A Prospective Multicenter Open-label Randomized Controlled Trial of Agili-C™ vs. Surgical Standard of Care (SSOC) for the Treatment of Joint Surface Lesions of the Knee
Phase: NA
Conditions: Cartilage or Osteochondral Defects in the Knee, Up to Moderate Osteoarthritis
Sponsor: Smith & Nephew, Inc.

Page  1 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
Protocol title:
A Post Approval Multicenter, Open-label, 
Randomized, Controlled Trial of Agili-C™  
vs. Surgical Standard of Care (SSOC) for 
the Treatment of Joint Surface Lesions of 
the Knee
Protocol number: CLN0021 Rev 8
This protocol and related documents are the confidential property of CartiHeal (2009) Ltd. 
No unpublished information contained herein may be disclosed without the prior written 
approval of CartiHeal (2009) Ltd.

Page  2 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
1.0
Table of Contents
1.0
TABLE OF CONTENTS
.............................................................................................2
2.0
STUDY PROTOCOL SYNOPSIS
.............................................................................................3
3.0
LIST OF ABBREVIATIONS
...........................................................................................11
4.0
BACKGROUND AND RATIONALE ...........................................................................................12
5.0
JUSTIFICATION FOR STUDY DESIGN.......................................................................................16
6.0
RESPONSE MEASURES
...........................................................................................25
7.0
STUDY METHODS AND PROCEDURE......................................................................................26
8.0
SAFETY AND MEDICAL DEVICE VIGILANCE.............................................................................39
9.0
DEFINITIONS
...........................................................................................39
10.0
STATISTICAL CONSIDERATIONS ...........................................................................................46
11.0
INTERIM ANALYSIS
...........................................................................................57
12.0
COMPLIANCE WITH IRB/EC REGULATIONS............................................................................58
13.0
COMPLIANCE WITH ELECTRONIC RECORDS; ELECTRONIC SIGNATURES REGULATIONS ..........58
14.0
CHANGES TO THE PROTOCOL
...........................................................................................58
15.0
SUBJECT CONFIDENTIALITY
...........................................................................................58
16.0
SUBJECT PRIVACY
...........................................................................................59
17.0
DOCUMENTATION
...........................................................................................59
18.0
SOURCE DOCUMENTS
...........................................................................................59
19.0
MONITORING PROCEDURE
...........................................................................................60
20.0
REGULATORY AND HEALTH AUTHORITY AUDITS ...................................................................61
21.0
HANDLING OF BIOLOGICAL SPECIMENS ................................................................................61
22.0
PUBLICATIONS
...........................................................................................62
23.0
RELEVANT PUBLICATIONS
...........................................................................................62
24.0
APPENDIXES
...........................................................................................64
APPENDIX 1: MRI PROTOCOL
...........................................................................................65
APPENDIX 2:  MRI DEFECT FILL ASSESSMENT METHOD....................................................................68
APPENDIX 3: WEIGHT BEARING X-RAY PROTOCOL ..........................................................................70
APPENDIX 4: OSTEOARTHRITIS KELLGREN AND LAWRENCE SCORE..................................................71
APPENDIX 5: AGILI-C™ SURGICAL TECHNIQUE.................................................................................73
APPENDIX 6: REHABILITATION RECOMMENDATIONS (MODIFIED FROM EBERT ET AL. 2012)...........79

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A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
2.0
Study Protocol Synopsis
Protocol No.:
CLN0021
Sponsor:
Adam Waksman, MVDr.
Director of Clinical Affairs – USA
CartiHeal
3 Reuten Dr. (2nd Floor)
Closter NJ, 07624
Title:
A Post Approval Multicenter Open-label Randomized Controlled Trial of Agili-
C™ vs. Surgical Standard of Care (SSOC) for the Treatment of Joint Surface 
Lesions of the Knee
Study Device:
 Agili-C™ is a porous scaffold designed for the treatment of joint surface 
lesions of the knee
Study Phase:
Post Approval Study
Study Type:
Interventional
Indication for Use:
The Agili-C™ scaffold is indicated for the treatment of an ICRS grade III or 
above knee-joint surface lesion(s), with a total treatable area of 1-7cm2 and 
without severe osteoarthritis (Kellgren-Lawrence grade 0-3)
Study Design:
Number of Centers: 22 
The subjects in the study will be randomized by site using variable block sizes.
The subjects in the study will be stratified by extent of osteoarthritis, defined 
dichotomously by the Kellgren–Lawrence grade: 
Strata I:   0 & 1
Strata II:  2 & 3
The study will recruit and take place in US and OUS sites 
Allocation: 2:1 (Agili-C™:SSOC)
Masking: Open-Label

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A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
Estimated Enrollment:
Up to 251 subjects who were enrolled into the Pivotal study and are 
continuing follow up  
Study Population:
Patients with joint surface lesions of the knee
Study Arms:
Experimental: Agili-C™
Control: Surgical Standard of Care 
Surgical Standard of 
Care Modalities  as per 
Algorithm (Control)
Surgical Care Modalities were chosen according to algorithm: 
Debridement (Deb.)
Microfracture (MFX)
Follow up:
60 months per subject 
Primary Study 
Objectives:
To evaluate the superiority of Agili-C™ vs. SSOC over long-term follow-up to 
60 months, as well as evaluating the long-term safety of the device.
Primary Endpoint:
Change from baseline to 60 months in the average overall KOOS score (Pain, 
Symptoms, QOL, ADL & Sports)
Safety Endpoint:
Adverse events, including serious adverse events, reoperations and revisions, 
up to 60 months
Confirmatory 
Secondary Endpoints:
This trial will have one primary endpoint and 6 confirmatory secondary 
endpoints for labeling purposes. These will be tested sequentially and Type I 
Error controlled hierarchically. Trial success will be declared if the primary 
endpoint has been met. Additional labeling claims will be made for 
confirmatory secondary endpoints met in sequence following success on the 
primary endpoint
Change from baseline to 60 months in KOOS Pain subscore
Change from baseline to 60 months in KOOS QOL subscore
Change from baseline to 60 months in KOOS ADL subscore
Change from baseline to 60 months in KOOS Symptoms subscore
Change from baseline to 60 months in KOOS Sports subscore

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A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
Overall KOOS responder rate (defined as an increase from baseline to 60 
months of  30 points on overall KOOS) 
Additional Secondary 
Endpoints: 
Change from baseline in average overall KOOS score (Pain, Symptoms, 
QOL, ADL & Sports) at 36 and 48Months
Change from baseline in IKDC Subjective Knee Evaluation at 36, 48 and 60 
Months
Change from baseline in Tegner score at 36, 48and 60 Months
Change from baseline in SF-12 v2 Physical Component Summary (PCS) 
score and Mental Health Component Summary (MCS) at 36, 48 and 60 
Months
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in patients with 
chondral lesions Change from baseline to 36, 48 and 60 months in the 
average overall KOOS score (Pain, Symptoms, QOL, ADL & Sports) in 
patients with osteochondral lesions
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in patients with single 
lesion
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in patients with multiple 
lesions  
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in patients without 
osteoarthritis (K/L 0-1)  
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in patients with 
osteoarthritis (K/L 2-3)  

Page  6 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in patients with total 
lesion(s) size 
  
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in patients with total 
lesion(s) size >3cm²  
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in patients without 
previous ligament reconstruction
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in patients with intact 
meniscus   
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in patients with 
previous partial meniscectomy 
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in patients with 
concomitant partial meniscectomy 
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in active patients 
Change from baseline to 36, 48 and 60 months in the average overall 
KOOS score (Pain, Symptoms, QOL, ADL & Sports) in non-active patients 
Inclusion Criteria:
1. 21 -75 years 
2.  Up to 3 treatable joint surface lesion(s), ICRS Grade III or above, on the 
femoral condyles and/or trochlea
3. Symptomatic total treatable area 1-7 cm2. Asymptomatic lesions will not 
be included in the calculation

