A Prospective Study of a Single Intra-Articular Injection of Autologous Protein Solution in Females With Primary Patellofemoral Osteoarthritis
Phase: NA
Conditions: Patellofemoral Osteoarthritis
Sponsor: Zimmer Biomet

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
1 of 46 
 
 
 
 
Protocol Title: 
A Prospective Study of a Single Intra-Articular 
Injection of Autologous Protein Solution in Females 
with Primary Patellofemoral Osteoarthritis 
 
Protocol Number: 
APSS-55-00 
 
Study Sponsor: 
Zimmer Biomet 
 
Biologics 
 
56 East Bell Drive 
 
Warsaw, IN 46582 
 
Protocol Version: 
Version 3.0 
 
Version Date: 
24 Feb 2016 
 
Study Investigator: Dr. Peter Verdonk, MD, Ph.D. 
 
Knee Surgery & Sports Traumatology 
 
Antwerp Orthopedic Center, Monica Hospitals 
 
Harmoniestraat 68,  
 
2018 Antwerp, Belgium 
 
 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
2 of 46 
 
CLINICAL PROTOCOL APPROVAL PAGE 
The signatories have read and understood the clinical protocol and agree to conduct the 
clinical investigation in compliance with this protocol: 
 
Protocol approved by Scientific Affairs Zimmer Biomet Biologics 
Krista Toler, M.S., MBA 
Scientific Affairs Manager 
Zimmer Biomet Biologics 
 
 
 Krista Toler, M.S., MBA 
Date 
 
Protocol approved by Research Zimmer Biomet Biologics 
Jennifer Woodell-May, PhD. 
Director of Research 
Zimmer Biomet Biologics 
 
 
Jennifer Woodell-May, PhD 
Date 
 
 
 
 
 
 
 
 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
3 of 46 
 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree: 
 To assume responsibility for the proper conduct of the study at this site and 
supervise all testing of the device involving human subjects 
 To conduct the study in compliance with this protocol, any future amendments, 
and with any other study conduct procedures provided by Zimmer Biomet 
Biologics. 
 To conduct the study in compliance with ISO 14155-2011, the ethical principles 
that have their origin in the Declaration of Helsinki, any regional or national 
regulations, as appropriate, and any additional requirements imposed by the 
Independent Ethics Committee (IEC) or regulatory authority, as appropriate. 
 To ensure that the requirements for obtaining informed consent from each 
subject are met. Not to implement any changes to the protocol without written 
agreement from Zimmer Biomet Biologics and prior review and written approval 
from my (IEC) except when necessary to eliminate an immediate hazard to 
patients. 
 That I am thoroughly familiar with the appropriate use of the study device, as 
described in this protocol and any other information provided by Zimmer Biomet 
Biologics. 
 That I am aware of, and will comply with, good clinical practice and all applicable 
regulatory requirements. 
 To ensure that all persons assisting me with the study are adequately informed 
about the Zimmer Biomet Biologics device and have been trained on their study-
related duties and functions as described in the protocol. 
 To not begin the study until the required approval/favorable opinion from the IEC 
or regulatory authority has been obtained. 
 
Signature 
 
 
 
Peter Verdonk, MD, PhD 
Date 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
4 of 46 
 
STUDY CONTACT INFORMATION 
Responsibility 
Name and Address 
Phone/E-mail Contact 
Principal 
Investigator 
Peter Verdonk, MD, PhD 
Antwerp Orthopedic 
Center 
Harmoniestraat 68 
2018 Antwerp 
Belgium 
Phone: + 32 3 240.28.70 
email: pverdonk@yahoo.com 
Study Sponsor 
Contact 
 
Ehab M. Esmail 
Director, Global Clinical 
and Regulatory Affairs 
Zimmer Biomet Biologics 
56 East Bell Drive 
Warsaw, IN 46581 
USA  
Phone: +1 574 372 6753 
email: ehab.esmail@zimmerbiomet.com 
 
nSTRIDE 
Program 
Manager 
Krista Toler, M.S., MBA 
Scientific Affairs 
Manager 
Zimmer Biomet Biologics 
56 East Bell Drive 
Warsaw, IN 46581 
USA 
Phone: +1 (574) 371-3812 
Email :  
Krista.Toler@zimmerbiomet.com 
 
Local Clinical 
Project 
Manager 
Linda Korthout 
Scientific Affairs  
Specialist 
Zimmer Biomet Biologics 
Toermalijnring 600 
3316 LC  Dordrecht 
The Netherlands 
Phone: + +31.610.072.853 
email: 
Linda.Korthout.external@zimmerbiomet.com 
 
 
 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
5 of 46 
 
STUDY SYNOPSIS 
Protocol Number: 
APSS-55-00 
Title: 
A Prospective Study of a Single Intra-Articular Injection of 
Autologous Protein Solution (APS) in Females with Primary 
Isolated Patellofemoral Osteoarthritis (PFOA) 
Sponsor: 
Zimmer Biomet Biologics 
Name of Product: 
nSTRIDE APS Kit with Anticoagulant Citrate Dextrose 
Solution-Formula A (ACD-A) 
Device 
Description: 
The APS Kit with ACD-A is a self-contained, sterile-packaged, 
single-use, disposable device designed to isolate anti-
inflammatory cytokines and growth factors from whole blood. 
The device system is to be used at the point of care to create 
an autologous protein solution. This device system consists of 
2 parts: the APS Cell Separator and the APS Concentrator. 
The APS Cell Separator separates the cellular components 
from plasma and red blood cells in whole blood. The cell 
suspension is then loaded into the APS Concentrator, which 
uses filtration through polyacrylamide beads to concentrate 
the cytokines in the injectable output. 
Intended Use: 
The nSTRIDE APS Kit with ACD-A is designed to be used for 
the safe and rapid preparation of APS from a small sample of 
blood at the patient’s point of care. The APS is to be injected 
intra-articularly for the treatment of osteoarthritis (OA). 
Study Center: 
The study will be conducted at a single center in Antwerp 
Belgium. 
Sample Size: 
50 subjects 
Study 
Populations: 
Females with isolated and symptomatic PFOA who have failed 
at least 1 prior conservative PFOA therapy (e.g. 
physiotherapy, simple analgesics, intra-articular injection) 
Study Objectives: 
Primary Objective 
The primary objective of this study is to evaluate clinical 
outcomes following a single injection of nSTRIDE APS in 
females with isolated PFOA 
Secondary Objectives 
A secondary objective of this study is to document the 
duration of treatment effect following nSTRIDE injection.  
Additionally blood chemistry characterize, erythrocyte 
sedimentation rate, C-reactive Protein, thyroid hormones T3, 
T4 and TSH, luteinizing hormone, and follicle stimulating 
hormone and analyze them with respect to clinical 
improvements in PFOA. This study will also allow for the 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
6 of 46 
 
documentation of clinical outcomes and treatment effect 
following a second injection of APS to treat PFOA.  
Study Design and 
Procedures: 
This single-center prospective follow-up will evaluate the 
effectiveness of a single dose of APS in females with isolated 
and symptomatic PFOA which failed at least 1 prior 
conservative PFOA therapy (e.g. physiotherapy, simple 
analgesics, intra-articular injection). This will be accomplished 
by assessing pain, other symptoms, activity, function of daily 
living, function of sports and recreations and knee related 
quality of life using the Knee Injury and Osteoarthritis 
Outcome Score (KOOS), the Kujala Anterior Knee Pain 
Symptom Questionnaire (KAKPAQ), the UCLA Activity Score, 
and numeric rating scales (NRS) for pain, function, and 
stiffness. Patients will also be evaluated for general quality of 
life using the EQ-5D-3L. Adverse events (AEs) related to the 
pathology, the nSTRIDE APS device or the procedure will be 
recorded. This study will also allow for the documentation of 
the same parameters following a second injection of APS to 
treat PFOA.  
 
Subjects will provide informed consent and be screened for 
eligibility (i.e., they will meet inclusion and exclusion criteria) 
within 2 months of treatment. If subjects meet the inclusion 
and exclusion criteria they will be eligible for treatment and for 
participation in the study. 
On the day of treatment but prior to treatment subjects’ 
demographics and osteoarthritic pathology will be 
documented. Subjects will complete baseline KOOS, 
KAKPAQ, NRS, EQ-5D-3L and UCLA activity questionnaires. 
Following the acquisition of baseline data, subjects will have 
their blood drawn for processing into nSTRIDE APS and 
measurement of blood chemistry. Subjects will receive a 
single intra-articular injection into the knee(s). If both knees 
are included in the study, both knees will be initially treated on 
the same date.  
 
