additional labeling claim beyond reduction in 
pain while maintaining control of type 1 error. The additional labeling claim 
concerns improvement in patient function.  This will be measured using change 
from baseline to Month 6 (180 days) in the WOMAC Function score.  In order to 
control type 1 error for this study, these two hypotheses were hierarchically 
specified.  First, the primary endpoint concerning WOMAC pain will be tested.  If 

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the 1-sided p-value ≤ 0.025, it will be concluded that the investigational treatment 
is superior to control in terms of pain reduction and the study will be considered 
as having met its Study Success criterion.  In this case, additionally, the treatment 
group difference in mean change from baseline to Month 6 (180 days) will also be 
tested for the WOMAC Function score using a 1-sided p-value ≤ 0.025. Testing 
of the conditional endpoint is contingent on demonstrating superiority in terms of 
WOMAC pain and it is not intended to require superiority in both WOMAC Pain 
and WOMAC Function for Study Success.  
 
3.2.3 Primary and Conditional Endpoints: 
The primary and conditional endpoints of WOMAC Pain and Function will be 
assessed at 6 months (180 days) post-treatment.  All subjects will continue to be 
followed out to 12 months (365 days) post-treatment.  When the last patient 
reaches the 6-month (180 days) time point, all available data will be reported to 
FDA.  Note:  Subjects will remain blinded to their randomized treatment 
throughout the study.   
3.2.4 Secondary Endpoints: 
WOMAC Total, (Pain, Function, Stiffness) Scores 2 (60 days), 3 months (90 
days) and 12 months (365 days) and  changes to these. 
 
 
 
 
WOMAC Stiffness Score at Month 6 (180 days) and changes to Month 6 (180 days).  
 
 
3.2.5 Safety Endpoint 
 
 
Adverse events will be compared between ACP treatment and the control in terms of 
both per patient incidence and total.  
  
3.3  Study Population 
The investigator will invite prospective patients to enroll in the study that meet 
the inclusion/exclusion criteria and have signed the informed consent. 
3.4  Study Subject Eligibility Criteria 
Candidates must meet all eligibility criteria to be eligible for study participation: 

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3.4.1 Inclusion Criteria 
1. The subject is 18 to 70 years of age. 
2. The subject present with complaints of continued pain of  primary knee for at least 
6 weeks. 
 
3. The subject has documented radiographic evidence of OA in the tibio-femoral or 
patella-femoral compartment of the target knee (Kellgren-Lawrence Grades II-III), 
using radiographs performed within 24 weeks of screening. 
4. The subject has a WOMAC pain score of at least 8 out of 20 and at least moderate 
pain (a score of 2) for at least 2 questions on activities 
3.4.2 Exclusion Criteria 
1. Grade I and IV on the target knee Kellgren-Lawrence grading scale  
2. Subject has clinically 3+ effusion of the target knee (stroke test grading 
system). 
3. Subject has significant (> 10⁰) valgus or varus deformities as evidenced by 
standard of care X-ray.  
4. Subject has had systemic or IA injection of corticosteroids in any joint within 
three months prior to screening.  
5. Viscosupplementation in any joint in the past six months. 
6. Subject which, in the investigator’s opinion, has an increased risk for post- 
procedure bleeding (e.g., bleeding disorder or taking anticoagulants except 
low-dose aspirin). 
7. Subject had prior open surgery on the target knee within 12 months or knee 
arthroscopy within 6 months   
8. Subject has inflammatory disease of either knee other than OA.  
9. Subject which, in the investigator’s opinion, has underlying medical 
conditions that could interfere with the evaluation of the outcome.  
10. Subject with positive pregnancy test, or breast feeding. 
11. Subject with plans to participate in other clinical trial involving medical or 
surgical intervention in the next 12 months.  
12. Subject with any condition (including cognitive impairment) that, in the 
opinion of the investigator, might interfere with the evaluation of the study 
objectives. 
13. Subject has rheumatoid arthritis or gout 
14. Subject has a history of or a current infection at the affected joint. 
15. Subject with plans to undergo any elective orthopedic surgery in the next 12 
months. 
16. Subject requires pain management therapy (with the exception of 
acetaminophen) not related to the target knee. 
 
 

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3.5        Kellgren Lawrence Grades of OA 
 
 
1 = Possible osteophytes only 
 
 
2 = Definite osteophytes and possible joint space narrowing 
 
 
3 = Moderate osteophytes and/or definite narrowing of the joint space 
4 = Large osteophytes and sever joint space narrowing and/or bony sclerosis 
3.6       Stroke Test Grading System 
 
 
Zero = No Wave produced on downstroke 
 
 
Trace = Small wave on medial side with downstroke 
 
 
1 + = Larger bulge on medial side with downstroke 
 
 
2+ = Effusion spontaneously returns to medial side after upstroke (no  
 
 
 
 
downstroke necessary 
 
 
3 + = So much fluid that it is not possible to move the effusion out of  
 
 
 
 
the medial aspect of the knee. 
 
 
Please reference Appendix 2-2 Knee Exam: Stroke Test Grading. 
3.7        WOMAC 
The WOMAC index is a 24–item questionnaire completed by the patient focusing on 
joint pain, stiffness, and loss of function related to OA of the knee. The WOMAC pain 
score ranges from 0 to 20, the WOMAC stiffness score ranges from 0-8, and the 
WOMAC physical function score ranges from 0 to 68. The overall WOMAC score is the 
sum of these components, and ranges from 0 to 96. Each of these scores is often 
normalized to a 100 point scale. For the overall score and each of its components, higher 
scores indicate greater disability.          
3.8        Allowed Concomitant Medications and Prohibited Treatments  
Only acetaminophen is permitted for pain while in the study. NSAIDS and other 
non-acetaminophen pain medication are not permitted for the first 6 months of the 
study. Oral steroids, steroid injections and Viscosupplementation injections are 
not permitted for the first 6 months (180 days) of the study. 
3.9        Screen Failures 
Screen failures are those subjects who have signed the informed consent, but are 
not eligible to start treatment following the Screening/Baseline assessments. A log 
of all subjects screened for the study but not entered into the study will be 

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maintained by each investigational site. The reason(s) for screen failure will be 
recorded on the log. 
3.10        Withdrawal Criteria 
Potential reasons for discontinuation may include, but are not limited to: 
Subject Withdrawal: Subject participation in a clinical trial is voluntary.  The 
subject may discontinue participation (refuse all subsequent testing and follow-up 
procedures) at any time without penalty or loss of benefits.   
Investigator Termination: The investigator may terminate the subject’s 
participation without regard to the subject’s consent if the investigator believes it 
is medically necessary and in the best interest of the subject.  
Lost to Follow-up: The subject does not complete the 6 month follow-up but has 
not “officially” withdrawn from the study.  Failure to return for follow-up visits is 
not a criterion for withdrawal. In order to consider a subject lost to follow-up, site 
personnel should make all reasonable efforts to locate and establish 
communication with the study subject.  All attempts should be documented within 
the source documents, indicating date, time, method, and site personnel.  A 
minimum of three documented attempts should be made without response from 
the study subject in order to classify a subject as lost to follow-up. Should subject 
discontinuation occur, the reason(s) for discontinuation must be documented in 
the source documents along with notification to Arthrex Inc. or designee. Subjects 
who withdraw or are discontinued from the study will not be replaced. 
3.11 
Study Duration 
The study enrollment period will be approximately 12 months (365 days). The co-
primary endpoints will be assessed at 6 months (180 days) post-
treatment.  Patients will continue to be followed out to 12 months (365 days) post-
treatment until the last patient reaches the 6-month (180 days) time 
point.  Therefore, the overall study duration will be approximately 24 months. 
3.11   Unscheduled Visits 
Unscheduled visits may occur due to changes in subject circumstances that require 
immediate attention. (e.g., adverse event: increased or uncontrolled pain requiring 
treatment). 
3.12 Subject Compensation 
Each subject who returns for each follow-up visit within the protocol required 
time frame will receive a reasonable compensation to offset the cost of meals, 
transportation, parking, and other such expenses, as approved by the IRB. 

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Compensation is provided to the subject by the investigational site. Compensation 
amounts are specified in the Informed Consent and the Clinical Trial Agreement. 
 
 

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4 Risk Analysis 
4.1 
 Benefits 
The Arthrex ACP system allows rapid and efficient concentration of platelets and 
growth factors from autologous blood for use at the treatment site.  The unique 
double syringe allows for convenient and safe handling as the whole preparation 
process takes place in a closed system. The ACP system is more affordable, easier 
to use, and has quicker procedure time when compared to other conventional PRP 
devices. WBCs and RBCs are NOT concentrated within the ACP system. These 
cells can cause a detrimental effect on the healing process due to release of 
derivative proteins and reactive oxygen species. 
If the procedure is successful, possible benefits may include significant decrease 
your knee pain, improvement in knee function and range of motion. It is not 
guaranteed that subject’s condition will improve as a result of participating in this 
study and may receive no direct benefit at all.  
4.2 
Risks and Mitigations 
 
Since ACP is autologous and prepared from a patient’s own blood, there are no 
issues with transmission of diseases such as human immunodeficiency virus 
(HIV), hepatitis, or Creutzfeldt-Jacob disease (CJD or “mad cow” disease).  Also, 
any immunogenic issues that could occur with allograft or xenograft preparations 
should not be a problem.23,38   
The potential risks associated with the ACP double syringe system can be split 
into two groups: 
 Preclinical – double syringe operation, and centrifugation 
 Clinical – delivery of ACP and the subsequent effects of ACP in the body 
From the preclinical side, the primary concern is associated with the function and 
ease of use of the syringe, such as difficulty drawing blood through the syringe, or 
difficulty depressing the plunger.  The risk to the patient, as a result of this is an 
additional needle stick.  Arthrex has implemented appropriate manufacturing 
assembly steps, user training, and product testing procedures to ensure that the 
syringes meet customer requirements.  Arthrex confirms that no other measures 
are necessary to mitigate risk.   
From the clinical side, the procedure requires a peripheral blood draw as well as 
an IA injection. Potential risks to the patient can include: deep and superficial 
infections; allergies and other reactions; development of a hematoma; damage to 
blood vessels and nerve damage resulting in pain or numbness; and delayed 
wound healing.  These risks can be mitigated by making sure that only trained 
personnel carry out all the blood draws and IA injections. 