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A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
4. Must be physically and mentally willing and able to comply with the post-
operative rehabilitation protocol and scheduled clinical and radiographic 
visits
5. Signed and dated  the IRB/Ethics Committee approved Informed Consent 
Form and HIPPA (if applicable)
6. Non-responsive to physical therapy for at least 3-4 weeks
Exclusion Criteria:
1. KOOS Pain Subscale score at baseline is less than 20 or more than 65 
(scale: maximum pain =0, pain free =100)
2. Bony defect depth deeper than 8mm, according to baseline MRI/X-
ray/arthroscopy
3. Articular cartilage lesions in the tibia or the patella, ICRS grades IVa or 
above 
4. Osteoarthritis of the index knee graded 4 according to the Kellgren-
Lawrence Grading
5. Significant instability of the index knee according to IKDC Knee 
Examination Form 2000, Grade C (abnormal) or D (severely abnormal)
6. Malalignment more than 8 degrees varus OR  8 degrees valgus according 
to standing X-ray
7. Lack of functional remaining meniscus, at least 5mm rim at the end of the 
procedure  
8. Meniscal transplantation in the past 6 months 
9. Any known tumor of the index knee
10. Any known history of intra-articular or osseous infection of the index knee
11. Any evidence of active infection anywhere in the body. Urinary Tract 
Infection (UTI)  patients can be included following antibiotic treatment, and 
provided that two consecutive cultures are negative (taken within at least 
2 weeks of each other)

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A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
12. Any known history of inflammatory arthropathy or crystal-deposition 
arthropathy
13. Any known systemic cartilage and/or bone disorder, such as but not 
limited to, osteoporosis, chondrodysplasia or osteogenesis imperfecta
14. Body Mass Index (BMI) > 35
15. Chemotherapy in the past 12 months
16. Any previous surgical cartilage treatment (such as: microfracture, ACI, 
OATS, etc.) in the index knee within the last 6 months
17.  Any previous ligamentous repair or malalignment correction in the index 
knee within the last 6 months
18. History of allergic reaction or intolerance of materials containing calcium 
carbonate or hyaluronate
19. Patient who is pregnant or intends to become pregnant during the study
20. History of any significant systemic disease, such as but not limited to: HIV, 
hepatitis, HTLV, syphilis, and coagulopathies
21. Known substance or alcohol abuse
22. Participation in other clinical trials within 60 days prior to the study or 
concurrent with the study
23. Known insulin dependent diabetes mellitus 
24. Unable to undergo either MRI or X-ray
25. Use of anticoagulation medication or antiaggregant medication; however 
up to 100 mg Acetylsalicylic acid (ASA) daily is allowed
26. Previous intra-articular steroid injection within the last 1 month
27. Prisoners
28. Uncontained lesion - Lack of vital bone wall, at least 2mm thick, 
completely surrounding the lesion - based on MRI/X-ray/arthroscopy
29. Inability to position the implant 2mm recessed relative to the articular 
surface  - based on MRI/X-ray/arthroscopy

Page  9 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
Methods:
Candidates will be evaluated by the investigator based on an MRI (NMT 
one year old),  X-ray (AP and Lateral; NMT one year old), clinical history 
and physical examination
Prior to Screening, the candidate will sign and date the ICF using the 
IRB/EC approved form in accordance with local regulations
Following signing of the informed consent, subjects will undergo Initial 
Screening using study questionnaires. 
The investigator will send the MRI and X-ray (AP and Lateral) for off-site 
evaluation. The X-ray will be evaluated by an independent radiologist, in 
order to determine the level of osteoarthritis according to Kellgren-
Lawrence grade.
In cases of K/L <4 and absence of clear exclusion criteria on MRI (as 
determined off-site), subjects will undergo Final Screening via 
Arthroscopy, not more than 90 days after Initial Screening. Arthroscopic 
findings will verify the subject's eligibility for study enrollment, and if 
found eligible will be Enrolled into the study and Randomized intra-
operatively into either Agili-C™ or SSOC
During the course of the procedure, mechanical-symptom generating 
lesions will be managed (such as synovectomy, loose body removal and 
partial meniscectomy)
o
Agili-C™:  Agili-C™ implantations will be performed via an 
arthrotomy or mini-arthrotomy procedure, using a designated 
surgical toolset 
o
SSOC: microfracture and/or debridement procedures will be 
performed arthroscopically according to standard practice 
Ligamentoplasty is not allowed concomitantly

Page  10 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
Follow-up will be performed at 2 weeks and at 3, 6, 12, 18 and 24 months 
post-procedure and yearly thereafter, until each patient reaches 60 
months follow up to evaluate the patient's knee condition and clinical 
health
Questionnaires will be completed at baseline and at 6, 12, 18 and 24 
months and yearly thereafter, until each patient reaches 60 months 
follow up.
Anterior-Posterior (A/P) and Lateral knee X-rays will be taken at 2 weeks 
and at 6, 12, 18, 24, 36, 48- and 60-months post procedure
Annual Knee MRI is optional, until each patient reaches 60 months follow 
up.
Knee and AE related medications will be recorded at each visit.
Patients that drop out or withdraw consent will not be replaced.
Statistical 
Considerations:
See Section 10.0

Page  11 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
3.0
List of Abbreviations
ACL = Anterior Cruciate Ligament
ADL=Activities of Daily Life
AE = Adverse Event
AIC = Akaike information criterion
ASA= Acetyl Salicylic Acid
CFR= Code of Federal Regulations
CIP = Clinical Investigation Plan (protocol)
CKC = closed kinetic chain
CPM = Continuous Passive Motion
CRA = Clinical Research Associate
CRF = Case Report Form
EAC = Endpoint Adjudication Committee 
EC = Ethics Committee 
FU = Follow up
FAS= Full analysis Set
FDA = Food and Drug Administration 
GCP = Good Clinical Practice
HA = Hyaluronic Acid
ICRS = International Cartilage Repair Score
IEC = Independent Ethics Committee
IFU= Information for User 
IKDC = International Knee Documentation Committee
IRB= Institutional Review Board
KOOS = Knee injury and Osteoarthritis Outcome Score
LFC = Lateral Femoral Condyle
LV = Last Visit
MCID= Minimum Clinically Important Difference
MCL = Medial Collateral Ligament

Page  12 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
MCSD= Minimal Clinically Significant Difference
MFC = Medial Femoral Condyle
MMRM = Mixed-Effect Model Repeated Measure
mITT= Modified intention to treat population 
MPFL = Medial Patellofemoral Ligament
MRI= Magnetic resonance imaging
NMT = Not More Than
NSAIDs=Non-Steroidal Anti-Inflammatory Drugs
OA = Osteoarthritis
OATS = Osteoarticular Transfer System
OKC = Open kinetic chain
OUS = Outside United States
PCL = Posterior Cruciate Ligament
PPS= Per Protocol Analysis Set
PSR = Periodic Summary Report
PRO = Patient Reported Outcome
ROM = Range of motion
SAE = Serious Adverse Event
SD = Source Documents
SDV = Source Document Verification
SSOC = Surgical Standard of Care
Trial Cohort = Patient Group for Efficacy Evaluation
US = United States
4.0
Background and Rationale
The development of the Agili-C™ implant was based on the innovative concept of using two 
well-known FDA-approved devices to create a scaffold for treating joint surface lesions. 

Page  13 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
4.1
Joint Surface Lesions
Joint surface lesions (JSL) involving the articular cartilage and the subchondral bone are a 
common clinical problem in orthopedics. JSL can be superficial, partial thickness cartilage 
defects, which do not involve the subchondral bone, and full thickness lesions which cross the 
osteochondral junction1. Lesions of the joint surface remain a major clinical challenge, due 
mainly to the poor self-healing ability of articular cartilage. If left untreated, these joint 
surface lesions can lead to secondary osteoarthritis (OA). Hence, symptomatic chronic full-
thickness defects of the knee joint surface require intervention for symptom relief and to 
prevent possible evolution towards OA. JSLs are very common, being reported in about 20% 
of all arthroscopic procedures2,3. JSLs are clinically important as they can be symptomatic and 
disabling, with pain and/or locking of the joint, and can lead to further cartilage loss and 
development of OA4. 
The natural history and consequence of JSLs in established OA joints has also been 
investigated. Davies-Tuck et al. prospectively recorded chondral lesions in a cohort of patients 
with osteoarthritis5. In this cohort, chondral injuries worsened in 81% of the cases and 
improved in only 4% over 2 years. In a similar prospective study, Wluka et al. showed that the 
presence of cartilage defects in patients with established symptomatic OA was associated 
with disease severity and was a predictor of joint replacement within 4 years6. 
In summary, JSLs can complicate and accelerate the course of OA. Thus, their treatment may 
be of functional benefit to the patient.
4.2
Coral Based Scaffolds 
Coralline skeletal material is composed of calcium carbonate in the crystalline form of 
aragonite. These biomaterials provide a three-dimensional (3D) structure with mechanical 
properties and high interconnected macroporosity (between 100 and 200 µm) required for 
vascular tissue ingrowth7. These characteristics are thought to confer aragonite its 

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A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
osteoconductive ability and make it suitable for bone repair. The calcium carbonate 
structures are gradually resorbed and replaced by functional bone tissue.
Coral derivatives are commonly used as a bone graft substitute and bone void fillers. Several 
products are FDA-cleared, for example, Pro-Osteon 200R (Biomet, K000515) and BoneMedik 
(Metabiomed, K070897) are biocompatible bone substitutes based on natural coral.  
4.3
Device Description
Agili-C™ is a porous scaffold designed for the treatment of knee-joint surface lesions. Agili-C™ 
consists of a porous, interconnected calcium carbonate (aragonite) derived from purified, 
inorganic coral exoskeleton (Figure 1). The lower part of the implant is composed of inorganic 
aragonite and the top of the implant is mechanically modified with drilled channels (Figure 
2). Histology performed by an independent laboratory in a series of preclinical studies 
confirmed the regeneration of hyaline cartilage, as demonstrated by the presence of collagen 
type II and aggrecan, and the lack of collagen type I in the repaired tissue, alongside the 
reconstruction of the subchondral bone.