Follow-up assessments will be conducted at 1, 3, 6, and 12-
months post injection; all subjects will complete KOOS, 
KAKPAQ, NRS, UCLA Activity Score, and EQ-5D-3L 
questionnaires. The investigative center will complete the 
Follow-up form and collect knee related AE information. 
Follow-up assessments may consist of a structured telephone 
interview, electronic self-report or, if standard of care, an 
office visit. Subjects will remain in the study until they 
complete the 12-month follow-up assessments. Under the 
conditions including but not limited to, a more invasive knee 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
7 of 46 
 
procedure, or voluntary withdrawal of consent, the subject’s 
study participation will be terminated.   
Study Duration: 
The maximum study duration for each subject is estimated to 
be 14 months. Time will be up to 2 months prior to treatment 
and follow-up 12 months post injection. 
Inclusion Criteria: 
 Female 
 Primary PFOA in one or both knees as diagnosed by the 
treating physician 
 Objective evidence of PFOA on one or both of a 
radiograph or MRI taken within 1year of treatment. 
 From 40-65 years of age, inclusive at time of injection 
 Failed at least 1 prior conservative PFOA therapy (e.g. 
physiotherapy, simple analgesics, intra-articular injection). 
Willing and able to comply with the study procedures 
 Signed informed consent form 
Exclusion Criteria:   Any systemic inflammatory condition ( e.g., rheumatoid 
arthritis) 
 Active malignancy at time of injection 
 Pregnant at time of injection 
 Lactating at the time of injection 
 Knee joint infections or skin diseases or infections in the 
area of the injection site.  
 Leukemia, metastatic malignant cells, or who are receiving 
chemotherapeutic treatment 
 Participating in another device or drug study 
Schedule of 
Assessments: 
 Informed Consent  (within 2 months of treatment) 
 Confirm eligibility; Treatment 
 Post-injection assessments: 
– 1 month (30 days ±7 days) 
– 3 month (91 days ±14 days) 
– 6 month (182 ±21 days) 
– 12 month (365 ±28 days) 
Assessment 
Tools: 
 Knee Injury and Osteoarthritis Outcome Score 
 Kujala Anterior Knee Pain Assessment Questionnaire 
 Numeric Rating Scale (pain, stiffness, function) 
 UCLA Activity Score 
 European Quality of Life 5 Dimensions 3 Levels 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
8 of 46 
 
TABLE OF CONTENTS 
CLINICAL PROTOCOL APPROVAL PAGE ................................................................................................2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ...............................................................................3 
STUDY CONTACT INFORMATION ........................................................................................................4 
STUDY SYNOPSIS ................................................................................................................................5 
TABLE OF CONTENTS ......................................................................................................................8 
ABBREVIATIONS AND TERMS ........................................................................................................... 10 
1 INTRODUCTION ............................................................................................................................. 11 
2 NSTRIDE APS KIT DESCRIPTION ....................................................................................................... 13 
3 RATIONALE ................................................................................................................................... 15 
4 STUDY OBJECTIVES ........................................................................................................................ 16 
4.1 STUDY OBJECTIVES ............................................................................................................................... 16 
4.1.1 Primary Objective ......................................................................................................................... 16 
4.1.2 Secondary Objectives .................................................................................................................... 16 
4.2 Study Outcome Measures ................................................................................................................ 16 
4.2.1 Primary Outcome Measures ......................................................................................................... 16 
4.2.2 Secondary Outcome Measures ..................................................................................................... 16 
5 RISK EVALUATION ......................................................................................................................... 18 
5.1 POTENTIAL RISKS TO STUDY PATIENTS ...................................................................................................... 18 
5.2 METHODS TO MINIMIZE RISKS ................................................................................................................ 18 
5.3 POTENTIAL BENEFITS OF THE PROCEDURE .................................................................................................. 18 
6 INVESTIGATIONAL PLAN ................................................................................................................ 19 
6.1 STUDY DESIGN .................................................................................................................................... 19 
6.2 DURATION OF STUDY AND SUBJECT PARTICIPATION ..................................................................................... 19 
6.3 STUDY VISIT DETAILS ............................................................................................................................ 21 
6.3.1 Informed Consent ......................................................................................................................... 22 
6.3.2 Pre-treatment ............................................................................................................................... 22 
6.3.3 Treatment .................................................................................................................................... 23 
6.3.4 Post-Treatment Follow-Up ............................................................................................................ 24 
6.3.5 Second Injection ........................................................................................................................... 25 
6.3.6 Study Exit ...................................................................................................................................... 25 
6.4 Description of Assessments and Other Forms .................................................................................. 26 
6.4.1 Informed Consent ......................................................................................................................... 26 
6.4.2 Demographics ............................................................................................................................... 26 
6.4.3 Medical History ............................................................................................................................. 26 
6.4.4 Knee Exam .................................................................................................................................... 26 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
9 of 46 
 
6.4.5 Images (Radiograph or MRI) .......................................................................................................... 27 
6.4.6 Clinical Lab Tests ........................................................................................................................... 27 
6.4.7 Inclusion/Exclusion Criteria ........................................................................................................... 27 
6.4.8 Pregnancy Test ............................................................................................................................. 27 
6.4.9 Knee Injury and Osteoarthritis Outcome Score (KOOS) ................................................................. 27 
6.4.10 Kujala Anterior Knee Pain Assessment Questionnaire (KAKPAQ) ................................................. 27 
6.4.11 Numeric Rating Scales (pain, stiffness, and function [NRS]) ......................................................... 27 
6.4.12 European Quality of Life 5 Dimensions 3 Levels (EQ-5D-3L) ......................................................... 27 
6.4.13 UCLA Activity Score ..................................................................................................................... 28 
6.4.14 Adverse Event Form (AE)............................................................................................................. 28 
6.4.15 Study Exit Form ........................................................................................................................... 28 
6.4.16 Protocol Deviation Form ............................................................................................................. 28 
7. STATISTICAL CONSIDERATIONS ..................................................................................................... 29 
8 MONITORING PLAN ....................................................................................................................... 30 
9 DATA MANAGEMENT AND RECORD RETENTION ............................................................................. 31 
10 AMENDMENTS TO THE STUDY PLAN ............................................................................................. 32 
11 DEVIATIONS TO THE STUDY PLAN ................................................................................................. 33 
12 STATEMENT OF COMPLIANCE....................................................................................................... 34 
13 SUSPENSION OR TERMINATION OF THE STUDY ............................................................................. 35 
14 ADVERSE EVENT AND SEFETY REPORTING ..................................................................................... 36 
14.1 DEFINITIONS ..................................................................................................................................... 36 
14.2 ADVERSE EVENT ASSESSMENTS ............................................................................................................. 37 
14.3 ADVERSE EVENT REPORTING ................................................................................................................. 38 
15 CLINICAL STUDY ADMINISTRATION AND INVESTIGATORS .............................................................. 39 
15.1 APPROVAL AND AGREEMENTS ............................................................................................................... 39 
15.2 INVESTIGATORS.................................................................................................................................. 39 
16 OTHER ETHICAL CONDUCT ........................................................................................................... 40 
16.1 IEC APPROVAL .................................................................................................................................. 40 
16.2 INFORMED CONSENT .......................................................................................................................... 40 
16.3 PATIENT COMPENSATION FOR INJURY ..................................................................................................... 40 
17 CONFIDENTIALITY ........................................................................................................................ 41 
18 REPORTING ................................................................................................................................. 42 
19 PUBLICATION POLICY ................................................................................................................... 43 
BIBLIOGRAPHY ................................................................................................................................. 44 
APPENDIX A: MANUFACTURER’S INSTRUCTIONS FOR USE ................................................................. 46 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
10 of 46 
 
Abbreviations and Terms 
ACD-A 
Anticoagulant Citrate Dextrose Solution, Solution A 
ACS 
Autologous Conditioned Serum 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
APS 
Autologous Protein Solution 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Forms 
EQ-5D-3L 
European Quality of Life 5 Dimensions 3 Levels 
FDA 
Food and Drug Administration (US) 
HA 
Hyaluronic Acid 
ICF 
Informed Consent Form 
I/E 
Inclusion/Exclusion 
IEC 
Independent Ethics Committee 
IFU  
Instructions for Use 
IRB 
Institutional Review Board 
IL-1,IL-6, IL-8 
Interleukin 1, Interleukin-6, Interleukin-8 
IL-1ra 
IL-1 receptor antagonist 
KAKPAQ 
 