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5 Device Description  
5.1 
Device Description 
The Arthrex ACP® double syringe is a specially designed outer syringe which 
holds approximately 16 mL of liquid. The syringe is made of polypropylene, a 
well-known biocompatible material used for a wide variety of medical devices. 
Within this outer syringe, a smaller syringe is connected over a Luer-lock (hub) 
female connector.  At the distal end of both syringes there is a male luer-lock 
connector (nozzle) for fitting the female connector (hub) or adaptor for 
connection to a syringe or cannula. A threaded screw cap (containing the Luer-
lock nozzle) at the distal end of the outer syringe can be removed to allow the user 
to fill the outer syringe (Figure 5.1.1). 
 
 
 
 
 
 
 
Figure 5.1.1 
ACP double syringe with cap 
The special design of the double syringe facilitates the rapid 
preparation of autologous PRP and concentrated PPP from a small 
sample of blood.  
A Rotofix 32 A bench top centrifuge is used to centrifuge the 
double syringe (Figure 5.1.2).  After centrifugation, the special 
design of the double syringe allows for the transfer of the 
supernatant (ACP) from the outer syringe into the smaller, inner 
syringe, under aseptic condition (Figure 5.1.3). 
 
 

 
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Figure 5.1.2 
Rotofix 32 A bench top centrifuge 
 
 
 
 
 
 
 
 
Figure 5.1.3 
Supernatant (ACP) is aseptically 
transferred into the small, inner syringe 
 
 
 
 
 
 
 

 
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ACP Kit Series I – IDE-ABS-10011-IDE 
 
Component # 
Description 
Qty 
ABS-10014U 
Double Syringe 
1 
REF-645 
Double Syringe Luer Cap 
1 
REF-337 
Tourniquet 
– 
Disposable, 
Latex-Free 
1 
REF-338 
Alcohol Pads 
1 
REF-01530 
Butterfly Needle Infusion Set, 
19G 
1 
REF-340 
Gauze Sponge, 2x2 in. 
1 
C12690-01 
Band-Aid, Latex-Free 
1 
REF-443 
Hypodermic Needle, 22G, 1.5” 
1 
 
Patient Labels (inside kit) 
2 
5.2   Principle of Device Operation 
The ACP® double syringe system is designed to facilitate the rapid 
preparation of autologous PRP from a small sample of blood. After 
centrifugation, the special design of the double syringe allows for 

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the transfer of the supernatant from the outer syringe into the inner, 
smaller syringe under aseptic condition. 
A butterfly needle is used to withdraw approximately 16 mL of 
patient blood.  The butterfly needle is removed and a screw cap is 
placed on the syringe.  The double syringe is put into one bucket of 
the bench top centrifuge (Rotofix 32 A) for 5 min. at 1500 rpm.
Thereafter, the supernatant is transferred to the inner syringe under 
aseptic condition by pressing the wings of the double syringe 
together.  See Figure 5.2.1 below for reference. 
Figure 5.2.1 Principle of Operation 
 
 
 
 
The ACP Kit contains the necessary 
components to facilitate blood draw
 
 
 
 
 
 
 
Withdraw blood using provided 
butterfly needle
 
 
 
 
 
Centrifuge 1500 rpm for 5 min 

 
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Transfer plasma into smaller 
syringe and unscrew 
 
 
 
 
 
 
 
ACP ready for use

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5.3   Analytical Study 
An analytical study was conducted to determine the amount of GFs, 
thrombocytes/platelets (T), erythrocytes/RBCs (E), and leukocytes/WBCs (L) 
present in ACP. 
The density of the blood cells, triglycerides, and 7 selected GFs in ACP were 
compared to whole blood drawn from 12 healthy test subjects and centrifuged 
using the ACP double syringe System. 
The GFs were determined on the basis of the whole blood samples and plasma 
samples using ELISA kits (R&D Systems, Inc.).  A blood cell count was also 
performed (Bioscientia Labs, Germany). 
 
Table 5.3.1 Analysis overview 
Sample 
Analysis 
Whole blood 
E, L, T 
Whole blood plasma 
GFs and triglycerides 
ACP 
E, L, T 
 
Results: 
The density of thrombocytes in the ACP was increased 2-fold compared to whole 
blood. The concentration of the leucocytes and erythrocytes in the ACP was 10% 
and 1% of the whole blood, respectively. 
The concentration of all GFs in the ACP was significantly higher than in the whole 
blood. 
The triglyceride values of the ACP do not differ from those for the whole blood. 
See Table 5.3.2 for a complete list of the test results. 
 
 
 
 
 

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Table 5.3.2 Results of the ACP analysis 
Cell Count 
Whole Blood 
ACP 
(Autologous Conditioned Plasma) 
Thrombocytes (T) 
[10E3 / μl] 
Mean 
SD 
242 
62 
550 
126 
Erythrocytes (E) 
[10E6 / μl] 
Mean 
SD 
4,97 
0,24 
0,05 
0,01 
Leukocytes (L) 
[10E3 / μl] 
Mean 
SD 
7,11 
1,67 
0,69 
0,83 
Growth Factors 
Whole Blood 
Plasma 
ACP 
IGF-I 
[ng/ ml 
Mean 
SD 
121 
50 
122 
51 
EGF 
[pg/ ml] 
Mean 
SD 
113 
116 
396 
112 
VEGF 
[pg/ ml 
Mean 
SD 
32 
40 
130 
124 
PDGF-AB 
[pg/ ml] 
Mean 
SD 
2467 
2210 
30979 
8525 
PDGF-BB 
[pg/ ml] 
Mean 
SD 
1760 
2042 
4529 
1458 
TGF-b-1 
[pg/ ml] 
Mean 
SD 
36506 
38380 
92824 
21504 
TGF-b2 
[pg/ ml] 
Mean 
SD 
98 
128 
197 
131 
Triglyceride 
[mg/ ml] 
Mean 
SD 
506 
126 
466 
171 

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6 Study Procedures 
6.1  
Subject Recruitment, Consent and Enrollment  
The investigator or designee should review all prospective subjects’ medical 
histories to screen for eligibility.   
6.1.1 Subject Recruitment 
 The investigator will provide patients who present to his practice with 
symptomatic knee pain and Radiographic evidence of OA in the tibio-femoral or 
patella-femoral compartment of the target knee (Kellgren-Lawrence Grades II- III), 
the opportunity to be considered as a candidate for this trial.  Pre-procedure 
screening to confirm the diagnosis is not considered part of the study; however the 
informed consent form will advise the subject that their medical history records 
used to confirm diagnosis and X-rays will be incorporated into the study record. If 
all X-ray required for inclusion have not been done or present in medical records 
within 24 weeks of screening, they must be taken prior to randomization. These X-
rays include: 
 Weight bearing hip to ankle Anterior –Posterior (AP) of the involved knee 
(extremity) 
 Standing AP of both knees in extension 
 Standing Posterior-Anterior (PA) weight bearing of both knees at 45 
degrees of flexion 
 Supine lateral of the involved knee 
 Sunrise view of both knees 
6.1.3 Consent 
The investigator will prepare an informed consent form (ICF) in accordance with 
this study protocol and all regulatory requirements (21 CFR Part 50) using the 
sample informed consent form provided by the sponsor. Changes to the ICF and 
amended ICF(s) must be approved by Arthrex’s Clinical Research prior to 
submitting to IRB. A copy of the final IRB-approved ICF or amended ICF(s) must 
be maintained as part of the study file. 
The subject candidate will be introduced to the study by the investigator. Interested 
patients will have the study thoroughly explained to them by the investigator 
and/or site coordinator. Additionally, informed consent forms will be provided to 
the patient so they may take home and review with significant others if desired. 
The informed consent process includes ensuring all of the patient’s questions are 
answered. Once the subject decides if they want to participate in the clinical trial, 