Page  15 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
   Figure 1: Coral exoskeleton
Agili-C™ is supplied sterile in various sizes from 6-20mm in diameter and 8-15mm in length, 
conically shaped (2°chamfer/morse), enabling treatment of different sized lesions. The 
implant is intended for single use only, and should not be re-sterilized. Agili-C™ implantation 
should only be performed by qualified surgeons. Single or multiple implants can be used in 
the same joint.
      Figure 2: Agili-C™ implant
4.4
Mode of Operation
The Agili-C™ implant is composed of calcium carbonate in aragonite crystalline form. The 
implant is intended to treat knee-joint surface lesions. The Agili-C™ implant exhibits a 
combination of interconnected porous architecture and crystalline structure.  This study is 
intended to demonstrate the superiority of the Agili-C™ when compared to SSOC in the 
treatment of joint surface lesions.  

Page  16 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
4.5
Device Traceability
Each Agili-C™ implant is identified by a lot number, serial number and expiration date. The 
Sponsor will keep records to document the physical locations of all investigational devices 
from shipment of investigational devices to the investigation sites until their return or 
disposal. Device usage will be documented by Principal Investigator in the patient’s medical 
chart and on the study CRF.
5.0
Justification for Study Design
5.1
Study Design
The current study compares the efficacy and safety of the Agili-C™ implant to Surgical 
Standard of Care treatment in patients suffering from joint surface lesions of the knee. The 
patient population is heterogeneous, involving different kinds of joint surface lesions: focal 
lesions, osteochondral defects and mild to moderate osteoarthritis, including multiple 
defects. 
5.2
Current Treatment Options
The patient population in the study may suffer from a diversity of joint surface lesions. 
Currently, no gold standard treatment exists which is applicable for all types of joint surface 
lesions. Small focal defects are frequently treated by microfracture, while large, multiple and 
diffuse lesions are typically treated by debridement.
As shown in a series of clinical studies OUS, the Agili-C™ implant offers the potential to treat 
a wide range of joint surface lesions, such as: focal defects, large and degenerative lesions, 
osteochondral defects and mild to moderate osteoarthritis. 

Page  17 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
5.3
Control Group Treatment Algorithm
As no single, current therapy can be used as a single comparator for the treatment of the 
above-described defect range, the most appropriate approach is to compare the device with 
the current general practice (e.g. Surgical Standard of Care) that includes two surgical options: 
Debridement and Microfracture – according to the following algorithm (Figure 3): 
Figure 3: Control Group Treatment Algorithm
In accordance with this algorithm, in two subgroups there is a possibility for mixed treatment 
in the same joint, according to the lesion’s size. For example, a male patient, 42 years old, 
with K/L=3 and two symptomatic lesions: one lesion - 1.4cm2 on the trochlea, and another 
lesion - 5.2cm2 on the medial condyle, will be treated with MFX in the small lesion and 
debridement in the large lesion. 

Page  18 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
5.4
Flow Chart
Figure 4: Study Flowchart
FU visits3-11:
2W, 3M, 6M, 12M, 18M, 24M,
36M, 48M, 60M

Page  19 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
5.5
Study Objective
To evaluate the superiority of Agili-C™ vs. SSOC
5.6
Clinical Hypotheses
The underlying clinical hypothesis of this study is that the Agili-C™ implant is superior to SSOC 
according to the overall KOOS score (Pain, Symptoms, QOL, ADL & Sports) at 60 months 
relative to baseline.
5.7
Overall Study Design
This is a post approval, multicenter, open-label, randomized, and controlled trial of Agili-C™ 
vs. SSOC for the repair of joint surface lesions. Candidates will be evaluated by the investigator 
based on an MRI and X-ray (NMT one year old), clinical history and physical examination. Prior 
to Screening, the candidate will sign and date the ICF. Following signing of the informed 
consent, subjects will undergo Initial Screening using study questionnaires. The PI will send 
the candidate’s MRI and standing X-ray for off-site K/L assessment. In case of K/L<4 and 
absence of clear exclusion criteria as seen on baseline MRI, not more than 90 days after Initial 
Screening, subjects will undergo Final Screening via Arthroscopy. Arthroscopic findings will 
verify the subject's eligibility for study enrollment, and if found eligible will be enrolled into 
the study and randomized intra-operatively into either Agili-C™ or SSOC. Agili-C™ 
implantations will be performed via an arthrotomy or mini-arthrotomy procedure, using a 
designated surgical toolset. In SSOC, microfracture and/or debridement procedures will be 
performed arthroscopically according to standard practice. Follow-up will be performed at 2 
weeks and at 3, 6, 12, 18- and 24-months post-procedure and yearly thereafter, until each 
patient reaches 60 months follow up, to evaluate the patient's knee condition and clinical 
health. Questionnaires will be completed at baseline and at 6, 12, 18 and 24 months and 
yearly thereafter until each patient reaches 60 months follow up. Anterior-Posterior (A/P) and 
Lateral knee X-rays will be taken at 2 weeks and at 6, 12, 18, 24, 36, 48- and 60-months post 
procedure. Annual Knee MRI is optional. 

Page  20 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
5.8
Patient Population 
The patient population is composed of patients with joint surface lesions of the knee.
5.9
Indication for Use
The Agili-C™ scaffold is indicated for the treatment of an ICRS grade III or above knee-joint 
surface lesion(s), with a total treatable area of 1-7cm2 and without severe osteoarthritis 
(Kellgren-Lawrence grade 0-3).
5.10 Number of Subjects
Up to 251 subjects, who were enrolled into the Pivotal study and are continuing follow up.
5.11 Number of Centers, Randomization and Allocation
Number of Centers participating: 22.
The subjects in the study will be randomized by site using variable block sizes.
The subjects in the study will stratified by extent of osteoarthritis, defined dichotomously by 
the Kellgren-Lawrence grade: 
Strata I:   0 & 1
Strata II:  2 & 3
The study will recruit subjects in US and OUS sites. 
5.12 Treatment Groups
Experimental: Agili-C™ 
Control: Surgical Standard of Care (SSOC)
5.13 Inclusion Criteria
1. 21 – 75 years 

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2.  Up to 3 treatable, joint surface lesion(s), ICRS Grade IIIa or above, on the femoral 
condyles or trochlea
3. Symptomatic total treatable area 1-7 cm2. Asymptomatic lesions will not be included 
in the calculation
4. Must be physically and mentally willing and able to comply with the post-operative 
rehabilitation protocol and scheduled clinical and radiographic visits
5. Signed and dated the IRB/Ethics Committee approved Informed Consent Form and 
HIPPA if applicable
6. Non-responsive to physical therapy for at least 3-4 weeks
5.14 Exclusion Criteria
1. KOOS Pain Subscale score at baseline is less than 20 or more than 65 (scale: maximum 
pain =0, pain free =100)
2. Bony defect depth deeper than 8mm, according to baseline MRI/X-ray/arthroscopy
3. Articular cartilage lesions in the tibia or the patella, ICRS grade IVa or above 
4. Osteoarthritis of the index knee graded 4 according to the Kellgren-Lawrence Grading
5. Significant instability of the index knee according to IKDC Knee Examination Form 
2000, Grade C (abnormal) or D (severely abnormal)
6. Malalignment more than 8 degrees varus OR  8 degrees valgus according to standing 
X-ray
7. Lack of functional remaining meniscus, at least 5mm rim at the end of the procedure  
8. Meniscal transplantation in the past 6 months 
9. Any known tumor of the index knee
10. Any known history of intra-articular or osseous infection of the index knee
11. Any evidence of active infection anywhere in the body. Urinary Tract Infection (UTI) patients 
can be included following antibiotic treatment, and provided that two consecutive cultures 
are negative (taken within at least 2 weeks of each other)
12. Any known history of inflammatory arthropathy or crystal-deposition arthropathy