Kajula Anterior Knee Pain Assessment Questionnaire 
KOOS 
Knee Injury and Osteoarthritis Outcome Score 
MDD 
Medical Device Directive 
NRS 
Numeric Rating Scale 
OA 
Osteoarthritis 
PETG 
Polyethylene terephthalate 
PFOA 
Patellofemoral Osteoarthritis 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
sIL-1RI, sIL-1RII 
Soluble forms of IL-1 receptor 
sTNF-RI,sTNF-RII Soluble forms of TNFα receptor 
T3, T4, TSH  
Thyroid hormones 
TNFα 
Tumor Necrosis Factor alpha 
UCLA 
University of California Los Angles 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
11 of 46 
 
1 INTRODUCTION 
 
Osteoarthritis (OA) is a degenerative and disabling articulating joint disease that affects 
both young, active patients and the elderly (1-4). Surgical intervention is a widely used 
and clinically successful option for treatment of severe degenerative OA. However, 
success rates for treating less severe OA vary. Current treatment options include 
nonsteroidal anti-inflammatory drugs, corticosteroid injections, and hyaluronic acid (HA) 
injections. Although these treatments may be effective in temporary pain relief for some 
OA patients, they do not address the biological mechanisms causing the disease (5). 
OA is characterized by chronic pain, cartilage degradation, loss of subchondral bone 
remodeling, and varying degrees of synovial inflammation. OA pain is a complex 
response resulting from the interplay between inflammation, anatomic pathology, 
articular cartilage innervation, nerve sensitization, and psychological factors. 
Inflammation associated with OA results in joint stiffness and pain; patients may 
experience local warmth, tenderness, and effusion (6). Although OA is classified as a 
non-inflammatory disease, inflammation is implicated in many symptoms and the 
progression of OA. Pro-inflammatory cytokines are involved in OA development (7-12). 
Cytokines such as interleukin (IL)-1, tumor necrosis factor alpha (TNFα), IL-6, and IL-8 
are integral in the initiation and maintenance of inflammation by mediating cell-to-cell 
interactions (13). Of these, IL-1 has been proposed to play a key role (14-16). The 
cytokines associated with inflammation in OA, primarily IL-1 and TNFα, are also 
implicated in cartilage matrix breakdown (17-19). These cytokines induce cells in the 
joint to produce matrix metalloproteinases that in turn are responsible for degradation of 
the cartilage matrix (20). The interactions between chondrocytes in articular cartilage, 
synovium, and IL-1 and TNFα result in a positive feedback loop that further increases 
inflammation and cartilage breakdown associated with increasing limitation in cartilage 
repair. IL-1, TNFα, IL-6, and IL-8, along with nerve growth factor, also lead to nerve 
sensitization and stimulation (21).  
Both IL-1 and TNFα are implicated in inflammation and cartilage breakdown, thus 
inhibition of these cytokines may be an effective therapy by limiting inflammation and 
matrix degradation. The anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-
1ra), a competitive IL-1 receptor antagonist, blocks the signaling activity of IL-1 and has 
no signal-inducing activity itself (22-24). Soluble forms of the IL-1 cell receptor 
competitively bind with IL-1 and reduce IL-1 biologic activity (25). Additionally, soluble 
forms of the cell receptors for TNFα, known as sTNF-RI and sTNF-RII, can bind to 
TNFα preventing it from binding to a surface receptor and thus inhibiting cell signaling 
(26). These anti-inflammatory cytokines are present systemically, but not in the 
concentrations or locations that may be clinically beneficial in the treatment of knee OA. 
The nSTRIDE APS Kit is designed to produce an autologous protein solution (APS).  
APS contains concentrated levels of anti-inflammatory cytokines including IL-1ra, sIL-
1RII, sTNF-RI, and sTNF-RII and of anabolic cytokines for cartilage, including insulin-
like growth factor 1 and transforming growth factor β1 (27). A method of balancing these 
cytokines by injection of autologous conditioned serum (ACS) has been explored. ACS 
is an autologous acellular plasma serum containing proteins. The ACS also contains up-
regulated levels of anti-inflammatory cytokines and has shown promise when compared 
to HA or saline for the treatment of OA (28). 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
12 of 46 
 
In summary, inflammatory and catabolic cytokines are strongly implicated in the OA 
degenerative process and inhibition of their action may be clinically beneficial. Anti-
inflammatory and anabolic cytokines found in whole blood may also reduce or reverse 
the degenerative process. Appropriate processing of whole blood substantially 
increases the concentrations of anti-inflammatory and anabolic cytokines. Thus, a likely 
mechanism of action of APS in reducing symptomatic OA and reducing or reversing the 
degenerative impact of inflammatory and catabolic cytokines is the introduction of 
greater than normal levels of anti-inflammatory and anabolic cytokines in a targeted 
fashion. 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
13 of 46 
 
2 NSTRIDE APS KIT DESCRIPTION 
 
The nSTRIDE APS Kit is a self-contained, sterile packaged, single-use, disposable 
device used at the point of care to concentrate anti-inflammatory cytokines and growth 
factors from whole blood. The device is to be used at the point-of-care to create an 
autologous solution. The nSTRIDE APS Kit with Anticoagulant Citrate Dextrose Solution 
– Formula A (ACD-A) contains two polymer blood processing devices and a 30 milliliter 
(ml) vial of Anticoagulant Citrate Dextrose Solution – Formula A (ACD-A). The first of 
the two devices is the nSTRIDE Cell Separator. It is a plastic tube containing a tuned-
density buoy and separates cellular components of whole blood when appropriately 
cycled in a centrifuge. The cell suspension produced is further processed by the second 
of the two devices, the nSTRIDE Concentrator. This device is a plastic tube containing 
polyacrylamide beads to further concentrate the cell suspension and produce an 
injectable output, the APS.  
Sixty milliliters (mL) of anticoagulated whole blood (55mL blood drawn into 5 mL ACD-
A) are injected into the APS Cell Separator. The device is centrifuged for 15 minutes; 
the plasma is discarded and the cell concentrate is resuspended and transferred to the 
Concentrator containing the acrylamide beads. The device is centrifuged for 2 minutes 
and the final product (output) is removed. The output (APS) is approximately 2.5mL and 
is intended to be administered via an intra-articular injection. 
APS contains high concentrations of anti-inflammatory molecules, and it has been 
shown to block inflammation and prevent cartilage degradation in vitro. In a prospective, 
randomized, controlled equine clinical study, APS reduced pain and improved function 
in horses with osteoarthritis. 
The components of the device are listed in the table below. 
Component Name 
Part Number 
nSTRIDE APS Kit 
800-3000ST 
 
The overall device classification is as follows: 
Device Classification: Class IIb, as defined in Annex IX of the Council Directive 
93/42/EEC Concerning Medical Devices, i.e., Medical Device 
Directive (MDD) 
Sterilization: 
The APS device is supplied as a sterile single-use unit. 
 
Intended Use: 
The nSTRIDE APS Kit with ACD-A is designed to be used for the safe and rapid 
preparation of APS from a small sample of blood at the patient’s point of care. The APS 
is to be injected intra-articularly for the treatment of knee osteoarthritis. 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
14 of 46 
 
Contraindications: 
APS should not be injected in the knees of patients having knee joint infections or skin 
diseases or infections in the area of the injection site. Please refer to the Instructions for 
Use (IFU) for a complete list of contraindications (Appendix 1). 
 
Manufacturing, Packaging and Labeling 
The investigational device is made primarily out of the raw material Cyrolite Med 2 
acrylic-based multipolymer compound, which is manufactured at Cyro Industries 
(Rockaway, NJ). All of the device components are manufactured and/ or assembled at 
Advanced Engineering  Inc.(Huntington, IN). Components are injection molded on a 50-
80 ton horizontal Nissei screw type injection molding machine and then assembled in a 
clean room environment under ISO 13485 and FDA guidelines. The complete 
assembled parts are packaged at Advanced Engineering Inc. in a clean room 
environment in a PETG Tray and sealed with a Tyvek lid. The sealed package is 
shipped to Steris Inc. (Libertyville, IL) for gamma sterilization and received back at 
Advanced Engineering Inc. for final inspection. The sterilized device packages are then 
kitted into the final carton, shrink wrapped in plastic in a clean room environment and 
shipped complete to Zimmer Biomet Inc. (Warsaw, IN). 
The APS devices will be labeled in accordance with local regulations for device labeling. 
 