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the site will obtain a signed consent from the subject and make arrangements to 
schedule them for Visit 2. 
Prior to any study procedures, all subjects must document their consent for study 
participation and authorization for use and disclosure of health information by 
signing the IRB approved Informed Consent form.  
6.1.4 Subject Status 
Only those patients who meet the inclusion / exclusion criteria and who have 
signed the informed consent for the trial and proceeded to Visit 1 will have a status 
of “Screened”. Subjects that are screened but do not meet inclusion/exclusion 
criteria will be considered, “Screen failed.” Once the subjected is treated (has 
either randomized treatment) they will be considered “treated”.  
Subjects that are treated (has either randomized treatment) and do not complete the 
follow final visit will be considered “early termination”. Subjects that complete 
Visit 8/12 months (365 days) will be considered complete. 
Subjects receiving treatment, but not meeting all inclusion / exclusion are 
considered treated, and will be followed per the protocol but will be considered 
protocol deviations.  
6.2   Study Visits 
For this study all subjects will have a screening visit and three treatment visits to 
receive a series of intra-articular injections one week apart. Subjects will then 
return for follow-up visits at 2 months (60 days), 3 months (90 days), 6 months 
(180 days) and 12 months (365 days) post-treatment 1st injection.   
6.2.1 Screening Visit 1 (-7 to -2 days) 
Once the subject has signed the informed consent and prior to treatment, he/she 
will have the following data collected and procedures conducted:  
 Medical history/Demographics 
 Physical exam (Temperature, heart rate and blood pressure) 
 Radiograph(s) (if not part of medical record) refer to section 6.1.1  
 Urine pregnancy test (for females with childbearing potential) 
 Concomitant Analgesics/Treatment review 
 WOMAC survey (pain, stiffness, function) 
 Inclusion/exclusion criteria review 
 Kellgren-Lawrence grading 
 Strokes Test Grading 

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 Inform subjects that they will return for visit 2 to receive their 1st IA 
injection and then to return at 1 week and 2 weeks for an additional IA 
injection. Additionally, inform that they will need to return for visits at 2, 3 
and 6 months post-treatment 1st injection.  
6.2.2 Treatment: Visit 2 (Day 0)  
All subjects will have the following procedures at visits 2 prior to randomization: 
 Concomitant Analgesics/Treatment review 
 Inclusion /Exclusion review 
 Whole Blood and ACP collected for analysis  
6.2.2.1 
Randomization 
Once confirmed that the subject has met all the inclusion/exclusion criteria, the 
principal investigator will be permitted to proceed to randomization of the subject. 
An automated Internet-based randomization system will ensure concealed 
randomization of eligible consenting subjects. Subjects will be randomized to one 
of 2 treatment groups. 
6.2.2.2 Investigational Arm:  Three IA injections of 3-6 mL ACP at 1 week 
intervals. (n=60) 
6.2.2.3 Control Arm:  Three IA injections of 3-6 mL Normal Saline at 1 week 
intervals. (n=30) 
Note: The volume of PRP produced during the ACP procedure differs per individual; 
therefore we are providing a range as noted in earlier justification. Additionally, the 
amount of Normal Saline will be determined by the volume of PRP produced during 
the ACP procedure, except   the control subjects will receive only the same volume of 
Normal Saline as produced by their own blood during the ACP procedure. 
   6.2.2.4 Venipuncture and Blood collection  
 
 
Refer to Venipuncture and Blood Collection Procedure (Appendix 2-3)  
6.2.2.5 Processing ACP 
 
 
Refer to Venipuncture and Blood Collection Procedure (Appendix 2-3) 
6.2.2.6 Blinding Procedure:  
 Subject blinding will be maintained by drawing blood from all subjects, then 
preparing and administering both treatments (ACP and Normal Saline) in a 
concealed, opaque syringe.   

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Blinding will be maintained by a separate clinician(s) designated to blind the 
syringes (i.e.: Laboratory Technician) from the staff designated to collect/assess 
patient outcomes and designated to administer the treatments (Investigator/ Sub-
Investigator).  
The subject, the evaluating physician, and coordinator will be blinded until 12 (365 
days) months. 
  
Refer to Blinding Procedure (Appendix 2-5) 
6.2.2.7 IA Injection Procedure 
 
 
Refer to Intra-articular Injection (Appendix 2-4) 
6.2.2.8 Adverse event/device events  
 Assess subjects during treatment for adverse events as defined in section 7. 
 Assess for complications as defined in section 7.  
6.2.2.9 Patient Management Plan 
Instruct patient on the following: 
1. He/she may experience transient pain, swelling, and/or effusion of the injected 
joint after IA injection. 
2. Pronounced pain and extensive swelling should be reported to the physician. 
3. He/she should avoid strenuous activities or prolonged weight-bearing for 
approximately 48 hours. 
4. He/she should be able to resume baseline activities after 48 hours. 
6.3 
Study Visits 
6.3.1 Treatment Visits   
 
 
All subjects enrolled in the study will have the following procedures at visit 3  
 
 
(1 week +/- 3 days) & visit 4 (2 weeks +/- 3 days): 
 WOMAC survey (pain, stiffness, function)  
 Concomitant Analgesics/Treatment review 
 Adverse event assessment /device complications as defined in Section 7 
 Venipuncture, processing, blinding and IA procedure.  
 Refer to Visit 3 and 4 Venipuncture and Blood Collection Procedure (Appendix 
2-3) 
 Refer to Blinding Procedure (Appendix 2-5) 

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 Refer to Visit 2, 3 and 4 Intra-Articular Injection  (Appendix 2-4) 
6.3.2 Follow-Up Visit 5 [2 months (60 days)+/- 7 days], Visit 6 [3 
months (90 days)+/- 7 days] & Visit 7 [6 months (180 days) 
+/- 14 days] 
 WOMAC survey (pain, stiffness, function)  
 Concomitant Analgesics/Treatment review 
 Adverse event assessment 
6.3.3  Visit 8 (12 months (365 days)  +/- 30 days) 
 WOMAC survey (pain, stiffness, function)  
 Concomitant Analgesics/Treatment review 
 
Adverse event assessments 

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7 Adverse Events 
7.1 
Definitions 
7.1.1 Adverse Events 
An adverse event (AE) is any undesirable experience (e.g., sign, symptom, illness, 
clinically significant abnormal laboratory value, or other medical event) occurring 
in a subject during the course of the study, whether or not it is related to the 
investigational treatment or procedure.  
An AE does include a/an: 
 Exacerbation of a pre-existing illness 
 Increase in frequency or intensity of a pre-existing episodic event or 
condition 
 Condition detected or diagnosed after study device use even though it may 
have been present prior to the start of the study treatment. 
 Continuous persistent disease or symptoms present at baseline that worsen 
following the start of the study 
An AE does not include a/an: 
 Medical or surgical procedure (e.g., surgery, endoscopy, transfusion); the 
condition that leads to the procedure is considered an AE 
 Pre-existing diseases or conditions present or detected at the start of the 
study that do not worsen 
 Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalizations for cosmetic elective surgery, social and/or convenience 
admissions) 
 The disease or disorder being studied, or sign or symptom associated with 
the disease or disorder, unless the disease, sign or symptom is more severe 
than expected based on the subject’s condition and/or requires intervention.  
7.1.2 Serious Adverse Events 
A serious AE is one that:  
 led to death, 
 led to serious deterioration in the health of a subject that: 
 resulted in a life-threatening illness or injury, 
 resulted in permanent impairment of a body structure or body 
function, 
 required inpatient hospitalization or prolongation of existing 
hospitalization, 

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 resulted in medical or surgical intervention to prevent permanent 
impairment to a body structure or a body function, or 
 led to fetal distress, fetal death or a congenital anomaly or birth 
defect. 
The following clarifications are provided for the serious AEs: 
 Life-threatening means that the subject was, in the view of the investigator, 
at immediate risk of death from the event as it occurred.  The definition 
does not include an event that, had it occurred in a more severe form, might 
have caused death. 
 Hospitalization for elective treatment of a pre-existing condition that did 
not worsen during the study is not considered a serious AE. 
 “Inpatient” hospitalization means the subject has been formally admitted to 
a hospital for medical reasons.  This may or may not be overnight.  It does 
not include presentation at a causality or emergency room.   
 Important medical events that may not result in death, or be life-
threatening, however based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
 It is significant for any other reason. 
7.1.3 Anticipated Adverse Events: 
Anticipated AEs are those events that are reasonably expected to occur as a result 
of the subject’s disease state or treatment. For this study, anticipated AEs 
associated with the procedure or post-procedure include, but are not limited to, the 
following; 
1. Infections, both deep and superficial. 
2. Allergies and other reactions to device materials. 
3. Hematoma. 
4. Arthraglia 
5. Joint stiffness 
6. Joint effusion 
7. Joint swelling 
8. Joint warmth 
9. Injection site pain 
10. Blood vessel damage 
11. Nerve damage 
12. Arthritis 
13. Arthropathy 
14. Gait disturbance 

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7.1.4 Unanticipated Adverse Device Events 
An Unanticipated Adverse Device Effect (UADE) is defined as any serious AE on 
the study subject’s health or safety, or any life-threatening problem or death caused 
by or associated with the treatment, if, the effect, problem or death was not 
previously identified in this Investigational Plan or Instructions for Use in its 
nature, frequency, or severity.  UADEs may also include other serious problems 
associated with the treatment that affect the rights or welfare of study subjects.  
 