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13. Any known systemic cartilage and/or bone disorder, such as, but not limited to,  
osteoporosis, chondrodysplasia or osteogenesis imperfecta
14. BMI > 35
15. Chemotherapy in the past 12 months
16. Any previous surgical cartilage treatment (such as: microfracture, ACI, OATS, etc.)in 
the index knee within the last 6 months
17.  Any previous ligamentous repair or malalignment correction in the index knee within 
the last 6 months
18. History of allergic reaction or intolerance of materials containing calcium carbonate 
or hyaluronate
19. Patient who is pregnant or intends to become pregnant during the study
20. History of any significant systemic disease, such as, but not limited to, HIV, hepatitis, 
HTLV, syphilis, and coagulopathies
21. Known substance or alcohol abuse
22. Participation in other clinical trials within 60 days prior to the study or concurrent with 
the study
23. Known insulin dependent diabetes mellitus 
24. Unable to undergo either MRI or X-ray
25. Use of anticoagulation medication or antiaggregant medication; however up to 100 
mg Acetylsalicylic acid (ASA) daily is allowed
26. Previous intra-articular steroid injection within the last 1 month
27. Prisoners
28. Uncontained lesion - Lack of vital bone wall, at least 2mm thick, completely 
surrounding the lesion - based on MRI/X-ray/arthroscopy
29. Inability to position the implant 2mm recessed relative to the articular surface  - based 
on MRI/X-ray/arthroscopy

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5.15 Risks
The Agili-C™ implant is designed to treat joint surface lesions. The device is a biodegradable 
implant. The PI must be a qualified orthopaedic surgeon that has undergone pre-procedure 
training by the Sponsor.  Following are risks that may occur while using the device:
Improper implantation due to incorrect surgical technique and not according to the 
IFU.
Creation of an improper implantation site may lead to implant breakage, instability, 
implant loosening and device failure.  
The defect site must exhibit vital bone on its entire circumference otherwise implant 
integration may not occur.   
Incorrect orientation of implant positioning may lead to improper healing. 
The implant must be inserted into the defect in a pressed fit manner. Non-press fit 
positioning may lead to failure due to lack of implant integration. 
Implantation using a non-designated surgical toolset may lead to implant fracture or 
misplacement.
Incorrect use of the surgical toolset can lead to bone breakage, damage to 
neurovascular structures, bone cyst formation or improper implantation site creation. 
The surgeon must take into consideration the joint geometry especially with regard to 
notch, lateral and trochlear lesions. If there is a chance of bone wall violation during 
creation of the implantation site the implant should not be used.
The device is composed of a porous brittle material, applying excess mechanical 
pressure during insertion may lead to implant breakage and particle generation.  
Particulate debris may cause an inflammatory response.
If the implant is inserted at or above the articular cartilage, damage to the counter or 
adjacent tissue can occur, as well as particulate debris generation and synovitis. 

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Protruding edges, if left untreated, may lead to injury of nearby tissue. It is required 
that all implant sharp edges be removed, breakage of protruding edges may lead to 
fragment or particulate debris generation which may require removal. 
Idiosyncratic rejection reaction. 
Multiple implants may impinge, leading to implant fracture, bone fracture 
particulate debris and implant loosening and bone cysts may develop.
Effusion, swelling, pain, synovitis, and systemic fever can occur due to infection, 
pseudo-septic reactions, reactive arthritis or aseptic arthritis. 
Inflammation might lead to degeneration of other articular surfaces, as well as 
ligament laxity and joint deformity.  Large joint effusion might impact venous return 
and lead to leg edema. The neurovascular structures might be compromised.
Suboptimal tissue ingrowth might occur: e.g. partial ingrowth, overgrowth, fibrous 
tissue ingrowth or partial coverage of the implant.
Chronic pain reactions including complex regional pain syndrome might ensue.
Implantation within avascular necrosis or cyst may lead to lack of implant integration 
and implant failure.
Entrapment of soft tissue between the implant and the bone during implantation 
may lead to small gap followed by penetration of synovial fluid, lack of integration 
and cyst formation.
Muscle atrophy. 
These risks can be reduced significantly when the procedure is performed by a qualified 
orthopedic surgeon adhering to the IFU, trained in the use of the investigative device.  
5.16 Potential Benefit of the Study Device 
Proper use of the study device may provide reduction in pain and improved function with the 
concomitant improvement in quality of life and daily activities. However, participants in the 

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study may experience no direct benefit, although the findings from the investigation may 
benefit future patients with similar conditions.
6.0
Response Measures
6.1
Safety Measures
Adverse events, including serious adverse events, reoperations and revisions, up to 60 
months
6.2
Study Arms
6.2.1 SSOC Group
In the SSOC group, due to variety of pathologies, two surgical options are available to provide 
ideal treatment options. As part of the enrollment process, all patients will undergo 
arthroscopy.  Patients will be treated by MFX and/or Deb (Figure 3) as described in Section 
7.3, the surgical technique is according to standard of practice. All symptomatic lesions in the 
joint should be treated. 
6.2.2 Agili-C™Group
Agili-C™ is intended to be implanted following arthroscopy via a mini-arthrotomy or 
arthrotomy approach, using the designated surgical tools and surgical technique described in 
Appendix 5.   The size of the implant(s) will be determined according to the size of the lesion(s) 
by the investigator according to the following algorithm (Figure 5):

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Figure 5: Implant Size Algorithm
6.2.3  Concomitant Procedures
Non-lesion related concomitant procedures, such as synovectomy, partial meniscectomy, 
high tibial osteotomy (HTO) and loose body removal are allowed, however ligamentoplasty is 
not allowed as concomitant; applicable for both treatment groups.
In case an HTO is performed concomitantly, the type of procedure and fixation technique will 
be documented. Additionally, the amount of HTOs will be stratified between the treatment 
arms. 
7.0
Study Methods and Procedure
7.1
 Introduction 
Prior to enrollment of any study subjects, the PIs will undergo Agili-C™ specific surgical 
training to familiarize themselves with the Agili-C™ implantation, as well as training on the 

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use of the various PROs and scales and other specifics of the protocol. Weight bearing X-ray 
imaging will be performed according to protocol in Appendix 3.  
During the course of the study, subjects will be instructed to report any unusual signs or 
symptoms to the PI (or designee), who will solicit and record information about Adverse 
Events and Serious Adverse Events (AEs/SAEs), concomitant medications, therapies, and 
treatments. All reported AEs/SAEs will be documented on the appropriate case report form.  
7.2
 Subject Entry Procedures
7.2.1 Informed Consent Form and Subject Privacy
The purpose, procedures, risks, benefits, and alternatives to study participation will be 
discussed with each potential subject who has a knee surface lesion. Prior to any study-related 
procedures, the subject must sign an IRB/EC approved ICF and HIPPA Form (if applicable). If 
any new relevant information becomes available, the Sponsor will provide an updated ICF and 
HIPAA forms for IRB review and approval. The subject should personally sign and date the ICF 
and HIPAA forms. Upon signing the Informed Consent Form and authorization forms, the 
subject is considered to be a consenting individual in the study and receives a Subject Number 
that will be used on all documentation for the subject throughout the study. 
After signing the Informed Consent Form, the consenting individual can then proceed with 
the screening evaluation.  Surgery (Visit 2) must be performed within 1-90 days of signing the 
Informed Consent Form. During this period, if the subject decides to withdraw consent, the 
subject will then be considered as a screen failure. This will be captured in the screening log 
as well as in the CRF End/Exit form. 