Device Supply, Storage, and Accountability 
The APS Kit with ACD-A will be supplied by Zimmer Biomet Biologics. The device can 
be stored at room temperature. The nSTRIDE device is CE marked for this indication 
and no special restrictions are necessary. 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
15 of 46 
 
3 RATIONALE 
 
Clinical trials have, in general, formally demonstrated the effectiveness and safety of 
various autologous therapies for the treatment of knee OA.  Differences in the 
processing of autologous therapies can yield substantial differences in the resulting 
output. Thus, making generalizations regarding the effectiveness across these 
autologous therapies is more complicated. Each autologous therapy requires 
independent efficacy evaluation. nSTRIDE APS has been shown to decrease pain, 
increase function and have a favorable safety profile in a pilot trial1. 
Further, demonstration of the treatment effects in patellofemoral OA (PFOA), an 
important subset of knee osteoarthritis is lacking. This study will evaluate a population 
of female patients with PFOA in which treatment with other modalities provides 
limited/short lived relief with the hope that APS treatment will provide and extend relief 
to these patients. The study will document the treatment effects and timeline of 
treatment effects for nSTRIDE APS following a single injection (per symptomatic knee). 
 
 
 
                                                          
 
1 A Pilot Study of a Single Intra-articular Injection of Autologous Protein Solution (APS) in 
Patients with Osteoarthritis (OA) of the Knee. (2014) Data on file Biomet Biologics 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
16 of 46 
 
4 STUDY OBJECTIVES 
 
The study objectives will document treatment effects, changes in quality of life, and 
treatment complications in female patients with PFOA following a single APS injection 
into the knee(s). 
4.1 Study Objectives 
4.1.1 Primary Objective 
The primary objective of this study is to assess clinical outcomes such as pain, other 
symptoms, function of daily living, function of sports and recreation, and other knee 
related quality of life measures of a single nSTRIDE APS injection in females with 
isolated PFOA. This will be accomplished by tracking these outcome measures for up to 
12 months post injection. 
4.1.2 Secondary Objectives 
Secondary objectives include documenting the duration of treatment effect following 
nSTRIDE APS injection and characterization of various blood components with respect 
to clinical improvement in PFOA. This study will also allow for the documentation of 
clinical outcomes and treatment effect following a second injection of APS to treat 
PFOA. 
 
4.2 Study Outcome Measures 
4.2.1 Primary Outcome Measures 
The following clinical endpoints will be assessed: 
 The time from the initial nSTRIDE injection to subsequent nSTRIDE 
           injection(s) or other intrusive treatment. 
 For each of the five KOOS subscales, (Symptoms, Pain, Quality of Life (QoL), 
Function, Sports and Recreational Activities) and at each post-injection time point 
the change from baseline up to 12 months.  
 The change from baseline in patellofemoral pain and instability measured by the 
KAKPAQ at each post-injection time point up to 12 months.  
 The change from baseline in knee pain, stiffness and function measured by the 
NRS at each post-injection time point up to 12 months.  
 The change from baseline in subject activity as measured by the UCLA Activity 
Score at each post-injection time point up to 12 months. 
 The change from baseline in quality of life as measured by the EQ-5D at each 
post-injection time point up to 12 months. 
4.2.2 Secondary Outcome Measures 
The following secondary endpoints will be assessed at 1, 3, 6 and 12 month. 
 
Clinical endpoint: 
 Composite of the primary endpoint following a second injection of APS. 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
17 of 46 
 
 Composite of the primary endpoint in relationship to the various blood 
components.    
 
Safety endpoint: 
 Incidence of treatment and knee related events 
 Incidence of device or procedure related events 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
18 of 46 
 
5 RISK EVALUATION 
 
5.1 Potential Risks to Study Patients 
Risks to patients in the study include risks associated with a blood draw, aspiration of 
joint fluid, and injection of a solution into the knee. These include allergic reaction to 
anesthesia, pain, stiffness, bleeding, bruising, infection, deep venous thrombosis, scar 
tissue formation, thrombotic complications or nerve/nervous systems damage. These 
possible risks may occur with any blood draw, aspiration, or joint injection procedure. 
Possible risks associated with the injection of APS include worsening pain and/or knee 
function, effusion, and infection. Another potential risk is possibility of injecting the APS 
of one patient into another patient when processing more than one donor at a time. This 
risk could be associated with the possibility of an inflammatory reaction by the patient 
receiving the injection and/or transmission of blood-borne pathogens.  There are no 
known specific risks due to the device itself. 
 
5.2 Methods to Minimize Risks 
The inclusion/exclusion criteria will assure that any subject who may be at increased 
risk from participating in this study will not be enrolled. 
 
This device will be used and administered only by trained healthcare professionals who 
are experienced in the study procedure and treatment  
 
Sticker labels are included in each kit to identify the subject associated with each 
syringe, device, and sample. The use of these labels will reduce the risk of sample mix-
up. Additionally, processing only one subject’s blood in the centrifuge at a time would 
eliminate the risk. 
 
5.3 Potential Benefits of the Procedure 
The potential benefit of APS in the treatment of PFOA is that it may provide 
symptomatic pain relief, help restore knee function and delay the necessity of more 
invasive procedures.  
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
19 of 46 
 
6 INVESTIGATIONAL PLAN 
 
6.1 Study Design 
This is a single center, one arm, prospective, outpatient study evaluating the 
effectiveness of a single nSTRIDE APS injection per symptomatic knee. The target 
population for this study is female patients with PFOA who have failed at least 1 prior 
conservative PFOA therapy (e.g. physiotherapy, simple analgesics, intra-articular 
injection). The target population is further refined in that, potential subjects must meet 
all of the inclusion criteria and none of the exclusion criteria below (6.3.2.). 
During the pre-treatment visit and prior to any study specific procedures that are not 
standard of care, the subject will have the study explained to them and will be asked to 
give written informed consent. The subject will be preliminarily assessed for study 
eligibility on any criteria that are obtained through means that are standard of care. The 
subject will be asked to abstain from analgesics for 48 hours prior to the treatment visit, 
which will be scheduled within 2 months of the pre-treatment visit and signed informed 
consent.   
At the pre-treatment visit, subjects formally complete the screening assessment 
(inclusion / exclusion criteria), including demographics, medical history, knee exam and, 
as needed, a pregnancy test. Upon eligibility confirmation, patients will be asked to 
respond to a battery of subject reported outcome measures including the KOOS, 
KAKPAQ, NRS, UCLA Activity Score, and EQ-5D-3L questionnaires. A blood sample of 
sufficient size to test for several hormones will be obtained. 
Upon completion of all questionnaires the subject will receive the treatment injection(s). 
A subject with bilateral PFOA in whom both knees are treated must be injected on the 
same date for the subject to be enrolled in the study. If any intra-articular injection other 
than nSTRIDE APS (in index knees[s]) is necessary during the study interval the subject 
will be exited from the study (see 6.3.6).  
 
At 1-, 3-, 6-, and 12-months after treatment subjects will complete questionnaires 
including, the KOOS, KAKPAQ, NRS, UCLA Activity Score, and EQ-5D-3L online.  
Subjects will be asked to abstain from analgesics for 48 hours prior to completing the 
questionnaires. The investigative center will complete the Follow-up form and collect 
knee related AE information. Follow-up assessments may consist of a structured 
telephone interview, electronic self-report or, if standard of care, an office visit. 
6.2 Duration of Study and Subject Participation 
This study will enroll up to 50 subjects over 12 months. Subject participation will be 
approximately 14 months from time of recruitment to study completion at 12 months 
post injection. 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
20 of 46 
 
Subjects will participate in the study until they complete the 12 month post treatment 
assessments (per protocol) 
Subjects who do not complete the study per protocol may be exited from the study in 
the following manner: 
 Subject voluntarily withdraws consent. 
 Subject lost-to-follow-up 
 Subject receives additional knee injection(s) other than nSTRIDE APS in index 
knee(s) 
 Subject receives more than two nSTRIDE APS injection(s) in index knee(s)  
 Subject undergoes other invasive treatment of the index knee(s) 
 Subject death 
Subjects have the right to withdraw from the study at any time, for any reason or no 
reason, without jeopardizing their medical care. 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
21 of 46 
 
6.3 Study Visit Details 
A schedule of assessments to be performed at each visit is presented below: 
 
1 If needed. 
2 Follow-up will be completed online or in the hospital (if standard of care) for KOOS, KAKPAQ, NRSs, UCLA Activity Score, and EQ-5D-3L 
3 If applicable, knee related events only. 
4 Subjects who are receiving an additional injection of nSTRIDE will complete a Patient Questionnaire (NRS). The site will complete a Follow-up, 
Procedure and Adverse Event form, if applicable.  
 