 
7.2  
Adverse Event Documentation 
AE information will be collected on all subjects.  All AEs must be reported in the 
source documents and in the Electronic Data Collection (EDC) database.  AEs will 
be evaluated by the investigator and differentiated by: 
 Serious, as defined in Section 8.1.2  
 Severity of the event, defined as:  
o Mild:  Awareness of signs and symptoms, but easily tolerated; are of 
minor irritant type, causing no loss of time from normal activities; 
symptoms would not require medication or a medical evaluation; signs 
and symptoms are transient. 
o Moderate: Discomfort severe enough to cause interference with usual 
activities; requiring treatment, but not extended hospitalization or 
intensive care for the subject. 
o Severe: Incapacitating with inability to do work or usual activities; 
signs and symptoms may be systemic in nature or require medical 
evaluation and/or treatment; requiring additional hospitalization or 
intensive care (prolonged hospitalization). 
 Relatedness to the device or procedure, defined as: 
o Unrelated: AE is due to the underlying disease state or concomitant 
medication or therapy not related to the study-specific treatment or 
procedures. 
o Probably not Related:  AE had minimum or no temporal relationship to 
the study-specific treatment or procedures and/or more likely 
alternative etiology exists. 
o Possibly Related: AE had a strong temporal relationship to the study-
specific devices or procedures and alternative etiology is equally or less 
likely compared to the potential relationship to the study-specific 
treatment or procedures.  
o Probably Related: AE had a strong temporal relationship to the study-
specific treatment or procedures and another etiology is unlikely. 

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o Unknown:  Relationship of the AE to the study-specific devices or 
procedures and alternative etiology is unknown. 
7.3   Adverse Event and Unanticipated Adverse Device Effect Reporting 
At every subject encounter, the investigator will determine if there has been an 
adverse event since the last encounter.   
For this study, serious adverse events must be reported to Arthrex or designee 
within 24 hours of event discovery by the site and entered into the EDC database.  
At the time of the initial report, the outcome (resolution status) may not be known.  
Updated information must be entered into the EDC database until final resolution 
of the event.  
UADEs must also be reported by the investigator to the approving IRB as soon as 
possible, but not later than 10 working days after the investigator first learns of the 
effect.  The sponsor must report to the FDA, all reviewing IRBs, and participating 
investigators within 10 working days of notification from the investigator of a 
UADE. 
The monitor will provide medical surveillance on adverse events and will evaluate 
all Serious Adverse Events (SAEs) 
           7.4  
 Device Complications 
For this study all device malfunctions including ; unable to pull up outer syringe, 
unable to pull up inner syringe, damaged parts, cracked parts, packaging – 
device/component missing, packaging – broken in package, leaking, air mixed 
with blood, piece broke from device , frozen or other will be collected and reported 
on associated eCRF. 
             7.5  Safety Monitoring 
As the study sponsor of this clinical study, Arthrex Inc. will be responsible to 
monitor it for safety.   In the circumstance where UADEs or serious AEs occur due 
to a procedure, Arthrex, Inc., will convene a review committee which will 
determine any unreasonable risk to subjects  or if the study should be reviewed for 
modification or early termination. 
 

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8 Statistical Method and Sample Size Calculation 
8.1  
Primary Effectiveness Hypothesis for Pain 
The primary effectiveness hypothesis for this study is that ACP treatment is 
superior to control in terms of mean change from baseline to Month 6 in the 
WOMAC Pain score. Symbolically, the null and alternative hypotheses may be 
expressed as follows:  
 
Ho:  δ(pain)ACP – δ(pain)Control ≤ 0 
 
Ha:  δ(pain)ACP – δ(pain)Control > 0 
Where δ(pain)ACP and δ(pain)Control are the expected mean changes from baseline 
to Month 6 in the WOMAC Pain score among patients in the ACP and control 
groups, respectively.  
8.2 
Conditional  Effectiveness Hypothesis for Function 
The study is designed to permit an additional labeling claim beyond reduction in 
pain while maintaining control of type 1 error. The additional labeling claim 
concerns improvement in patient function.  This will be measured using change 
from baseline to Month 6 in the WOMAC Function score.  In order to control type 
1 error for this study, these two hypotheses were hierarchically specified.  First, the 
primary endpoint concerning WOMAC pain will be tested.  If the 1-sided p-value 
≤ 0.025, it will be concluded that the investigational treatment is superior to 
control in terms of pain reduction and the study will be considered as having met 
its Study Success criterion.  In this case, additionally, the treatment group 
difference in mean change from baseline to Month 6 will also be tested for the 
WOMAC Function score using a 1-sided p-value ≤ 0.025. Testing of the 
conditional endpoint is contingent on demonstrating superiority in terms of 
WOMAC pain and it is not intended to require superiority in both WOMAC Pain 
and WOMAC Function for Study Success.  
The conditional effectiveness hypothesis for this study is that ACP treatment is 
superior to control in terms of mean change from baseline to Month 6 in the 
WOMAC Function score. Symbolically, the null and alternative hypotheses may 
be expressed as follows:  
 
Ho:  δ(function)ACP – δ(function)Control ≤ 0 
 
Ha:  δ(function)ACP – δ(function)Control > 0 
Where δ(function)ACP and δ(function)Control are the expected mean changes from 
baseline to Month 6 in the WOMAC Function score among patients in the ACP 
and control groups, respectively.  

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Formal testing of the conditional endpoint will only take place if the null 
hypothesis involving the primary endpoint is rejected at 1-sided alpha=0.025.  In 
that case, the null hypothesis concerning the conditional endpoint will be tested, 
also at 1-sided alpha=0.025.  By structuring the hypothesis testing hierarchically 
and by the ‘closed testing principle’ no multiplicity adjustment is necessary. 
8.3 
Statistical Methods for Testing Superiority  
 
8.3.1 MMRM 
Superiority testing will be performed using a mixed model for repeated measures 
(MMRM) analysis of covariance (ANCOVA) Model.39 The MMRM approach is a 
direct likelihood approach requiring specialized statistical software.  For this study, 
all MMRM parameters will be estimated using SAS PROC MIXED.  The MMRM 
model is notable for its inclusion of all available data from all eligible subjects and 
does not require their exclusion as in complete case analysis or arbitrary 
assignment of some value as in Last Observation Carried Forward (LOCF). 
Inclusion of outcome data from time points earlier than Months 6 informs the 
implicit imputation of missing Month 6 values through the covariance matric used 
to model the random effects.  
 
The random effects in the MMRM model will based on the so-called ‘unstructured 
covariance matrix’ in which variances over time are allowed to vary as are the 
pair-wise correlations over time. 
The values over time will include all WOMAC scores, namely at each of the 3 
follow-up time points, visit 5 / 2 months, visit 6 / 3 months, and visit 7 / 6 months. 
All WOMAC values will be included in the analysis even if they are obtained out-
of-window.  However, the fraction of out-of-window visits will be summarized at 
each time point. 
The contrast indicated by the primary hypotheses above, δ(pain)ACP – 
δ(pain)Control  will be estimated as the treatment group contrast from baseline to 
Month 6 in the WOMAC score derived from the MMRM.  The null hypothesis is 
that the true value of this contrast is equal to zero.  The same approach will be 
taken for the WOMAC Function score if superiority in pain relief is demonstrated. 
 
 
8.3.2 Covariates in MMRM 
 
The MMRM model must contain an indicator variable for treatment group, a 
categorical time factor, and treatment group by time interaction.  It is also 
necessary to include to the baseline value of the WOMAC outcome variable (either 
pain or function) so that significance levels will apply equally to values over time 
and to changes from baseline.  Often a factor for site is included in the MMRM to 
account for randomization within site.  Given the modest sample size and in 

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response to FDA Advisory items c.1.b (dated July 23, 2015), site will not be 
included in the primary MMRM.  Instead, the impact of site heterogeneity on 
estimated treatment group differences will be evaluated in supporting analyses by 
introducing an additional random effect as described below.  
It is often considered useful to include additional baseline covariates in order to 
further reduction of potential bias due from missing values. Candidate variables 
include age, gender, BMI, and prior analgesic use. However, in response to FDA 
Advisory item c.1.b, these variables will not be included in the primary MMRM 
model. Instead, additional baseline covariates will be added to the model in 
exploratory analyses only if any of these variables appear with clinically 
significant imbalance between treatment groups. The purpose of these analyses 
would to be determine the extent to which such imbalance impacts on estimated 
treatment group differences and associated significance levels. 
 
8.3.3 Details Concerning the MMRM 
 
As stated above, the covariance matrix for MMRM is an unstructured covariance 
matrix in which each of the 3 variances (2 months, 3 months, and 6 months) are 
free to vary as are the 6  pairwise covariances.  That is, the covariance matrix for 
the MMRM will not inlcude any random effects per se, but accounts for 
correlations among errors by specifying the form of the covariance matrix.  The 
MMRM employs an unstructured covariance in order to produce inferences that 
are valid under the so-called ‘missing at random’ (MAR) assumption which is 
more generally true than the ‘missing completely at random’ assumption that is 
required for validity of analyses restricted to complete cases. 
The longitudinal model will be specified as a repeated measures model that 
expresses the WOMAC score as a linear function of treatment, time, treatment-by-
time interaction, and a covariate of the baseline pain measurement.  
The model can be mathematically expressed as:  
Yi = Xiβ + ei 
 Yi is change from baseline to Month 6 in WOMAC Pain or Function scores 
 βis a vector of fixed-effect regression parameters which includes: 
o μ, the overall mean  
o θ, the treatment effect   
o τ, a vector of post-baseline time effects  
o η, a vector of treatment-by-time interaction effects,  
o φ, a vector of covariate effect parameters that only includes baseline 
WOMAC score but in general could include additional baseline variable,  
 X is a design matrix for the fixed effects, and  
 e is the error vector with  
o E(e) = 0 and  

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o Var(e)=σe2Vunstructured.  
 