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7.2.2 Withdrawal Criteria
The subject has the right to withdraw from the study at any time without consequences, as 
indicated in the Patient Informed Consent documentation.
7.3
Study Visits
7.3.1 Screening Visit (Visit 1)
Following signing an informed consent, as described in section 7.2.1, candidates will undergo 
Initial Screening that includes lesion(s) assessment according to MRI and X-ray (not more than 
1 year old), clinical history, physical examination and Patient Reported Outcome (PRO). A 
standing X-ray will be sent off-site for Kellgren–Lawrence evaluation to exclude K/L grade 4. 
The PI will be informed regarding subject eligibility according to K/L grade.
Initial Screening Visit (Visit 1) Activities: 
1. Sign Informed consent   
2. Assign Patient Number
3. Perform clinical examination 
4. Review standing X-ray (AP and lateral, NMT 1 year old)
5. Review MRI (NMT 1 year old) 
6. Record Medical history 
7. Determine initial eligibility according to available inclusion/exclusion criteria
8. The investigator will complete:
a. IKDC Knee Examination Form 2000
b. ICRS Knee History Registration
9. The patient will complete the following questionnaires: 
a. KOOS subscales
b. Tegner score
c.
 SF-12 Health Survey (v2)

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d. ICRS Cartilage Injury Standard Evaluation Form 2000 
e. 2000 IKDC Subjective Knee Evaluation Form 
10. Analgesic, anti-inflammatory and prescription medication recording
11. The patient’s MRI and standing X-ray (AP and lateral) will be sent off-site for OA 
evaluation according to Kellgren-Lawrence (K/L) score. In case of K/L < 4 (e.g. not 
severe OA) and absence of clear exclusion criteria as seen on the baseline MRI 
the PI will be informed that the patient is eligible for the study and the patient 
will continue to Visit 2.
In case of bilateral symptomatic knees, it is recommended that the most symptomatic knee 
be chosen for treatment in the study, as long as the inclusion/exclusion criteria are met. In 
case of equally symptomatic knees, the Investigator and the subject will determine which 
knee will be treated in the study. The knee that does not enter the study can be treated 
according to general practice.  If during Visit 2 (Final Screening/Procedure Visit (arthroscopy)), 
the knee chosen is found to not meet the inclusion/exclusion criteria, the patient will be 
determined to be intra-op ineligible and not be included in this study for both knees.
7.3.2 Final Screening/Procedure Visit (Visit 2)
Between 1 to 90 days after initial screening, subjects will undergo Final Screening (Visit 2) 
via arthroscopy. If found eligible, the subject will be enrolled into the study and 
randomized intra-operatively into either Agili-C™ or SSOC. Stratification will be performed 
based on K/L score performed off-site. 
For the SSOC group, lesion treatment will be determined according to subject's age, lesion 
size and K/L grade (Table 1) as per the control group selection algorithm (Figure 3).

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Table 1: SSOC Sequence of Selection Criteria
Criteria 
Initial Screening, at site 
(Visit 1)
X-ray evaluation, off-
site
(Visit 1)
Arthroscopy & Final Screening, 
at site (Visit 2)
Age
X
K/L grade
X
Lesion Size
X
Final Screening/Procedure Visit (Visit 2) Activities: 
1.
Review of inclusion/exclusion criteria
2.
Arthroscopy
3.
Final enrollment
4.
Randomization 
5.
Treatment (Agili-C™/ SSOC)
6.
Film implantation procedure
7.
Analgesic, anti-inflammatory and prescription medication recording
8.
Record AEs/SAEs 
9.
Complete surgery debriefing forms
Arthroscopy Procedure
The arthroscopy procedure will be conducted according to hospital practice. Once subjects 
have fulfilled all the inclusion and none of the exclusion criteria, they will be enrolled into the 
study and randomized. The arthroscopy procedure should be video recorded according to 
hospital practice and documented post-procedure by the PI or study team on the relevant 
CRF assessment forms. The following structures should be carefully assessed by visualization 
and palpation:
Synovia
Patellar surface
Trochlea surface
Medial and lateral condylar surface 

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Medial and lateral tibial surface
Medial and lateral meniscus
Cruciate ligaments
Additionally, each lesion, regardless if symptomatic or not and if treated or not, should be 
documented according to the following parameters: location, severity (ICRS grade) and size 
(maximum length and maximum width).  A company representative will be allowed to 
participate in the arthroscopy and to film the implantation procedure. 
Post-Procedure Treatment 
Recommended treatment for both groups is per the recommended rehabilitation protocol, 
see Appendix 6. 
7.3.3 Two weeks post-procedure ± 1.5 week (Visit 3)
1. Record Adverse events 
2. Analgesic, anti-inflammatory and prescription medication recording
3. X-ray (AP and lateral)
7.3.4 Three months post procedure visit ± 2 weeks (Visit 4) 
1. Analgesic, anti-inflammatory and prescription medication recording
2. Record AEs/SAEs
3. MRI will be performed at 3 months to an initial cohort of at least 25 patients 
per study groups to evaluate presence of cysts
7.3.5 Six months post-procedure ± 12 weeks (Visit 5)
1. Weight bearing X-ray (AP and lateral) 
2. The investigator will complete the IKDC Knee Examination Form 2000
3. The patient will complete the following questionnaires, either on-site or off-
site: 
a. KOOS subscales

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b. Tegner score
c.
 SF-12 Health Survey (v2)
d. 2000 IKDC Subjective Knee Evaluation Form 
4. Analgesic, anti-inflammatory and prescription medication recording, either 
on site or off-site
5. Record AEs/SAEs either on site or off-site
6. MRI will be performed at 6 months to an initial cohort of at least 25 patients 
per study groups to evaluate presence of cysts
7.3.6 Twelve months post-procedure ± 16 weeks (Visit 6)
1. MRI according to CartiHeal protocol
2. Weight bearing X-ray (AP and lateral) 
3. The investigator will complete the IKDC Knee Examination Form 2000
4. The patient will complete the following questionnaires, either on site or off-
site: 
a. KOOS subscales
b. Tegner score
c.
 SF-12 Health Survey (v2)
d. 2000 IKDC Subjective Knee Evaluation Form 
5. Analgesic, anti-inflammatory and prescription medication recording, either 
on site or off-site
6. Record AEs/SAEs, either on site or off-site
7. Off-site Defect fill evaluation (per MRI)
7.3.7 18 months post-procedure ± 16 weeks (Visit 7)
1. Weight bearing X-ray (AP and lateral) 
2. The investigator will complete the IKDC Knee Examination Form 2000

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3. The patient will complete the following questionnaires, either on site or off-
site: 
a. KOOS subscales
b. Tegner score
c.
 SF-12 Health Survey (v2)
d. 2000 IKDC Subjective Knee Evaluation Form 
4. Analgesic, anti-inflammatory and prescription medication recording, either 
on site or off-site
5. Record AEs/SAEs, either on site or off-site
7.3.8 24 months* post-procedure ± 16 weeks (Visit 8)
1. MRI according to CartiHeal protocol
2. Weight bearing X-ray (AP and lateral) 
3. The investigator will complete the IKDC Knee Examination Form 2000
4.  The patient will complete the following questionnaires, either on site or off-
site: 
a. KOOS subscales
b. Tegner score
c.
 SF-12 Health Survey (v2)
d. 2000 IKDC Subjective Knee Evaluation Form 
5. Analgesic, anti-inflammatory and prescription medication recording, either 
on site or off-site
6. Record AEs/SAEs, either on site or off-site
7. Off-site Defect fill evaluation (per MRI)
*Subjects that underwent surgical intervention in the index knee (interarticular surgery) prior 
to the 24M follow up visit, will complete up to 24-months of follow-up visits. These Subjects 
will not be asked to continue the study beyond the 24M follow-up visit.

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7.3.9 Annual post 24 months visits ± 16 weeks (until patient reaches 
60 months*)
1. Weight bearing X-ray (AP and lateral) 
2. The investigator will complete the IKDC Knee Examination Form 2000
3.  The patient will complete the following questionnaires, either on site or off-
site: 
a. KOOS subscales
b. Tegner score
c.
 SF-12 Health Survey (v2)
d. 2000 IKDC Subjective Knee Evaluation Form 
4. Knee and AE treatment related medication recording, either on site or off-
site
5. Record AEs/SAEs, either on site or off-site
6. MRI – optional
* Subjects that underwent surgical intervention in the index knee (interarticular surgery) 
after the 24M follow-up visit, will not perform additional follow-up visits, beyond the time 
of the event (unless additional visits are required to follow their medical condition).
7.4
Study Schedule  
Table 2: Study Schedule
Procedures
Screening 
Visit
Final 
Screening/
Procedure 
Visit
2 week
Post-
Procedure 
Visit
(± 1.5 
weeks)
3 µ, 6^, 12 
and 18  
Months 
Post-
Procedure
Visit
(± 16 
weeks)
24 
Months 
Post-
Procedure
Visit
(± 16 
weeks)
36 
Months 
Post-
Procedure
Visit
(± 16 
weeks)
48
Months 
Post-
Procedure
Visit
(± 16 
weeks)
60 
Months 
Post-
Procedure
Visit
(± 16 
weeks)
Unscheduled 
Visit
Number of 
Visit
Visit 1
Visit 2
Visit 3
Visits 4-7
Visit 8
Visit 9
Visit 10
Visit 11
Obtain 
Informed 
Consent
X