 
 
 
Post-Treatment Follow-Up 
 
 
Pre-Treatment 
Treatment 
1 
Month 
(30 days 
± 7 
days) 
3 
Month 
(91 days 
± 14 
days) 
6 
Month 
(182 
days 
±21 
days) 
12 
Month 
(365 
days 
± 28 
days) 
2nd 
injection4 
Study 
Exit 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion / 
Exclusion 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Knee Exam 
X 
 
 
 
 
 
 
 
Pregnancy Test1  
X 
 
 
 
 
 
 
 
Follow-up2 
 
 
X 
X 
X 
X 
X 
 
Demographics 
X 
 
 
 
 
 
 
 
KOOS 
X 
 
X 
X 
X 
X 
 
 
KAKPAQ 
X 
 
X 
X 
X 
X 
 
 
NRS  
X 
 
X 
X 
X 
X 
X 
 
UCLA Activity 
Score 
X 
 
X 
X 
X 
X 
 
 
EQ-5D-3L 
X 
 
X 
X 
X 
X 
 
 
Routine 
Laboratory Test 
X 
 
 
 
 
 
 
 
Procedure Details 
 
X 
 
 
 
 
X 
 
Adverse Events3 
 
X 
X 
X 
X 
X 
X 
X 
Study Completion 
 
 
 
 
 
 
 
X 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
22 of 46 
 
6.3.1 Informed Consent 
Prior to participation in this study, the completion of any required non-standard of care 
procedures or collection of any study specific data, the patient must complete an 
informed consent process and sign and date the informed consent form. Designated 
center staff will explain the purpose of the registry, data to be collected, how data will be 
used, time and travel commitments and other expectations of a registry subject. The 
subject will be given the opportunity to discuss the study with the investigator, including 
any medical aspect of their disease or the study treatment. If the subject decides to 
participate he/she will sign and date the informed consent form along with the 
Investigator and other staff participating in the consent process and the treatment visit 
will be scheduled. A copy of the ICF will be given to the subject.  
6.3.2 Pre-treatment  
After completing the informed consent, eligibility for the study will be confirmed and 
documented.  
Inclusion Criteria 
Subjects will be assessed to ensure they meet all of the inclusion criteria to be eligible 
for study enrollment: 
1. Patient must be female 
2. Isolated PFOA in one or both knees as diagnosed by the treating physician 
3. Objective evidence of PFOA on one or both of a radiograph or MRI taken within 1 
year of treatment 
4. From 40-65 years of age, inclusive at time of injection 
5. Failed at least 1 prior conservative PFOA therapy (e.g. physiotherapy, simple 
analgesics, intra-articular injection). 
6. Willing and able to comply with the study procedures 
7. Sign informed consent form 
 
Exclusion Criteria 
Subjects will be assessed to ensure they do not meet all of the exclusion criteria to be 
eligible for study enrollment: 
1. Any systematic inflammatory condition (e.g. rheumatoid arthritis) 
2. Active malignancy at time of injection 
3. Pregnant at time of injection 
4. Lactating at time of injection 
5. Knee joint infections or skin diseases or infections in the area of the injection site 
6. Leukemia, metastatic malignant cells, or who are receiving chemotherapeutic 
treatment 
7. Participation in another device, biologic or drug study 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
23 of 46 
 
Prior to treatment, each subject’s Medical History and Demographics will be collected. 
Knee examination will be performed to the extent required to confirm inclusion / 
exclusion criteria. 
As applicable, a pregnancy test will be completed to confirm inclusion / exclusion 
criteria.  
Subject Reported Outcomes 
The following baseline assessments will be completed prior to treatment and after final 
confirmation of eligibility: 
 KOOS 
 KAKPAQ 
 NRS (for pain, stiffness, and function) 
 UCLA Activity Score 
 EQ-5D-3L 
Routine Laboratory Test  
After confirmation of eligibility criteria and collection of baseline information the subject 
will have blood drawn for analysis. A blood sample sufficient to allow for analysis of the 
following will be taken: 
 Erythrocyte sedimentation rate 
 C-reactive protein 
 Thyroid hormones – T3, T4 and TSH 
 Luteinizing hormone 
 Follicle stimulating hormone 
 
6.3.3 Treatment 
The treatment visit should be completed within 2 months (60 days) after signed 
informed consent. The subject will be asked to abstain from analgesics for 48 hours 
prior to treatment.  
Blood Draw and APS Preparation 
To produce the APS volume, draw 5 ml of ACD-A into a 60 ml syringe. Attach syringe to 
an 18-gauge butterfly apheresis needle and prime with ACD-A. Draw 55 ml of whole 
blood into the syringe and gently mix. This will produce 60 ml of anti-coagulated blood. 
Inject the 60 ml of anti-coagulated whole blood into the nSTRIDE Cell Separator. Place 
the nSTRIDE Cell Separator and a counterbalance (or second sample) into the 
centrifuge and run for 15 minutes at 3200 RPM. Using a 30 ml syringe, remove the 
plasma from the nSTRIDE Cell Separator and discard appropriately. Using a 10 ml 
syringe, extract 2 ml of the cell concentrate from the nSTRIDE Cell Separator and 
suspend the cells by shaking the syringe and nSTRIDE Cell Separator for 30 seconds 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
24 of 46 
 
while the nSTRIDE Cell Separator and syringe are attached. Extract remaining cell 
concentrate into the syringe. Inject the cell concentrate into the upper chamber of the 
nSTRIDE Concentrator which contains polyacrylamide beads. Spin the paddle on the 
nSTRIDE Concentrator to mix the cell concentrate and beads. Place the nSTRIDE 
Concentrator and counterbalance (or second sample) into the centrifuge and spin for 2 
minutes at 2000 RPM. Using another 10 ml syringe, extract the final APS product. The 
first APS volume should be used for the treatment injection. For further details of 
processing whole blood to APS, consult the training material or contact the sponsor 
directly.  
If both knees will be treated, two portions of nSTRIDE APS may be made concurrently 
using two separate kits. 
Injection Procedure 
The APS (approximately 2.5mL) is intended to be administered as a single injection into 
the knee joint. The general procedure for injection(s) is as follows: 
1. Prepare knee(s) per investigators standard protocol for knee injections 
a. Investigator will avoid injecting any anesthetic into the joint space to 
avoid diluting the APS 
2. Insert an 18-22 gauge needle into the joint space 
3. Attach an empty syringe to the needle and aspirate and discard all available joint 
fluid 
a. This step must be completed to remove all available fluid so the 
injected APS is not diluted in the joint space 
b. Aspiration will be completed on all treated knees without exception 
4. Remove the aspiration syringe and attach the syringe containing the APS 
5. Inject the approximately 2.5mL of APS into the joint space 
The position of the knee (e.g. extended or bent) and needle approach to the joint space 
(e.g. lateral or medial) is at the discretion of the person performing the injection. 
The subject should be instructed not to exceed pre-injection activity levels for 14 days. 
Procedure Details and complications or immediate post-injection AEs will be recorded. 
6.3.4 Post-Treatment Follow-Up 
Follow-up assessments will be conducted at 1-, 3-, 6-, and 12-months after treatment. 
The follow-up assessments times and windows are defined below. All follow-up 
assessments should be conducted within the appropriate time window. 
 1 month (30 days ±7 days) 
 3 month (91 days ±14 days) 
 6 month (182 days ±21 days) 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
25 of 46 
 
 12 month (365 ±28 days) 
Follow-up visits may consist of a structured telephone interview, electronic self-report 
or, if standard of care, an office visit. The investigative center will contact the subject to 
complete the Follow-up form and collect knee related AE information. The subject will 
be asked to complete the following Patient Questionnaires:  
 
 KOOS 
 KAKPAQ 
 NRS (for pain, stiffness, and function) 
 UCLA Activity Score 
 EQ-5D-3L 
6.3.5 Second Injection 
As determined by the treating physician, each subject unresponsive to the first injection 
may receive a second injection of nSTRIDE APS within the 12-month time frame, but 
not earlier than 3 months. During the visit of the second injection the site will complete a 
Follow-up and Adverse Event form, if applicable. The subject will be asked to complete 
a Patient Questionnaire (i.e., Numeric Rating Scales) prior to the injection and the site 
will complete an additional Procedure form for each additional injection. 
 
Subjects may receive up to two procedures in each knee but will remain time indexed to 
the initial procedure. Repeat procedures will be performed in the same manner as the 
initial procedure. If both knees are included in the study, both knees will be initially 
treated on the same date.  
 
If the subject received an additional nSTRIDE injection they will be followed according 
to section 6.3 and the subject will continue participation in the study. 
 