The specific model to be used may be expressed as:  
 
 
 
Y = bint + bbase + bT + b2M + b3M + b6M + bTb2M + bTb3M + bTb6M  
With parameters as explained below.  
 
Parameter 
Represents 
Y 
Change from baseline 
bint 
Model intercept 
bbase 
Baseline value 
bT 
Indicator for Active Treatment 
b2M b3M, b6M 
Indicator for each visit 
bTb2M, bTb3M, bTb6M 
Indicators allowing varying treatment differences at each visit 
 
From this model estimates of treatment effect at specific visits and specifically at 
Month 6 difference may be obtained as follows.  
TM6 = bint + bbase + bT + bTbM6 
SM6 = bint + bbase  
ΔM6 = TM6 - SM6 = bT + bTbM6 
Where e.g. TM6 and SM6 are the expected changes from baseline to Month 6 in the 
WOMAC scores in the active and sham control groups, respectively, in terms of 
these model parameters, the superiority hypotheses are:  
H0: ΔM6 = 0  H1: ΔM6 > 0 when larger values reflect improvement or  
H0: ΔM6 = 0  H1: ΔM6 < 0 when smaller values reflect improvement 
The following SAS Proc Mixed statements provides the test for this null 
hypothisis.  The key results is listed among the results provided by the ‘slice’ 
option of the LSMEANS statement. One of these will provide the treatment group 
contrast at Month 6.  
proc mixed data=dataset method=ml; 
  class patid trt time; 
  model womac_pain = trt time trt*time womac_pain_bl / s chisq; 

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  repeated time / type=un subject=patid; 
  lsmeans trt*time  / slice=time; 
  run;  
 
The Month 6 treatment group contrast, the p-value associated with the null 
hypotheses and 95% two-sided confidence interval will be derived from the 
MMRM in order to test the superiority hypotheses for the primary endpoint and 
co-primary endpoints.  
8.4  
Sample Size Analysis 
 
 
8.4.1 Primary Superiority Test 
The power for the MMRM tests were approximated by the power for the 
corresponding two-sample t-test using industry standard software.40  Power for the 
t-test is a function of the magnitude of the treatment group difference relative to 
the standard deviation of change scores.  Preliminary data to evaluate clinical 
effect size was available from the safety and efficacy pilot study (BB-IDE 14796).  
In 15 patients per group, the mean (SD) WOMAC Pain Total score for the ACP 
and control groups at 6 months post-treatment were  2.5 (3.6) and 9.1(3.2)  
respectively. At screening, the baseline mean (SD) values were 10.2 (1.8) and 10.5 
(2.0). Therefore, the large difference at Month 6 is not explainable by baseline 
differences. These data imply a treatment group difference in mean improvements 
equal [10.2-2.5=7.7] minus [10.5-9.1=1.4] = 6.3 in favor of ACP and a standard 
deviation of approximately equal to 3.4.   This standard deviation also applies to 
change from baseline if the correlation between baseline and change scores is 
equal to 0.5.  Given the small sample size of the pilot study, a 95% two-sided 
confidence interval for the true difference was determined to be (-9.0 to -4.2) in 
order to account for the uncertainty in estimated treatment group mean differences.  
Specifically, on the basis of the   pilot study, a superiority treatment group 
differences as small as -4.2 cannot be statistically ruled out.  Therefore, as -4.2 
represents a conservative estimate of the treatment group difference for purpose of 
sample size analysis.  Under these assumptions, the standardized mean difference 
(Cohen’s effect size) is equal to 1.235. This effect size is typically considered very 
large.  Cohen’s benchmark for a large effect size in the behavioral sciences is 0.80.  
In order to mitigate against any potential bias present in the preliminary study, the 
expected effect size is further reduced from 1.235 to 0.80.  From another 
perspective, a treatment group difference of -4.2 in mean improvements is 
clinically significant as follows. The mean WOMAC Pain prior to surgery is 
slightly more than 10 (range 0 to 20).   Therefore, a treatment group difference of -
4.2 in the mean improvement in WOMAC Pain score represents about a 40% 
treatment group difference in the mean percent improvements.  A group difference 

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in mean percentage changes so large is likely clinically significant given the 
known reliability and validity of the WOMAC Pain score.   
Randomization will be 2:1 in order to increase precision when characterizing the 
safety profile of the investigational treatment.   We assume a one-sided type 1 error 
of α=0.025 and a standardized mean difference of 0.80 and determined that a total 
sample size of N=78 (52 ACP and 26 control) patients are required for 90% power.  
This value is increased by 15% to N=90 (60 ACP and 30 control) to account for 
potential loss-to-follow-up or other exclusions from the primary effectiveness 
analysis set. 
 
8.4.2 Conditional Superiority Test 
Among 15 patients per group, the mean (SD) WOMAC Function score for the 
ACP and control groups at 6 months post-treatment were 7.9 (11.7) and 31.3 
(12.0), respectively. At screening, the baseline mean (SD) values were 32.1 (9.5) 
and 31.4 (10.2). Therefore, the large difference at Month 6 is not explainable by 
baseline differences. These data imply a treatment group difference in mean 
improvements equal [31.1-7.9=23.2] minus [31.3-31.4=-0.1] = 23.3 in favor of 
ACP and a standard deviation approximately equal to 11.9.   Given the small 
sample size of the pilot study, a 95% two-sided confidence interval for the true 
difference was determined to be (-31.9 to -14.9).  Therefore, the pilot study cannot 
rule out treatment group differences as small as -14.9 and so -14.9 represents a 
conservative estimate of the treatment group difference for purpose of sample size 
analysis 
Under these assumptions, the standardized mean difference (Cohen’s effect size) is 
equal to 14.9/11.9=1.25 which is nearly the same as observed for WOMAC Pain 
scores. For the same reason stated above, the study will be designed to detect an 
effect size of 0.80 with 90% power and the same final sample size of N=78 (52 
ACP and 26 control) patients increased by 15% to N=90 (60 ACP and 30 control) 
to account for potential loss-to-follow-up or other exclusions is assumed. 
 
8.5    Secondary Endpoints 
 
The following will be summarized in descriptive analyses:  
 WOMAC Stiffness Score at Month 6 and changes to Month 6 
 WOMAC Total, (Function, Pain, Stiffness Scores) at 2 (60 days), 3 (90 
days), and 12 months (365 days) and changes to these time points. 
There will be no adjustment for multiplicity for the secondary endpoints. 
8.6   Concomitant Analgesics/Treatment 
Use of medication for joint pain will be recorded at each study visit according to, 
category (OTC NSAID, prescription NSAID, acetaminophen, and narcotic). The 

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use of analgesic at 6 months (180 days) will be evaluated as an exploratory 
endpoint in the descriptive analyses. The data collected will include medication 
name and the total daily dose. Additionally, concomitant treatments (e.g., physical 
therapy) will be recorded at each evaluation visit. 
   8.7     Safety Endpoints 
The primary safety endpoints for this study are based on adverse events. Details 
regarding analyses of adverse events are provided below. Briefly, adverse event 
endpoints will include, but are not limited to, the following patient specific 
endpoints:  
 Any adverse event (per patient) 
 Any treatment related AE 
 Any serious AE 
 Any serious AE that is treatment related 
 Patient death 
 
Specific endpoints such discomfort and pain, erythema, swelling, bruising, 
hemorrhage, and papules will be compared between treatment groups in terms of 
both per patient incidence rates and total counts.  Fisher’s exacts tests will be used 
to provide descriptive comparisons between incidence rates.  Counts of AEs will 
be displayed overall and over time.    
8.8 
Other Elements of Analysis Plan  
     8.8.1Analysis Sets 
The following analysis sets are defined:  
Intent-to-treat (ITT): The ITT analysis set will include all randomized patients. 
Modified Intent-to-treat (mITT): The mITT analysis set will include all patients with 
any exposure to a study treatment (active or placebo), where patients will be classified 
by the group in which they are randomized, regardless of the treatment received; and 
who have at least one WOMAC assessment subsequent to randomization. Primary, 
secondary, and exploratory effectiveness analyses will be conducted in the mITT 
analysis set. It is necessary to only include patients with at least one post 
randomization WOMAC assessment for use in the MMRM.  Baseline carried 
forward is likely to produce substantial bias in estimated treatment differences.  It 
is reasonable to expect that baseline carried forward bias is substantial and perhaps 
even larger than might be expected from excluding a very small number of patients 
with no follow-up subsequent to randomization. For this reason, baseline carried 