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Procedures
Screening 
Visit
Final 
Screening/
Procedure 
Visit
2 week
Post-
Procedure 
Visit
(± 1.5 
weeks)
3 µ, 6^, 12 
and 18  
Months 
Post-
Procedure
Visit
(± 16 
weeks)
24 
Months 
Post-
Procedure
Visit
(± 16 
weeks)
36 
Months 
Post-
Procedure
Visit
(± 16 
weeks)
48
Months 
Post-
Procedure
Visit
(± 16 
weeks)
60 
Months 
Post-
Procedure
Visit
(± 16 
weeks)
Unscheduled 
Visit
Assignment of 
Subject 
Number
X
Review 
Inclusion/ 
Exclusion 
criteria
X
X (intra 
operative)
BMI
X@
Medical 
History
X
Baseline MRI
X*
MRI according 
to CartiHeal 
protocol
X**
X**
X"
X"
X"
X***
Defect Fill 
Evaluation 
according to 
MRI, off-site
X
X**
Baseline 
standing X-ray 
(AP & Lateral)
X*
Weight 
bearing AP & 
Lateral X-ray
X#
X
X
X
X
X
X***
IKDC Knee 
Examination 
form 2000 
(Surgeon)
X
X
X
X
X
X
X##
OA 
Classification
Kellgren-
Lawrence 
score, off-site
X
ICRS Cartilage 
Injury 
Standard 
Evaluation 
Form 2000 
(Subject)
X

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Procedures
Screening 
Visit
Final 
Screening/
Procedure 
Visit
2 week
Post-
Procedure 
Visit
(± 1.5 
weeks)
3 µ, 6^, 12 
and 18  
Months 
Post-
Procedure
Visit
(± 16 
weeks)
24 
Months 
Post-
Procedure
Visit
(± 16 
weeks)
36 
Months 
Post-
Procedure
Visit
(± 16 
weeks)
48
Months 
Post-
Procedure
Visit
(± 16 
weeks)
60 
Months 
Post-
Procedure
Visit
(± 16 
weeks)
Unscheduled 
Visit
ICRS Knee 
History 
Registration 
(Surgeon)
X
SF-12 v2 
X
X
X
X
X
X
2000 IKDC 
Subjective 
Knee 
Evaluation 
Form
X
X
X
X
X
X
KOOS 
Subscales
X
X
X
X
X
X
Tegner score
X
X
X
X
X
X
mICRS 
cartilage 
injury 
mapping and 
classification
X
Arthroscopy 
and 
randomization
X
Knee and AE 
related 
medication 
recording
X
X
X
X
X
X
X
X
X
AEs/SAEs
X
X
X
X
X
X
X
X
Tissue biopsy 
with histology
X****
Video 
recording - 
Implantation 
procedure
X
@   Weight and Height, only at screening  
#    X-ray may be performed lying down or standing, per patient comfort
*    Screening MRI and X-ray must not be older than 1 year
** MRI and Defect Fill evaluation is performed at 12 and 24 months. Additionally, MRI will be performed at 3 
and 6 months to an initial cohort of at least 25 patients per study groups to evaluate presence of cysts

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  *** MRI and X-ray will be performed according to PI decision
**** According to PI decision if surgery is performed. The biopsy will be sent to a central lab.
µ The 3 month visit may take place ±2 weeks
^ The 6 month visit may take place ±12 weeks
  Not applicable for the 3 months visit
“ Optional MRI
  ## According to PI decision
7.5
Unscheduled Visit
Each time the subject returns to the study site, the PI (or designee) will solicit and record 
information about AEs, Knee and AE treatment related medications and therapies. All 
applicable procedures should be performed including MRI and X-ray (according to PI's 
decision).
7.5.1 Unscheduled Visit without Surgery  
Unexpected symptoms might lead to an unexpected visit. In such visits, the following should 
be performed: 
1. Investigator completes the IKDC Knee Examination Form 2000 (optional)
2. Knee and AE treatment related medication recording
3. Record AEs/SAEs
7.5.2 Unscheduled Visit with Surgery
In case of a secondary procedure, the following should be performed: 
1. Investigator completes the IKDC Knee Examination Form 2000 (optional)
2. ICRS cartilage repair assessment form (if applicable)
3. Record AEs/SAEs
4. Knee related and/or AE related medication recording
5. Tissue and/or implant removal and histology (if relevant) 
6. Video recording of the procedure with images captured (if applicable)

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The study protocol does not require a tissue biopsy. If clinically required, the tissue should be 
sent to a central lab for histological assessment as determined by the Sponsor.   The Sponsor 
should be notified in advance and a Sponsor’s representative will be allowed to participate in 
the procedure and film it. 
7.6
Compliance with Protocol
The PI is responsible for compliance with the protocol at the investigational site. The PI is also 
responsible for reporting all issues of protocol non-compliance to the respective IRB/EC and 
to the Sponsor. A representative of the Sponsor will make frequent contact with the PI and 
research staff and will conduct regular monitoring visits at the site to review subject and 
device accountability records for compliance with the protocol, e.g., subject eligibility criteria, 
randomization assignments, concomitant and subsequent procedures performed and follow-
up visit schedule. 
7.7
Discontinued Subjects 
The Principal Investigator will record on the CRF and will report to the Sponsor and the IRB/EC 
the reasons that subjects discontinue from the study, including subjects who sign the 
Informed Consent Form but do not proceed to randomization.
7.8
Study Termination 
If conditions arise during the study that indicate that the study or an investigational site 
should be terminated, the Sponsor will provide notification in accordance with 21 CFR and 
will advise the FDA, PIs, IRB/ECs, and appropriate institutional officials. The report will include 
the IDE number, the full name of the research protocol, the name(s) of the clinical 
investigators and the reason(s) for the suspension or termination. 
Conditions that may warrant termination of the study or site include, but are not limited to:
1.
Any unanticipated problems involving risks to human subjects or others 

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2.
Any instance of serious or continuing noncompliance with these regulations or the 
requirements or determinations of the IRB; or
3.
Any suspension or termination of IRB approval
4.
Study completion
7.9
Study Duration 
Study participation for an individual subject is expected to last up to 64 months, including the 
time to randomization and treatment (including arthroscopy) and the 60-month follow-up 
period. Study duration at each investigational site may last 6 to 7 years including recruitment 
phase, follow-up and close out. Study duration per patient will be up to 5 years total. 
7.10 Documentation
All tests will be performed prior to implantation procedure as required by the study protocol. 
Device handling will be recorded. The standard treatment and care provided to all subjects, 
alongside the application of the study device, will be performed and recorded in the subject’s 
medical files and on the appropriate study CRF. 
7.11 Deviations from Study Protocol
Any deviations from the study protocol should be notified to the Sponsor, documented on 
study deviation forms, and reported to the IRB/EC as required by local regulations.
8.0
Safety and Medical Device Vigilance
All adverse events occurring during the study will be recorded on the appropriate case report 
form page by the investigator.  The nature, severity and relation of the adverse event to the 
study device will be documented. If an adverse event occurs, the first concern will be the 
safety of the study participants. All AEs occurring during the study will be followed throughout 
the study until resolved or stabilized or until follow-up is no longer possible. 

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9.0
Definitions
9.1
Adverse Event (AE)
AE is defined as any untoward medical occurrence in a subject. This definition does not imply 
that there is a relationship between the adverse event and the device under investigation.  
An AE can therefore be any unintended sign, symptom, disease or injury or any untoward 
clinical signs (including an abnormal laboratory findings) in subjects, users or other persons 
whether or not related to the investigational medical device. The following should be 
reported as AE:
Untoward medical conditions or signs or symptoms that were absent before 
starting study treatment.
Untoward medical conditions or signs or symptoms present before starting 
study treatment and worsen (increase severity or frequency) after starting 
study treatment.
Abnormal laboratory findings.
Clinical signs or symptoms that require therapy.
9.2
Serious Adverse Events (SAE)
A SAE is an adverse event that:
Led to a death
Led to a serious deterioration in the health of the subject that:
Resulted in a life-threatening illness or injury.
Resulted in a permanent impairment of a body structure or a body function.
Required in-patient hospitalization or prolongation of existing hospitalization.
Resulted in medical or surgical intervention to prevent permanent 
impairment to body structure or a body function.
  Led to fetal distress, fetal death or a congenital abnormality or birth defect.