6.3.6 Study Exit 
Subjects will participate in the study until they complete the 12 month post injection 
assessments. When the 12 month assessment has been collected, subject participation 
in the study will be considered completed. Subjects who exit the study in this fashion will 
be considered complete per protocol. 
Subjects who do not complete the study per protocol may be exited from the study in 
the following manner: 
 Subject voluntarily withdraws consent. 
 Subject lost-to-follow-up 
 Subject receives additional knee injection(s) other than nSTRIDE APS in index 
knee(s) 
 Subject receives more than two nSTRIDE APS injection(s) in index knee(s)  
 Subject undergoes other invasive treatment of the index knee(s)  

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
26 of 46 
 
 Subject death 
Once a subject’s study participation ends a study exit form will be completed to 
document the circumstances of subject’s exit.  
If subject withdraws consent, center should attempt to document the reason for 
withdrawal. 
If subject is exited due to lost-to-follow-up, dates of the three times email reminders 
were sent should be recorded.   
If the subject exits subsequent to other invasive treatment, the type of treatment should 
be recorded.  
If both limbs are included in the study, both limbs will exit the study at the same time 
such that an intrusive treatment other than nSTRIDE in either limb will result in the exit 
of both limbs.  
 
If subject exits subsequent to death the date and cause of death should be recorded. 
6.4 Description of Assessments and Other Forms 
6.4.1 Informed Consent 
The informed consent form will, in writing understandable to the subject, describe the 
study and its purpose. It will outline the potential benefits and the potential risks as well 
as what alternative procedures may be available. The confidentially of the subject’s 
participation will be confirmed and the confidentiality of the subject’s data and the study 
data will be described. Any compensation or lack thereof as well as any anticipated 
expenses will be disclosed. Subject will be informed that any new findings which may 
affect their participation will be disclosed. As applicable circumstances under which the 
investigator or the sponsored may terminate the study will be explained. All applicable 
local laws must be respected while obtaining subject’s informed consent. 
6.4.2 Demographics 
Demographics collected will include but are not limited to height, weight, age, and 
length of knee pathology, 
6.4.3 Medical History 
Information regarding systemic inflammatory conditions, currently active malignancy, 
pregnancy, lactation status, leukemia and current chemotherapeutic drug use will be 
obtained. 
6.4.4 Knee Exam 
A knee exam will be performed, and the results will be used to determine subject 
eligibility. 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
27 of 46 
 
6.4.5 Images (Radiograph or MRI) 
A knee radiograph (or MRI) may be used for objective evidence of PFOA. The X-ray or 
MRI must have been taken within 1 year of the injection procedure. As standard of care 
it is expected that one or both of these image studies will be available. If images are not 
available eligibility cannot be determined. 
6.4.6 Clinical Lab Tests 
On the day of the procedure a sufficient amount of blood will be taken for analysis of the 
following: 
 Erythrocyte sedimentation rate 
 C-reactive protein 
 Thyroid hormones – T3, T4 and TSH 
 Luteinizing hormone 
 Follicle stimulating hormone 
 
6.4.7 Inclusion/Exclusion Criteria 
This lists all of the criteria the subject must meet to be eligible for the study.  All 
questions must be answered “Yes” for all inclusion criteria and “No” for all exclusion 
criteria for a subject to be eligible for the study. 
 
6.4.8 Pregnancy Test 
Diagnostic clinical test which determines pregnancy status.  
 
6.4.9 Knee Injury and Osteoarthritis Outcome Score (KOOS) 
The KOOS is a validated instrument which measures knee pain and function using five 
subscales: pain, symptoms, function in daily living, function in sport and recreation, and 
quality of life. The instrument consists of 42 standardized questions each having 5 point 
Likert response scale. 
 
6.4.10 Kujala Anterior Knee Pain Assessment Questionnaire (KAKPAQ) 
The KAKPAQ is a reliable and valid measurement of patellofemoral pain and instability. 
The weighted questionnaire examines 13 domains, including pain and functionality.  
 
6.4.11 Numeric Rating Scales (pain, stiffness, and function [NRS])  
The NRS is a validated measure of pain. The NRS is an 11 point Likert type scale 
anchored by 0 “no pain” and 10 “worst possible pain”. Subjects rate their average pain 
over the last 24 hours. Likewise subjects rate their stiffness and function on an 11 point 
Likert type scale. 
 
 
6.4.12 European Quality of Life 5 Dimensions 3 Levels (EQ-5D-3L)  
The EQ-5D-3L is a validated instrument which assesses an individual’s current health 
status and heath related quality of life. The EQ-5D-3L assess five dimensions, mobility, 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
28 of 46 
 
self-care, usual activities, pain/discomfort, and anxiety/depression over three levels of 
severity. 
 
6.4.13 UCLA Activity Score 
The UCLA Activity Score is a validated measure of subject activity. Subjects rate their 
current activity level from “wholly inactive” to “regularly participate in impact sports”.  
 
6.4.14 Adverse Event Form (AE) 
AE2 forms will document a description of the AE, onset and resolution dates, severity, 
seriousness, treatment, and relatedness to the device and the procedure. The form will 
also document whether the event was anticipated or unanticipated. 
 
Possible AEs associated with the joint fluid aspiration and injection procedure include 
worsening of pain and/or knee function, effusion, burning sensation, swelling, erythema, 
and infection.  
 
6.4.15 Study Exit Form 
This form will document the termination of a subject’s study participation and capture 
the reason for the exit from the study. 
 
6.4.16 Protocol Deviation Form 
This form will document the deviations from the study protocol.  
 
 
 
                                                          
 
2 Adverse Events (AEs) can be reported as one main diagnosis (like fever), instead of recording many 
symptoms in different AEs 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
29 of 46 
 
7. STATISTICAL CONSIDERATIONS 
 
As a study to track treatment effects following APS injections for knee OA, the planned 
statistical analyses are exploratory in nature.  Data analysis may be conducted 
intermittently as needed or as requested by investigators without a power penalty and 
consist primarily of summary statistics and inferential statistics for changes in 
dependent measures over time. 
Specific data analyses include but are not limited to: 
 Demographics and other pro-treatment characteristics will be summarized and 
characterized with appropriate descriptive statistics including error measures.  
Statistics may include mean, mode, median, range, inter-quartile range, 
minimum, maximum, frequency, cumulative frequency percentage and 
cumulative percentage. Results may be presented in a narrative and graphically. 
 Subject reported outcome measures will be summarized and thoroughly 
characterized with the appropriate descriptive statistics including error measures. 
Statistics may include mean, mode, median, range, inter-quartile range, 
minimum, maximum, frequency, cumulative frequency percentage and 
cumulative percentage. Results may be presented in a narrative and graphically. 
These measures will also be analyzed using inferential statistics to assess 
changes over time. As appropriate a repeated measure ANOVA or Wilcoxon 
signed rank test will be completed for each outcome measure. If a significant 
trend is identified, significance among time points may be further explored using 
the appropriate pair-wise comparisons. In all cases a p-value equal to or less 
than 0.05 will be considered significant. No corrections for multiple pair-wise 
comparisons will be made. 
 Clinical Lab results will be summarized and characterized with the appropriate 
descriptive statistics. Statistics may include mean, mode, median, range, inter-
quartile range, minimum, maximum, frequency, cumulative frequency percentage 
and cumulative percentage. Clinical lab results will also be analyzed for 
correlation with positive clinical outcomes. 
 Missing data will be ignored in statistical calculations while using the appropriate 
n (sample size) for any given statistic or test. 
 Patients who signed informed consent but did not receive the study treatment will 
not be included in the analyses.  
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
30 of 46 
 
8 MONITORING PLAN 
 
The investigators will allow onsite inspection of subjects’ source documentation as 
requested by the sponsor or required by an IEC, IRB or regulatory authorities.  
Monitoring activities may take place at the trial center or any ancillary facility where 
study conduct takes place. The investigators will provide access to all source 
documentation and adequate work space. The investigators will be available to the 
sponsor, IEC, IRB or other regulatory authorities to discuss study issues as requested. 
Data monitoring will occur at the sponsor’s discretion and consistent with sponsor’s 
quality policies and in all cases where data irregularities are identified.  As needed 
intermittent monitoring visits will be conducted to compare data entered into the 
database to an unsystematically selected sample of the subjects’ source documents.  
Monitoring efforts will be expanded if the sample suggests irregularities. 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
31 of 46 
 
9 DATA MANAGEMENT AND RECORD RETENTION 
 
Case report forms will be used to record demographic, procedural, and follow-up data. 
The subject data collected will be entered into a secure database by the clinician, 
designated staff or subjects (for online assessment completion). Subject data stored in 
the study database will be identified by the subject number and possibly subject initials.  
The unique number will identify the subject and will be included on all case report forms.  
Authorized representatives of the sponsor (i.e. the monitor[s], the auditor[s], the IEC will 
be granted direct access to the subject’s original medical records for verification of 
clinical trial procedures and/or data, as needed, to monitor the conduct of the study. By 
signing a written informed consent form, the subject or the subject’s legally acceptable 
representative is authorizing such access. The information obtained in this study may 
be published in scientific journals or presented at scientific meetings, however, the 
identity of individual participants will not be revealed. All records identifying the subject 
will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available.   
 