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forward will not be conducted. It is acknowledged that if there are more than a 
very small percentage of patients with no follow-up subsequent to randomization, 
results from this clinical trial may not be adequately interpretable to provide 
sufficient evidence of effectiveness depending upon the robustness of primary 
analyses and the consistency of supporting analyses. 
As Treated (AT): The AT analysis set will include all patients randomized with any 
exposure to a study treatment (active or placebo), where patients will be classified by 
the treatment actually received.  Safety analyses will be performed in the AT analysis 
set.  If there are no patients receiving the incorrect treatment, then this analysis set will 
be identical to mITT.   
Per protocol (PP): The PP analysis set will include subjects with no major protocol 
deviations. In particular, the PP analysis will exclude patients that start but do not 
complete all injections associated with a study treatment.  The PP analysis set will also 
exclude patients with major violations of inclusion or exclusion criteria or who receive 
confounding concomitant medication expected to significantly impact the primary 
outcome measure.  Secondary effectiveness analyses will be performed using the PP 
analysis set.  
The primary and conditional hypotheses will also be tested using the ITT analysis 
set and in an analysis set restricted to complete cases using the same MMRM.  
Comparison among results from these three analyses will provide FDA the 
capability of determining robustness of conclusions relative to assumptions 
regarding missing data.  In the case of no missing data, these three analyses are 
identical.  Therefore, it will be a study goal to minimize the number of patients 
with early termination and missing data for other reasons as the most important 
way of addressing this issue.  
          8.8.2 Randomization and Blinding 
A site stratified, randomized block randomization will be performed such that 
within each block, patients will be allocated to either ACP or control in a 2:1 
randomization ratio  Patients, physicians, and study personnel will be blinded to 
treated until end of the study to prevent bias in estimated treated differences.  
8.8.3 Description of baseline characteristics 
Demographic and baseline characteristics will be tabulated and compared between 
the investigational group and control group. Variables to be compared will include 
baseline knee assessment, disease severity, age, gender, Body Mass Index (BMI), 
weight and height, race and ethnicity, disease histories, and concomitant 
medications and therapies. 

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Descriptive p-values will be determined using Wilcoxon rank sum tests for 
continuous measures and chi-square or exact tests for categorical variables.  
However, focus will be on clinical significance of group differences and only 
secondarily on p-values, since these p-values are not associated with planned 
comparison. If there are clinically significant group differences for any baseline 
variable, then supporting analyses will include adding these covariates to the 
MMRM used in primary superiority testing and evaluating the impact of the 
imbalance on primary findings.  
8.8.4 Description of Effectiveness Outcome 
WOMAC Pain, Function, Stiffness, and Total scores and the as well as change 
scores will be summarized at each planned follow-up visit [Pre-Op, 1 Week, 2 
Weeks, 2 Months (60 days), 3 Months (90 days), 6 Months (180 days), and 12 
Months (365 days)] using means, standard deviations, medians, minimum, and 
maximum values. Standardized effect sizes (mean difference divided by the 
standard deviation of differences) will be computed at each time point for each 
continuous measure in order to facilitate assessment of group differences across 
measures as well as time.  Pooled t-tests and Wilcoxon rank sum tests will be 
provided as additional descriptive measures.  There will be no imputation of 
missing values for secondary endpoint and exploratory endpoints and no control 
for type I error in the set of exploratory endpoints. Graphical displays of selected 
endpoints will be provided to provide visual assessments of group differences over 
time. 
                      8.8.5    Site Poolability 
A random effects model for site to site heterogeneity among treatment group 
differences in mean improvement in WOMAC Pain score will be evaluated. If 
important heterogeneity is observed, further analyses will be performed aimed at 
determining the source of this heterogeneity and its impact on estimates of 
treatment group differences. 
      
 
     8.8.6   Treatment of Missing Data 
All patients contributing at least one follow-up WOMAC Total score will be included 
in the primary superiority test through the use of the mixed model for repeated 
measures (MMRM) in the mITT analysis set. In this way patients with incomplete 
follow-up  are retained and contribute to the primary superiority test. 
As noted elsewhere, FDA has previously recommended to not include many baseline 
covariates in the MMRM due to the modest sample size.  Therefore, the only baseline 
covariates available for implicit imputation of changes from baseline to Month 6 (180 
days) is the baseline value itself and treatment group.  It follows then, that for the ITT 
analysis, the MMRM will implicitly impute missing changes from baseline to Month 6 

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(180 days) for patients with no follow-up data as the within treatment group mean 
change score modified by the effect of the baseline value 
 
8.7      Subgroup Analyses 
 
 
 
Primary and selected secondary effectiveness analyses and selected adverse event  
 
 
 
comparisons will be stratified according to site subject demographics and baseline  
 
  
 
characteristics. 
 
 
8.8 
Safety Analysis 
Assessment of safety will be based primarily on the incidence and severity of 
complications and adverse reactions associated with the treatment.  Adverse event rates 
will be summarized by type of AE and for specific AEs in two ways: 1) per patient 
using counts and percentages and 2) by event, summarizing event counts by visit 
interval over time.  Treatment and procedure related events will be summarized by 
severity.  Events listings will be provided that include details such as relatedness, 
severity, onset and resolution status will be provide for all events and for relevant 
subsets of events such as serious events and related events. All safety endpoints will be 
summarized separately for investigational and control groups. Incidence rates for 
grouped and individual adverse events will be compared using counts, percentages, and 
descriptive Fisher’s exact test nominal p-values. Grouped adverse events will include 
events at least possibly related to study treatment and serious adverse events. 
8.9 Adverse events counts over time 
The numbers of specific adverse events occurring pre-discharge and for each study 
interval will summarized separately for each relevant cohort.  Counts of systemic 
adverse events will be summarized on a per patient basis.  All other adverse events will 
be summarized on a per procedure basis.   
8.9.1 Adverse event detail listings 
Adverse events listings will be provided for all patients exposed to a study treatment 
and will provide details regarding adverse event type, relation to procedure, action 
taken, and clinical outcome.  Separate listings will be constructed for adverse events 
with “definite” relationship to the treatment, “severe” adverse event, “severe treatment-
related”, serious adverse events, and for all adverse events. The listing for all adverse 
events will be sorted by adverse event type.  
Additional listings will be provided that include all adverse events among procedures 
requiring revision, removal, or replacement and all adverse events among patients who 
died. 

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9  Study Administration 
9.1 
Role of the Study Sponsor 
As the study sponsor of this clinical study, Arthrex, Inc., has the overall 
responsibility for the conduct of the study, including assurance that the study meets 
and is conducted within the regulatory requirements specified by each reviewing 
regulatory authority. In this study, Arthrex Inc. will have certain direct 
responsibilities and may delegate other responsibilities.  
9.2 
General Duties  
Arthrex Inc. will be responsible for submitting the Investigational Device 
Exemption (IDE) application to FDA and ensuring IRB approval prior to shipping 
study product to sites. Additionally, Arthrex Inc. is responsible for ensuring 
investigators are properly trained on the study product, conducting and ensuring 
proper clinical site monitoring and subject informed consent is obtained. Arthrex 
Inc. will also supply qualified clinical sites with study product/devices that obtain 
IRB approval for this study. 
As the study sponsor of this clinical study, Arthrex Inc. will be responsible to 
monitor it for safety.   In the circumstance where unanticipated adverse device 
Events or serious adverse events occur due to a procedure, Arthrex, Inc., will 
convene a review committee which will determine any unreasonable risk to 
subject  or if the study should be reviewed for modification or early termination. 
Arthrex Inc. or designee is responsible for providing quality data that satisfies 
regulations and informing the study investigators of unanticipated adverse device 
events and deviations from the protocol as appropriate.  Arthrex Inc. or designee 
will prepare written reports and a final report. 
9.3 
Subject Confidentiality  
During the investigation, confidentiality shall be observed by all parties involved.  
All data shall be secured against unauthorized access.  Subject confidentiality will 
be maintained throughout the clinical study in a way that assures that data can 
always be tracked back to the source data. For this purpose, a unique subject 
identification number will be assigned that allows identification of all data reported 
for each subject.  Subject names should be maintained separately from case report 
forms whenever possible. 
Data relating to the study might be made available to third parties (for example, in 
case of an audit performed by regulatory authorities), provided the data are treated 
as confidential and that the subject’s privacy is guaranteed. 

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9.4 
Selection of Investigators  
Arthrex, Inc. will select qualified investigators, who have orthopedic qualifications 
and experience in treating osteoarthritis including intra-articular (IA) injections. 
All qualified Investigators must sign a study agreement. Arthrex will provide the 
investigators with the information they need to conduct the study properly. 
In the selection of study investigators, the Sponsor requires each investigator to 
have adequate experience with the investigational product, and to demonstrate a 
commitment to subject safety and consistency through adherence to study 
protocols.  The Sponsor will closely monitor compliance with the protocol 
throughout the study. 
9.5 
Supplemental Applications  
As appropriate, Arthrex, Inc. will submit changes to the investigational plan to the 
appropriate regulatory authorities. The sponsor will notify the site when there are 
changes in the investigational plan. Each investigator is required to submit the 
amendment to their IRB to obtain re-approval. 
9.6 
Submitting Reports  
Arthrex Inc. will submit all applicable reports required by the FDA.  This includes 
Serious Unanticipated Adverse Device Effect (UADE), withdrawal of IRB or 
regulatory approval, current investigators list, annual progress reports, recall 
information, and final reports. The investigational device exemption (IDE) 
regulations define an unanticipated adverse device effect (UADE) as “any serious 
adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or 
application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects” (21 CFR 812.3(s)). 
Investigative site personnel will notify Arthrex Inc. or designee as soon as possible 
but no longer than 24 hours of any UADE or death. Investigational site personnel 
will notify Arthrex, Inc. or designee of any withdrawal of IRB approval within 5 
days.  Arthrex Inc. or designee will also assist in the preparation of annual progress 
reports and a final report for the IRB.  
9.7 
Maintaining Records  
The investigational site will maintain copies of correspondence, data, shipment of 
devices, all adverse events, and other records related to the clinical trial.  
Investigational site will maintain records related to the clinical trial for a period no 
less than 2 years following the date a marketing application is approved for the 
device for the indication for which it is being investigated; or, if no application is 

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to be filed or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and FDA is notified. The investigational site 
shall notify Arthrex, Inc. before disposing of the clinical trial records.  
9.8 
Institutional Review Board (IRB) Approval 
The protocol, informed consent form, and authorization for the use and disclosure 
of health information (HIPAA) must be reviewed and approved by the respective 
IRB and Arthrex Inc. or designee before subject enrollment.  Changes to the 
informed consent must be approved in writing by Arthrex Inc. or designee in 
addition to the IRB (as applicable) before the change is implemented.  
Prior to site activation, a signed copy of the IRB approval letter addressed to the 
investigator must be submitted to Arthrex Inc. or designee, certifying trial 
approval.  Investigators are responsible for submitting and obtaining initial 
approval and continuing approval from the IRB and forwarding copies of the 
approval letters to Arthrex Inc. or designee. The original letters are to be kept on 
file at the site.   
 