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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be serious when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above.
Inpatient hospitalization or prolongation of existing hospitalization means that hospital 
inpatient admission and/or prolongation of hospital stay were required for treatment of AE, 
or that they occurred as a consequence of the event. Hospitalization for elective treatment 
of a pre-study condition that did not worsen while on study and hospitalizations for treatment 
of non-adverse events (e.g. cosmetic surgery or diagnostic procedure) are not considered 
serious adverse events.
9.3
Adverse Events Classification
AEs reported by the subject or observed by the investigator will be individually listed on an 
adverse event form in the CRF as follows: the specific event or condition, whether the event 
was present pre-study, the dates and times of occurrence, duration, severity, relationship to 
study device and/or procedure, specific countermeasures, and outcome. 
Note: Event which was present pre-study is not considered as an adverse event unless it has 
worsened since the enrolment to the study.
All AEs will be characterized by the following criteria:
Intensity or Severity
Relatedness
Outcome
Treatment or Action Taken
AEs and SAEs are recorded as of Enrolment 
9.4
Intensity/Severity Definition
The intensity or severity of the AE will be characterized as follows:

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Mild: Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required.
Moderate:  Mild to moderate limitation in activity; some assistance may be needed; 
        no or minimal medical intervention/therapy required.
Severe:  Marked limitation in activity, some assistance usually required; medical  
  intervention/therapy required, hospitalization possible.
9.5
Relationship to Investigative Device or SSOC
The Investigator and Medical Director will separately evaluate and document the relationship 
between an AE or SAE to the investigative device or the SSOC according to the parameters 
defined in Table 3. In case of disagreement between the investigator's evaluation and the 
Medical Director's evaluation, an independent evaluator, a physician, well versed in safety 
assessments of medical device clinical trials, will evaluate the case and determine the 
relationship between an AE or SAE to the investigative device or the treatment procedure.
Table 3: Adverse Event Relationship Criteria
Relationship
Criteria
Unrelated 
The temporal sequence of the AE onset relative to treatment by the 
investigational device/SSOC is not reasonable.
OR
There is another obvious cause of the AE
Unlikely
related
The relationship with the use of the device/SSOC can be reasonably explained 
by another cause, but additional information may be obtained.
Possibly 
related
The relationship with the use of the investigational device/SSOC is weak but 
cannot be ruled out completely. Alternative causes are also possible (e.g. an 
underlying or concurrent clinical condition or/and an effect of another device, 
or treatment
Probably 
related
The relationship with the use of the investigational device/SSOC seems 
relevant and/or the event cannot reasonably explained by another cause, but 
additional information may be obtained.
Related
The AE can be explained only by the use of the investigational device/SSOC.

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Uncertain
The relationship between the AE and the device is uncertain
9.6
Outcome
The clinical outcome of the AE or SAE will be characterized as follows:
Death - The SAE CRF must be completed for this outcome.
Recovered - The patient returned to baseline status.
Ongoing - Patient did not recover and symptoms continue.
Recovered with sequelae - The patient has recovered but with clinical sequelae from 
the event.
Unknown - The patient outcome is unknown.
9.7
Treatment or Action Taken
The treatment or action taken after the occurrence of an AE or SAE will be reported as:
Interventional Treatment - Invasive intervention such as: surgery or intra-articular 
injection.
Non-surgical intervention - such as physical therapy
Medical Treatment - Medication initiated for event
None - No action is taken
9.8
SAE Reporting Requirements
9.8.1 Notification to the Sponsor: Initial and Follow-up
If the investigator identifies a SAE, a SAE report form must be completed and sent by email to 
the Sponsor and CartiHeal or entered into the eCRF within 24 hours of the investigator’s 
knowledge of the event. Copies of hospital case reports (i.e., hospital progress notes, results 
of applicable diagnostic tests, lab results and biopsy results) should be sent as soon as they 
become available. Autopsy reports and other documents, as applicable, should be sent upon 
request.

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Reports should be made to the CartiHeal’s Medical Director/Director of Clinical Affairs:
Dror Robinson
Tel: (972) 9 8810400
E-mail: dror@cartiheal.com; safety@cartiheal.com 
Adam Waksman
Tel: 1-201-7259663; 972-54-4273026 
E-mail: adam@cartiheal.com; safety@cartiheal.com 
The PI notification to the Sponsor should then be updated in the eCRF or by written 
notification when new/additional information is available. 
Any fatal or life-threatening event should be reported immediately. These preliminary 
reports will be followed as soon as reasonably possible by detailed descriptions that will 
include a completed SAE form, copies of hospital case reports, autopsy reports, and other 
documents, when requested and applicable.
If applicable, the investigator should also inform the representative of the appropriate IRB/ 
Ethics Committee, as per the local requirements. A copy of the report cover letter should be 
filed within the study file.
9.8.2 Follow- Up of Serious Adverse Events
Follow-up of SAEs that occur during the study will continue until their satisfactory resolution 
or stabilization.
If/when supplementary information is available, a follow-up SAE Report Form must be 
entered into the eCRF by the site or emailed within 24 hours to the Sponsor.
The contact information for follow up SAE reporting is the same as for initial SAE report (see 
above section). 
Once e-mailed, the SAE form and accompanying documentation should be placed in the 
Safety section of the investigator’s file. If supplementary information on a SAE has to be sent, 
the SAE form has to be used marked as ‘follow-up report‘.

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All other SAE/AEs will be followed for new information/resolution as possible, or may be 
defined as ‘ongoing without further follow-up by the Investigator and Sponsor’s decision.
9.9
Notification to Authorities
Events will be reviewed to determine any reporting obligations. Reporting will occur within 
the timelines described as per local regulations. Sponsor or designee will conduct and report 
the results of an evaluation to the appropriate authority and all participating investigators 
according to local regulations.  
9.10 Anticipated Adverse Events Related to the Implant include: 
Transient or chronic pain and/or swelling and/or effusion of the operated joint 
Bone marrow edema  
Allergic or pseudo-allergic reaction and/or elevation of acute phase reactants
Pseudo-septic reaction 
Reactive arthritis
Bone cyst, bone fracture, bone deformities or bone aseptic necrosis
Implant fracture, loosening or extrusion, with or without generation of particulate 
debris
Abrasion of counter or nearby tissues
Failure to induce tissue regeneration
Tissue hypertrophy or intra-lesional bone formation
Wound complications: 
o
superficial or deep infections  
o
septicaemia 
o
wound dehiscence
o
hematoma or site drainage

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Intra-articular adhesions, hypertrophic tissue, hypertrophic synovitis, intra-articular 
adhesion, hypertrophic synovium or host reactions 
Inflammation of the joint and surrounding tissues 
Joint locking and limited range of motion, stiffness and arthrifibrosis
Deep Vein Thrombosis
Infection and related symptoms
Elevation of the subchondral bone plate
Degeneration of the surrounding cartilage
Lack of cartilage integration 
Delamination
Progression of degenerative changes and osteoarthritis 
Muscle atrophy
9.11 Anticipated Adverse Events – Related to tool-set include:
Postoperative hematoma
Deformity or fracture of the bone 
Insertion of the tool can lead to a damage of nerve or vascular elements 
Heat damage to bone might occur especially with worn out drill bits 
Metal fragments might chip of the tools and lead to foreign body reaction 
Tool fragments might get stuck in the bone 
Failure to create an appropriate recipient site     
10.0 Statistical Considerations
10.1 Design Considerations 
This is a two-arm, post approval, open-label, randomized, multi-center study in which 
subjects are assigned to treatment (Agili-C™) or control (SSOC) in a 2:1 ratio. 
The subjects in the study were randomized by site using variable block sizes.