The investigators will maintain all study records for the minimum time required in the 
country in which the study is conducted.  
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
32 of 46 
 
10 AMENDMENTS TO THE STUDY PLAN 
 
Investigators will not modify, change or otherwise amend the protocol without prior 
written consent of the sponsor. As applicable, if a protocol amendment substantially 
alters the scientific validity of the study or affects the subjects’ rights, safety, welfare, or 
their willingness to continued participation in the study, the subject should generally be 
re-consented on an updated and approved (as required by local law and regulation) 
ICF.  New procedures or processes which substantially alter the scientific validity of the 
study or affects the subjects’ rights, safety, welfare, or their willingness to continued 
participation the study will not be implemented until an approval or favorable opinion 
has been granted by the reviewing IEC or IRB, as applicable. 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
33 of 46 
 
11 DEVIATIONS TO THE STUDY PLAN 
 
Investigators are not allowed to deviate from this CIP without prior authorization by the 
sponsor except under emergency situations when necessary to preserve the rights, 
safety or well-being of study patients. 
 
Deviations and non-compliances will be recorded together with an explanation. 
Deviations or non-compliances that impact the rights, welfare, or safety of patients shall 
be reported to the sponsor and IEC as required and as soon as possible. 
 
If appropriate, corrective and preventive actions will be discussed by the sponsor, 
investigator, and/or the IEC to determine a suitable course of action. 
 
Deviations from the CIP will be documented on the appropriate form. 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
34 of 46 
 
12 STATEMENT OF COMPLIANCE 
 
This protocol has been developed and the study will be run in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki (2013). Further the 
study will be run in compliance with ISO 14155 (2nd ed) 2011. Both investigators and 
sponsor will conduct this study in accordance with any applicable local or regional laws 
and regulations. 
Investigators will neither conduct procedures specific to the study nor collect subject 
data without prior approval or favorable opinion of any IEC or IRB under whose 
jurisdiction the conduct of this study falls. It is acknowledged that in some geographic 
areas IEC or IRB review and approval of study data collection activities may not be 
required. 
During the conduct of study activity, the investigators and the sponsor shall act in 
accordance with any further requirements as imposed by an IEC, IRB or other 
regulatory agency. 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
35 of 46 
 
13 SUSPENSION OR TERMINATION OF THE STUDY 
 
The study may be terminated at any time by the sponsor, however, follow-up of all 
enrolled patients will continue through the 12-month follow-up. The study will be closed 
and the data will be archived according to the appropriate regulations. 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
36 of 46 
 
14 ADVERSE EVENT AND SEFETY REPORTING 
 
14.1 Definitions 
Adverse Event 
An AE is any knee related untoward medical occurrence in a subject receiving nSTRIDE 
APS; it does not necessarily have to have a causal relationship with nSTRIDE APS. An 
AE can therefore be any knee related unfavorable and unintended sign (including 
abnormal laboratory finding), symptom, or condition temporally associated with the use 
of nSTRIDE APS whether or not considered related to nSTRIDE APS. 
Only events that occur during or after treatment can be considered AEs. An 
unanticipated AE is one that is not part of the normal disease profile and has not been 
previously documented in information about the device. 
Serious Adverse Event (SAE) 
An SAE is an AE that leads to 1 of the following conditions:  
 Death 
 Serious deterioration in the health of the subject that results in 1 of the following 
situations: 
 Life-threatening illness or injury 
 Permanent impairment of a body structure or a body function 
 Medical or surgical intervention to prevent permanent impairment to body 
structure or body function 
 Inpatient hospitalization or prolongation of existing hospitalization 
 
Fetal distress, fetal death, or a congenital abnormality or birth defect 
 
Adverse Device Effect (ADE) 
An ADE is an AE that is considered, upon assessment by the primary clinical 
investigator, related to the study device.  
 
Serious Adverse Device Effect  
A serious ADE is one that has resulted in any of the consequences characteristic of an 
SAE or that might have led to any of these consequences if suitable action had not 
been taken or intervention had not been made.  
 
Device Deficiency  
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, 
safety or performance. 
NOTE: Device deficiencies include malfunctions, use errors, and inadequate labeling. 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
37 of 46 
 
14.2 Adverse Event Assessments 
All knee related AEs, including the following will be documented on and adverse event 
form and assessed by the primary clinician with respect to relatedness, severity, and 
seriousness.  
 Observed or volunteered problems 
 Complaints  
 Physical signs and symptoms 
 Medical condition which occurs during the study, having been absent at baseline 
 Medical condition present at baseline, which appears to worsen during the study 
Each AE record will include a description of the event, date of onset, date of resolution, 
severity, treatment as applicable, relationship to study device, or procedure and 
seriousness. Each AE must be recorded separately. 
Severity will be assessed using the following definitions: 
 Mild: Aware of sign or symptom, but easily tolerated 
 Moderate: Discomfort enough to cause interference with usual activity 
 Severe: Incapacitating with inability to work or do usual activity 
Relationship to the study device or procedure will be assessed by the investigator 
using the following definitions: 
 Definitely Not: Evidence exists that the AE definitely has a cause other than the 
study procedure (e.g., pre-existing condition or underlying disease, intercurrent 
illness, or concomitant medication) and does not meet any other criteria listed.  
 Unlikely: A temporal relationship exists between the event onset and study 
procedure. Although the AE may appear unlikely to be related to the study 
procedure, it cannot be ruled out with certainty; and/or the event cannot be 
readily explained by the subject’s clinical state or concomitant therapies. 
 Likely: A temporal relationship exists between the event onset and the study 
procedure, and appears with some degree of certainty to be related based on the 
event symptoms and the nature of the study procedure. It cannot be readily 
explained by the subject’s clinical state or concomitant therapies.  
 Definitely: Strong evidence exists that the study procedure caused the AE. There 
is a temporal relationship between the event onset and the study procedure. 
There is strong mechanistic evidence that the event was caused by the study 
procedure. The subject’s clinical state and concomitant therapies have been 
ruled out as a cause. 
Seriousness, If the AE meets any of the SAE criteria mentioned in section 14.1, it is 
regarded as serious.  

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
38 of 46 
 
14.3 Adverse Event Reporting 
All AEs will be documented as described above and entered into the EDC system. 
 
As needed, reporting of AEs outside of study collection will be completed according to 
local laws and regulations. 
 
Device deficiencies must be reported to Zimmer Biomet within 2 business days using 
the  Product Experience Report.  
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
39 of 46 
 
15 CLINICAL STUDY ADMINISTRATION AND INVESTIGATORS 
 
15.1 Approval and Agreements 
The sponsor and the principal investigator for this clinical research center shall agree to 
this document and any modifications. A justification for any modifications will be 
documented. Signing the signature page provided within this document will indicate 
approval and agreement with the protocol and methods of modifying the protocol. 
15.2 Investigators 
The principal investigator’s, qualifications and contact information will be updated and 
maintained by the sponsor. The name(s) and address(es) of other institutions involved 
in the clinical investigation as well as a complete list of monitors along with their contact 
information will also be maintained by the sponsor. 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
40 of 46 
 
16 OTHER ETHICAL CONDUCT 
 
16.1 IEC Approval 
Prior to initiation of the study, the chairman or the recording secretary of the IEC 
charged with the responsibility of approving the investigation must sign the IEC approval 
form, and a copy of the approval will be retained by the sponsor.  
16.2 Informed Consent 
Prior to the performance of any study-specific procedures, the subject will have undergo 
a thorough informed consent procedure as described above (6.3.1). 
 
The ICF includes all of the relevant elements currently required by European regulations 
(ISO 14155), the Declaration of Helsinki of 1964, and its subsequent revisions. 
 
16.3 Patient Compensation for Injury 
All subjects participating in the study will have insurance coverage by the sponsor, 
which is in line with applicable laws and/or regulations. 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
41 of 46 
 
17 CONFIDENTIALITY 
 
The information contained herein is provided to you in confidence and should not be 
disclosed to others, without written authorization from Zimmer Biomet Biologics, except 
to the extent necessary to obtain informed consent from those persons to whom the 
device will be administered. 
 