9.9 
Investigator Agreement and Financial Disclosure 
The principal investigator at each site will sign the investigator’s agreement before 
beginning the study, as required by federal regulations. The principal investigator 
agrees to be responsible for conducting the investigational study in accordance 
with the signed agreement, the investigational protocol, and all applicable FDA 
regulations. 
In accordance with federal regulations, all investigators will be required to sign a 
Financial Disclosure form, which certifies the investigator’s and his/her immediate 
family’s financial interest in Arthrex Inc. and study outcomes.  Investigators must 
inform Arthrex Inc. or designee of any changes to the information within the 
financial disclosure throughout the course of the study and for a period of two (2) 
years after the device is approved by the FDA or the study is terminated, 
whichever is later. 
9.10 Study Monitors and Visits 
 
 
Arthrex shall select monitors qualified by training and experience to monitor the  
 
 
investigational study in accordance with FDA regulations for IDE studies   
 
 
including 21 CFR 812.21, CFR 50, 21 CFR 54, 21 CFR 56, this investigational  
 
 
plan, HIPPA, and Good Clinical Practice (GCP). The qualifications of monitors  
 
 
will be on file at Arthrex Inc. and will follow Arthrex Inc.’s standard operating  
 
 
procedures and the written monitoring plan for this study.  All monitors (Arthrex  
 
 
Clinical Research or designee) will have training on the monitoring plan,   
 
 
monitoring plan amendments, associated documents (e.g., standard operating  
 
 
procedures or other documents referenced in the monitoring plan).  

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   Arthrex Clinical Research or designee monitoring activities objective is to prevent 
or mitigate issues with study conduct, data collection/reporting and subject safety. 
Arthrex Clinical Research monitor will review critical data remotely via the EDC 
and/or data reports routinely. Critical data includes: 
 protocol eligibility including medical history, physical and enrollment. 
 safety assessments / Adverse Events/device effects 
 investigational product accountability 
 study endpoints –WOMAC scores 
 concomitant medications 
 deviations 
 
Arthrex Clinical Research team will review site trial file in eTMF (e.g. VEEVA)
 
ongoing basis. Sites will be required to upload all regulatory site files in the
 
Arthrex Clinical Research team will review /quality checks on all uploaded site
 
completeness, accuracy and version control. The eTMF will contain the following 
 
documents: 
 Clinical trial agreement (executed initially and all amendments) 
 Curriculum vitae for each research team member on delegation log will be 
signed and updated every 2 years. 
 Delegation of authority log-for each member of the research team performing 
study related activities.  
 Financial disclosure statement 
 Investigation product accountability logs, labels, DFUs and packing slips 
 Good Clinical Practice Certificate/CITI (e.g. initial and updates) for all 
members of research team. 
  IRB Documentation (initial approvals, continuing reviews, change in research, 
ICF , advertisement and reporting requirements) 
 Medical license (investigators, nurses, PA current with all renewals)  
 Non-subject Deviation log 
 Pre-screening logs 
 Protocol signature page 
 Research team training documents (investigator meeting, procedure training, 
Veeva, EDC Certificate, protocol updates) 
 
 
 
 
  

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Arthrex 
Clinical 
Research 
monitors 
or 
designees 
will 
query 
(via 
EDC/email/phone) research sites if issues or questions are identified during remote 
monitoring. Unresolved issues may identify the need to increase the frequency of 
on-site monitoring.  
Arthrex Clinical Research monitors or designees will visit each clinical site 
routinely (after the 1st subject is enrolled and every 8 -12 weeks) to perform on site 
monitoring. The monitors will be reviewing 100% of the critical data in the EDC 
database and verifying with source documents (i.e. the electronic medical record, 
professional notes, laboratory reports, study-specific worksheets, etc.). 
In the event that information in the EDC database does not match the 
corresponding information on the source document, the study monitor will 
generate an electronic data query for site resolution. The study monitor may 
request further documentation, such as clinic notes or lab reports, when adverse 
events or complications are identified and reported. 
Critical data includes: 
 Informed consent process-see section 6.1.2 
 Protocol eligibility including medical history, physical and enrollment-see 
section 6.1.3 
 Randomization/blinding process-see section 6.2.2.1 & 6.2.2.4 
 Safety assessments / Adverse Events/device effects-see section 7.0 
 Investigational product accountability 
 study endpoints –WOMAC scores-see section 3.7 
 concomitant medications-see section 8.6 
 deviations-see section 9.17 
 
Additionally, the study site will be evaluated for study conduct, timeliness of data 
form completion and data accuracy.  
Arthrex Clinical Research monitors or designees review findings with Investigator, 
/research team during site visits. These findings will include study updates, 
training as needed, action items and at a minimum if present., “identified non-
compliance” (e.g., ICF process issues, protocol eligibility issues, AE reporting 
issues, data collection of  critical endpoint issue and deviations).  
Repeated site non-compliance will be documented and subject to a corrective 
action plan. If a corrective action plan is not followed, the clinical site may be 
withdrawn from the study by the sponsor. 
 
Arthrex’s site monitor will forward a follow up letter with findings from site visit,  
open action items and pending issues that must be addressed before the next 
monitoring visit.  
 

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9.11 Investigational Site Qualification 
Investigational sites will be qualified and selected by Arthrex’s CRA based on 
investigator qualification, research staff expertise and availability, subject 
availability, and overall site reputation. The site qualification will be scheduled to 
include time with the Investigator, study coordinator, and other study personnel. 
Areas of discussion include review of personnel training, investigator 
qualifications, and adequacy of potential subject pool, FDA-regulated study 
experience, and this study’s specific requirements for procedures and equipment, 
and a review of staffing and equipment availability and appropriateness.  A written 
follow-up letter will be submitted to the Investigator documenting any concerns 
and/or completion of study activities during the pre-study visit. 
9.12 Investigational Site Training 
Study conduct-specific training of clinical trial personnel is the responsibility of 
study manager, the study monitor, and/or the site personnel. Study training will 
occur before the first device use. The investigator is responsible for ensuring that 
his/her staff conducts the study according to protocol.  To ensure compliance with 
the Investigational Plan and regulatory requirements as well as accurate data 
collection, site training will include a detailed review of this Investigational Plan, 
Electronic Data Collection (EDC), AE reporting, device handling and inventory, 
monitoring logistics, and regulatory requirements.  
Arthrex’s Clinical Research personnel will ensure that site study personnel: 
 Submit this Investigational Plan to their IRB for appropriate review and 
obtain written approval for the conduct of the study prior to consenting any 
subject for this study; 
 Maintain all study correspondence, this Investigational Plan, and all related 
and required records on file at their facility, and 
 Confirm the investigator understands his/her full responsibility for the 
study investigation at their individual medical practices, clinics, or medical 
facilities. 
Procedure Training  
All Investigators and site personnel participating in the study will receive device-
specific detailed training from Arthrex personnel. 
All training will be conducted and documented prior to first use of the study 
device. Hands-on training will be conducted prior or during the first treatment.  
9.13 Investigator Responsibility for Study Conduct 
Study investigators will ensure that all work and services they provide will be 
conducted in compliance with the signed investigator agreement, the 
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HIPAA, for protecting the rights, safety, and welfare of subjects under the 
investigator’s care, and for control of investigational devices/product.  It is the 
responsibility of each site principal investigator to provide the current study 
protocol to all sub-investigators and other staff responsible for study conduct, as 
well as provide for the training of all sub-investigators or other staff involved in 
the conduct of this research.  Specific responsibilities are listed in the Investigator 
Agreement and include: 
 That informed consent is obtained in accordance with 21 CFR Part 50. 
 That there is IRB approval prior to commencement of study activities at the 
site. 
 That investigational device/product is only to be used with subjects under 
the investigator’s supervision. 
 That they disclose to sponsor sufficient accurate financial information to 
allow applicant to submit accurate disclosure statement under 21 CFR Part 
54. 
 To prepare and submit to Arthrex Inc. or designee and IRB complete, 
accurate and timely reports on this investigation when necessary, according 
to 21 CFR 812.50. Types of reports to be submitted include reports 
pertaining to Unanticipated Adverse Device Effects, withdrawal of IRB 
approval, and deviations from the investigational plan. The investigator is 
required to submit an annual report to his/her IRB with a copy to Arthrex 
Inc. or designee. 
 That upon completion or termination of clinical investigation at sponsor’s 
request, investigator shall return remaining supply of investigational 
product/device or otherwise dispose of the device as the sponsor directs.  
 That upon completion of the trial, a final written report to the reviewing 
IRB, within three (3) months of completion or termination of the study. 
The final report must include: 
o Device name 
o Number of subjects screened, enrolled, withdrawn and completed 
o Number of devices received, used and returned 
o Summary of all adverse events (anticipated and unanticipated) 
o Summary of serious adverse events 
o Summary of all protocol deviations 
o Brief statement of results, outcomes and conclusions. 
 Maintain records and reports (see Records below) on file at the 
investigational site for a minimum of two (2) years after the later of either 
the completion/termination of the investigational study or the date the 
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studied.  They may be discarded only upon approval from Arthrex.  The 
principal investigator must contact Arthrex’s CRA before destroying any 
records and reports pertaining to the study to ensure that they no longer 
need to be retained.  In addition, Arthrex must be contacted if the 
investigator plans to leave the investigational site to ensure that 
arrangements for a new investigator or records transfer are made prior to 
investigator departure.  
 Records  
Records to be maintained by the investigator in the designated 
investigational center’s Regulatory Binder include: 
o Investigational plan and all amendments 
o Signed Investigator Agreement 
o Signed Financial Disclosure 
o IRB approval letter including all versions of the  consent and HIPAA 
(for US sites) or the country-specific requirement authorization form(s) 
o IRB Membership list or Letter of Assurance 
o All correspondence relating to the study between the site and Arthrex. 
o CVs and professional licenses for all investigators 
o Site personnel signature and responsibility list 
o Clinical monitor sign-in log 
o Subject Screening/Enrollment log 
o Investigational device inventory log including: date, quantity, and lot 
numbers of all devices, identification of all persons the device was used 
on and final disposition.  
The following records must be maintained for each subject enrolled in the study: 
 Signed Consent Form and Authorization for the Use and Disclosure of 
Health Information 
 Compete, accurate, and current data collection forms 
 AE reports and any supporting documentation 
 Protocol deviations 
 Complete medical records, including procedure reports, lab reports, 
professional notes, etc. 
 Records pertaining to subject death during the investigation (including 
death records, death certificate, and autopsy report if performed). 
Arthrex reserves the right to secure data clarification and additional medical 
documentation on subjects enrolled in this study at any time.  