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.  Subject 
names will not be supplied to the sponsor. Subject data will be stored in a computer 
database by the sponsor, maintaining confidentiality. Subjects in this database, will be 
identified by subject number. This number will identify the subject and will be included 
on all case report forms. Authorized representative of the sponsor (i.e. the monitor[s], 
the auditor[s], the IEC, and regulatory authorities) will be granted direct access to the 
subject’s original medical records for verification of clinical trial procedures and/or data, 
without violating the confidentiality of the subject, to the extent permitted by the 
applicable laws and regulations, and that by signing a written informed consent form, 
the subject or the subject’s legally acceptable representative is authorizing such access.  
Identities of individuals participating in clinical research will be kept as confidential as is 
possible within the law. While the information obtained in clinical studies may be 
published in scientific journals or presented at scientific meetings, the identity of 
participants will not be revealed. 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
42 of 46 
 
18 REPORTING 
 
At the completion of this study, the sponsor will analyze the data, generate a final 
report, and forward the report to all investigators. The investigators will submit a copy of 
the report to the reviewing IEC.   
 
The sponsor will notify the accredited IEC and the competent authority of the end of the 
study within a period of 90 days. The end of the study is defined as the last subject’s 
last visit.  
 
In case the study is ended prematurely, the sponsor will notify the accredited IEC and 
the competent authority within 15 days, including the reasons for the premature 
termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the 
study, to the accredited IEC and the Competent Authority. 
 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
43 of 46 
 
19 PUBLICATION POLICY 
 
All data, results and any intellectual property derived from the data or results of the 
study are the property of the sponsor. The sponsor may use the data as they deem 
necessary, such as for submissions to governmental regulatory authorities, disclosure 
to other investigators and scientific communications. Sponsor will engage investigators 
to actively participate in scientific communication production at the sponsor’s discretion. 
The sponsor recognizes the right of the investigators to publish data and results derived 
from the study. However, prior to submitting for publication, presentation, using for 
instructional purposes, or otherwise disclosing results obtained from the study, the 
investigators agree to allow the sponsor a period of at least 30 days to review the 
proposed publication or disclosure prior to its submission for publication or other 
disclosure. Publications or disclosures of study results shall not include confidential 
information belonging to the sponsor. If the proposed publication/disclosure risks the 
sponsor’s ability to patent any invention related to the study, the publication or 
disclosure will be modified or delayed for a sufficient time to allow the sponsor to seek 
patent protection of the invention. This statement does not give the sponsor any 
editorial rights over the content of a publication or disclosure, other than to restrict the 
disclosure of the sponsor’s confidential information. The Investigators may also request 
data summaries of all data in the study. These requests will be fulfilled at the sponsor’s 
discretion. If the written contract for study conduct includes publication provisions 
inconsistent with this statement, then that contract's publication provisions shall apply 
rather than this statement.  
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
44 of 46 
 
 
 
BIBLIOGRAPHY 
 
(1)  Buckwalter JA, Martin JA. Sports and OA. Curr Opin Rheumatol 2004 Sep;16(5):634-9.  
 
(2)  Kim HJ, Lee YH, Kim CK. Biomarkers of muscle and cartilage damage and inflammation 
during a 200 km run. Eur J Appl Physiol 2007 Mar;99(4):443-7. 
 
(3)  Lequesne MG, Dang N, Lane NE. Sport practice and OA of the limbs. OA Cartilage 1997 
Mar;5(2):75-86. 
 
(4)  Neidhart M, Muller-Ladner U, Frey W, et al. Increased serum levels of non-collagenous 
matrix proteins (cartilage oligomeric matrix protein and melanoma inhibitory activity) in 
marathon runners. OA Cartilage 2000 May;8(3):222-9. 
 
(5)  Brzusek D, Petron D. Treating knee OA with intra-articular hyaluronans. Curr Med Res 
Opin 2008 Dec;24(12):3307-22. 
 
(6)  Bonnet CS, Walsh DA. OA, angiogenesis and inflammation. Rheumatology (Oxford) 
2005 Jan;44(1):7-16. 
 
(7)  Abramson SB, Amin A. Blocking the effects of IL-1 in rheumatoid arthritis protects bone 
and cartilage. Rheumatology (Oxford) 2002 Sep;41(9):972-80. 
 
(8)  Fernandes JC, Martel-Pelletier J, Pelletier JP. The role of cytokines in OA 
pathophysiology. Biorheology 2002;39(1-2):237-46. 
 
(9)  Goldring MB. OA and cartilage: the role of cytokines. Curr Rheumatol Rep 2000 
Dec;2(6):459-65. 
 (10)  Goldring MB. The role of cytokines as inflammatory mediators in OA: lessons from 
animal models. Connect Tissue Res 1999;40(1):1-11. 
 (11)  Pelletier JP, McCollum R, Cloutier JM, Martel-Pelletier J. Synthesis of metalloproteases 
and interleukin 6 (IL-6) in human osteoarthritic synovial membrane is an IL-1 mediated 
process. J Rheumatol Suppl 1995 Feb;43:109-14.:109-14. 
 (12)  Vuolteenaho K, Moilanen T, Hamalainen M, Moilanen E. Effects of TNFalpha-
antagonists on nitric oxide production in human cartilage. OA Cartilage 2002 
Apr;10(4):327-32. 
 (13)  Kidd BL, Urban LA. Mechanisms of inflammatory pain. Br J Anaesth 2001 Jul;87(1):3-11. 
 (14)  Chambers MG, Bayliss MT, Mason RM. Chondrocyte cytokine and growth factor 
expression in murine OA. OA Cartilage 1997 Sep;5(5):301-8. 
 (15)  Pelletier JP, Faure MP, DiBattista JA, et al. Coordinate synthesis of stromelysin, 
interleukin-1, and oncogene proteins in experimental OA. An immunohistochemical 
study. Am J Pathol 1993 Jan;142(1):95-105. 
 (16)  Verbruggen G. Chondroprotective drugs in degenerative joint diseases. Rheumatology 
(Oxford) 2006 Feb;45(2):129-38. 
 (17)  Goldring MB. Anticytokine therapy for OA. Expert Opin Biol Ther 2001 Sep;1(5):817-29. 
 (18)  Goldring MB, Otero M, Tsuchimochi K, Ijiri K, Li Y. Defining the roles of inflammatory 
and anabolic cytokines in cartilage metabolism. Ann Rheum Dis 2008 Dec;67 Suppl 
3:iii75-82.:iii75-iii82. 
 (19)  Goldring MB. Update on the biology of the chondrocyte and new approaches to treating 
cartilage diseases. Best Pract Res Clin Rheumatol 2006 Oct;20(5):1003-25. 
 (20)  Shlopov BV, Gumanovskaya ML, Hasty KA. Autocrine regulation of collagenase 3 
(matrix metalloproteinase 13) during OA. Arthritis Rheum 2000 Jan;43(1):195-205. 
 (21)  Niissalo S, Hukkanen M, Imai S, Tornwall J, Konttinen YT. Neuropeptides in 
experimental and degenerative arthritis. Ann N Y Acad Sci 2002 Jun;966:384-99.:384-
99. 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
45 of 46 
 
 (22)  Arend WP, Malyak M, Guthridge CJ, Gabay C. Interleukin-1 receptor antagonist: role in 
biology. Annu Rev Immunol 1998;16:27-55.:27-55. 
 (23)  Cominelli F, Pizarro TT. Interleukin-1 receptor antagonist: a "novel" acute phase protein 
with antiinflammatory activities. J Clin Invest 1997 Jun 15;99(12):2813. 
 (24)  Dinarello CA. The role of the interleukin-1-receptor antagonist in blocking inflammation 
mediated by interleukin-1. N Engl J Med 2000 Sep 7;343(10):732-4. 
 (25)  Symons JA, Young PR, Duff GW. Soluble type II interleukin 1 (IL-1) receptor binds and 
blocks processing of IL-1 beta precursor and loses affinity for IL-1 receptor antagonist. 
Proc Natl Acad Sci UO S A 1995 Feb 28;92(5):1714-8. 
 (26)  Van Zee KJ, Kohno T, Fischer E, et al. Tumor necrosis factor soluble receptors circulate 
during experimental and clinical inflammation and can protect against excessive tumor 
necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci U S A 1992 Jun 
1;89(11):4845-9. 
 (27)  O'Shaughnessey K, Klaassen MA, Kaeding C, Lattermann C, Farr J, Hoeppner J, et al. 
Examining the cytokine profiles of whole blood and autologous protein solution of 
patients with OA: preliminary results. 2012. 
(28)   Baltzer AW, Moser C, Jansen SA, Krauspe R. Autologous conditioned serum 
(Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage 2009 
Feb 1;17(2):152-60. 
 
 

APSS-55-00  
 
CONFIDENTIAL 
Clinical Investigation Plan  
 Version 3.0 - 24 Feb 2016 
46 of 46 
 
APPENDIX A: Manufacturer’s Instructions for Use