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9.14 Investigational Site Termination 
Arthrex reserves the right to terminate an investigational site for any of the 
following reasons: 
 Failure to secure subject informed consent or Authorization for the Use and 
Disclosure of Health Information prior to study enrollment. 
 Failure to report Unanticipated Adverse Device Events within 24 hours of 
discovery to Arthrex and/or designee and ten days (to the IRB) of learning 
of the event. 
 Failure to report serious adverse device events within 24 hours of discovery 
to Arthrex and/or designee. 
 Repeated investigational plan violations. 
 Repeated failure to appropriately complete case report forms. 
 Failure to enroll an adequate number of subjects. 
 Loss of or unaccounted for investigational product inventory. 
 Administrative decision by the company. 
9.15 Final Monitoring Visit 
Upon completion of the clinical study (when all subjects enrolled have completed 
the follow-up visits, the data collection and queries have been completed, and no 
additional information is required of the site for data management / statistical 
review),  a final study close-out visit will be conducted by the Study Monitor. The 
study monitor will verify disposition of investigational devices and review 
regulatory documents to confirm that the investigator’s regulatory files are current 
and complete, and that any outstanding issues from previous visits have been 
resolved.  Other issues that will be reviewed at this visit include, but are not 
limited to: long-term retention of study files, possibility of site audits, publication 
policy, and verification that the investigator will notify the IRB regarding study 
closure. A final follow-up letter will be drafted and submitted to the Investigator to 
document that all investigational plan-related activities have been completed and 
that the clinical study is completed and may be closed at the site. 
9.16 Protocol Amendments 
All protocol amendments must be approved by Arthrex Inc. All amendments must 
have FDA approval in addition to IRB approval.   
9.17 Protocol Deviations 
A study deviation is defined as any event where the clinical investigator or site 
personnel did not conduct the study according to the protocol.  

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Any deviations from this protocol undertaken to protect the life or physical well-
being of a subject in an emergency situation must be reported to the Arthrex Inc. or 
designee within 48 hours of occurrence and the respective IRB as soon as possible, 
but in no later than five (5) calendar days after the emergency occurs.  
All deviations will be reported to Arthrex Inc. or designee.  
Subject specific deviations will be reported in the EDC.   
Study deviations are as follows: 
 Informed Consent Form (ICF) 
o Wrong ICF version signed 
o Other deviation related to informed consent version. 
 Protocol  
o Study procedure not done per protocol 
o Study procedure or visit not done 
o Study procedure or visit Out of study window 
o Other procedure not done per protocol 
 Eligibility 
o Subject did not meet eligibility criteria  
o Other deviation related to eligibility criteria  
 Source Document 
o Missing or incomplete source document 
o Other deviation related to source document 
 Regulatory 
o Subject enrolled without IRB approval 
o Other deviations related to Regulatory  
Non-subject specific deviations, (e.g. unauthorized use of an investigational device 
outside the study, unauthorized use of an investigational device by a physician who has 
not signed an investigator agreement, improper storage and IP accountability etc.), will 
also need to be reported to the sponsor.  Investigators will adhere to procedures for 
reporting study deviations to their IRB in accordance with their IRB reporting policies 
and procedures.  
FDA regulations require that investigators maintain accurate, complete, and current 
records, including documents showing the dates of and reasons for each deviation from 
the protocol.  
9.18 Publication 
The publication of the principal results from any single center experience within 
the trial is not permitted, and any exceptions to this rule require the prior approval 
from Arthrex, Inc.  

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9.19  Audits / Inspections 
In the event a site is audited or inspected by the IRB or, FDA, the investigator 
should notify the sponsor immediately. The investigator will provide all requested 
information to the auditor or inspector.  
 
 
 

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Appendix 2-1 Schedule of Events 
ACP IA FOR KNEE OA 
SCHEDULE OF EVENTS 
 
Screening 
Treatment Visits 
Follow –up Visits 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Day -2 to 07 
Day 0 
Week 1 
+/- 3 days 
 
Week 2 
+/- 3 days 
 
2 months 
+/- 7 days 
 
3 months 
+/- 7 days 
 
 
6 months 
+/- 14 
days 
 
 
EOS or 1year  
+/- 30 days 
 
Informed Consent 
X1 
 
 
 
 
 
 
 
History & Demographics 
X2 
 
 
 
 
 
 
 
Physical  Exam  (VS) 
 Knee Exam 
 Kellgren-Lawrence Grading 
 Strokes Test Grading 
X3 
 
 
 
 
 
 
 
Concomitant Medication/Therapy 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
WOMAC 
X5 
 
X5 
X5 
X5 
X5 
X5 
X5 
Enrollment  
Pregnancy (urine)  
Radiograph 
X6 
X6 
 
 
 
 
 
 
 Randomization 
 
X 
 
 
 
 
 
 
Visit 
X7 
X7 
X7 
X7 
X7 
X7 
X7 
X7 
Treatment  
 X8 
X8 
X8 
AE 
 
 X9 
 X9 
X9 
 X9 
X9 
X9 
X9 
Deviation 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
Completion  
 
 
 
 
 
 
 
X11 
Heme Profile 
 
X12 
 
 
 
 
 
 

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 1. Informed Consent process is conducted and the form is signed prior to any study related procedures. 
2. Medical & Surgical History and Demographics are collected at Screening 
3. Physical Exam (including Knee exam,  Kellgren-Lawrence  & Strokes Test) is done at screening  
4. Pain medication and therapy  review are collected at screening and reviewed at each study visit  
5. WOMAC is completed at screening visit  to confirm Inclusion Criteria # 4 
6. Available Inclusion/Exclusion Criteria is collected at screening and confirmed at V2 (Day 0) prior to 
randomization. Radiographs to confirm Inclusion #3 and exclusion #1 and 3. Radiographs are done prior to 
Randomization, if not complete and part of subject’s medical historical medical record. Urine pregnancy is done 
at screening as when applicable.  
7. Visit Data collected all study Visits.  
8. Treatment form is collected at V2, V3 & V4.  
9. Adverse Events are collected as applicable at V2 thru V8. 
10. Deviations are collected at each V1 thru V8. 
11. Study Completion is done at Visit 8 or sooner if discontinues prior to Visit 8. 
12. Whole blood and ACP collected for analysis.  

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Appendix 2-2 Knee Exam: Stroke Test Grading  
 

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Appendix 2-3 ACP Venipuncture and Blood Collection Procedure:  
 

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Appendix 2-4 Intra-Articular Injection Procedure: Visits 2, 3 & 4 
 
 

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Appendix 2-5 Blinding Procedure 
 

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Appendix 2-6 Case Report Forms 
 
 

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