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The subjects in the study will be stratified by extent of osteoarthritis, defined dichotomously 
by the Kellgren–Lawrence grade: 
Strata I:   0 & 1
Strata II:  2 & 3
10.2 Analysis Populations
10.2.1 Safety Set
The safety population will consist of all patients for whom treatment with either Agili-C™ or 
SSOC was performed.
10.2.2 Full Analysis Set
The full analysis set (FAS) will consist of all treated subjects in the Agili-C™ arm and treated 
subjects in the SSOC arm, for whom there is a valid overall KOOS score at baseline and at 
least one valid overall KOOS score post-baseline.
Consistent with ICH-E9, subjects with major entry violations will be excluded from FAS. 
“Major” is defined by having the potential to affect trial results and the decision of whether 
an entry violation is considered major will be performed by the Medical Director.
FAS will be used for the primary analysis.
Treatment of missing data:
1. KOOS Subscale Score: 
As per KOOS scale guideline, subscale scores will be computed based on observed 
items only if not more than 2 items are missing. Where more than two items are 
missing, the KOOS subscale score will be scored missing. 
2. Overall KOOS Score:

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Overall KOOS Score will be defined as the average over the KOOS subscales, if not 
more than two subscales are missing. Where more than two KOOS subscales are 
missing, the Overall KOOS score will be scored missing.
10.3 Per Protocol Analysis Set (PP)
The PP analysis set is the subset of FAS Subject with no major protocol violations and with 
valid observations on the primary endpoint (Overall KOOS) at 12 months, at least. 
Treatment of missing data: missing data in the PP population will be dealt with using the 
same procedures described for FAS; i.e. subscale data will be scored as per user manual 
10.4 Treatment of Efficacy Data Following a “Failure”
For both Agili-C™ & SSOC groups, any secondary Invasive Intervention in the treated 
joint, regardless if related or unrelated to the original treatment, will be considered a 
Treatment Failure.  Invasive Intervention incudes: open procedure, mini-open 
procedure, arthroscopic procedure and any intra articular injections, such as: HA, 
PRP, steroids and stem cells. 
Subjects who are treatment failures will have their subjective questionnaires (i.e. 
KOOS, IKDC, Tegner and SF-12 Health Survey)  scores imputed as their baseline 
scores for analysis purposes.
For Agili-C™ group only:
Failure to implant the device in indicated patients will be considered 
Treatment Failure. However failure to implant the device in contraindicated 
patient/condition will not be considered Treatment Failure. The latter subjects 
will not be included in the efficacy analyses.

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10.5 Primary Analysis
The primary analysis will be conducted on the full analysis set using the same statistical 
models that were used in the analyses in the pivotal trial. The primary goal of the post 
approval study is to demonstrate superiority of the Agili-C™ device relative to SSOC at 
Month 60 by testing the hypothesis: 
H0 : 
1 = 0 vs. HA : 1 > 0.
Where 1 and 0 are the mean improvements in KOOS Overall score from baseline to Month 
60 for Agili-C™ and SSOC subjects, respectively. To test this hypothesis, the posterior 
probability of superiority: 
1 > 0 | Data) will be evaluated. The post approval study will 
have met its primary objective if the posterior probability exceeds 0.975 at the final analysis.
As noted above, subjects with ‘treatment failure’ have subsequent outcome values set to 
their baseline value. The analysis plan specifies that subjects with otherwise missing values 
are to have their missing values imputed through the Bayesian model. Month 60 
imputations are informed by observed data at earlier time points. Non-informative priors 
distributions are used in all analyses. The SAS procedure PROC BGLIMM (SAS Institute) will 
be used to determine the posterior probability that Agili-C™ is superior to SSOC in terms of 
mean changes from baseline to Month 60 in KOOS Overall Score.  The BGLIMM procedure is 
a sampling-based procedure that provides Bayesian inference for generalized linear mixed 
models (GLMMs). GLMMs are hierarchical models that combine a generalized linear model 
with normally distributed random effects. The “Bayesian approach estimates the joint 
posterior distribution of all parameters in a model, including all fixed- and random-effects 
parameters. The Monte Carlo method numerically integrates out the random effects and 
propagates the uncertainties to the marginal posterior of the fixed-effects parameters. 
PROC BGLIMM uses efficient Markov chain Monte Carlo (MCMC) sampling tools to estimate 
the posterior marginal distributions and use them for further inference” (SAS® 9.4 Help and 
Documentation ).

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Therefore, the statistical model used to determine the posterior probability of superiority is 
the Bayesian analogue to a Mixed Model for Repeated Measures (MMRM). The priors on 
the fixed effects are very diffuse normal distributions. The prior on the covariance matrix 
was made minimally informative by setting the degrees-of-parameter to a small value (0.5) 
and by setting the scale parameter to a relatively large value similar in magnitude to the 
variances observed for KOOS Overall Score changes. The Statistical Analysis Report, Version 
1.2, September 22, 2021 includes example SAS code for this analysis. 
The pivotal trial SAP, Section 9.5.2 specified that analyses of secondary endpoints will be 
done by “performing a repeated measures analysis using a mixed effects model with terms 
for treatment, visit, and treatment-by-visit interaction.” As was done for the pivotal trial, for 
comparison purposes, MMRM will  also be applied to the primary endpoint and continuous 
confirmatory endpoints as well as in covariate analyses designed to evaluate whether 
relative effectiveness varies among relevant subgroups. To provide meaningful within-group 
estimates from the Bayesian analysis, the values of the baseline score included as a 
covariate in the model will be mean centered based on the same analysis data set that 
served as input (i.e., FAS or PP as appropriate). This results in a within-group estimate at the 
mean value of the baseline covariate, which is also consistent with how SAS Proc Mixed 
constructs within group estimates for MMRM.
Two classes of subjects have their 24, 36, 48 & 60 month scores imputed. First, treatment 
failures (defined in section 12.3) have all scores subsequent to treatment failure imputed to 
the be their baseline values prior to the analysis.  Missing data for subjects lost-to-follow-up 
are either implicitly imputed using maximum likelihood methods or sampling-based 
methods or through the use of multiple imputation. The MMRM will utilize an unstructured 
covariance matrix which allows variances and covariances to vary over time.   

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10.6 Statistical Analyses 
10.6.1 Overview
The data will be summarized in tables listing the mean, standard deviation or standard 
error, median, minimum, maximum, and number of subjects in a group for continuous data 
(e.g. age, weight) or in tables listing count and percentage for categorical data (e.g. gender, 
previous surgical treatment). Data will be presented by visit and treatment arm. Data listings 
by subject will be provided. The effects of noncompliance, dropouts, and covariates, and 
their interactions with treatment will be assessed to determine the impact on the general 
applicability of results from this study. 
Primary and confirmatory secondary analyses will be conducted in the FAS. All efficacy 
endpoints will be tested on the FAS analysis set as well. Safety analyses will be conducted on 
the safety analysis set composed of all treated subjects.
Deviations from the current statistical considerations, should there be any, will be described 
in an amendment to the protocol and/or the statistical analysis plan (SAP). Any such 
deviations will be justified and described in the final report as appropriate. 
10.6.2 Subject Disposition
Subject disposition will be tabulated; the number of enrolled, treated, prematurely 
terminated, and completed subjects will be summarized separately according to treatment 
and by visit (where relevant). A list of dropouts will be prepared including treatment, reason 
for discontinuation and time of discontinuation. 
10.7 Efficacy 
10.7.1 Primary Endpoint Analysis
The primary endpoint analysis is described above in section 10.5.  Statistical power for 
testing the primary efficacy hypothesis was approximated as follows.  In the FAS, the mean 

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(SD, N) improvement was 43.0 (20.1, N=160) and 20.5 (20.9, N=79) among subjects treated 
with Agili-C and SSOC, respectively, or a group difference of 22.5. Since this is a 5-year study, 
for the purpose of sample size justification, it was assumed that the sample sizes would be 
75% as large, or 120 and 59, respectively.  It was further assumed that the SD would be 20% 
higher than the maximum of 20.1 and 20.9 or 25.  Under these assumptions, statistical 
power based on a pooled t-test with 1-sided type 1 error rate of 
 is 99%.  If the 
mean improvement at 5 years is only 80% as large as observed at Month 24 for Agili-C, i.e., 
34.4, or a group difference of only 13.9, then statistical power is 93.5%.  Under these 
assumptions, as long as the group difference in mean improvements from baseline to 
Month 60 is at least as large as 11.2, then power is at least 80%.  Further, these 
computations are conservative since the statistical modelling will include information for 
subjects up to the point of loss-to-follow-up. Therefore, statistical power appears adequate 
for confirming Month 60 superiority given the results from Month 24 and reasonably 
conservative assumptions. 
10.7.2 Secondary Confirmatory Endpoint Analyses
This trial has 6 confirmatory secondary endpoints that will be tested hierarchically in the 
order presented below to preserve overall Type I Error = 0.05. The following confirmatory 
hypotheses will be tested similarly to the primary endpoint as described in the preceding 
section:
Confirmatory I
H0: Change in KOOS QOL (Agili-C™) at 60M   Change in KOOS QOL (SSOC) at 60M
H1: Change in KOOS QOL (Agili-C™) at 60M  >  Change in KOOS QOL (SSOC) at 60M
Confirmatory II
H0: Change in KOOS Pain (Agili-C™) at 60M   Change in KOOS Pain (SSOC) at 60M
H1: Change in KOOS Pain (Agili-C™) at 60M  >  Change in KOOS Pain (SSOC) at 60M

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Confirmatory III
H0: Change in KOOS ADL (Agili-C™) at 60M   Change in KOOS ADL (SSOC) at 60M
H1: Change in KOOS ADL (Agili-C™) at 60M  >  Change in KOOS ADL (SSOC) at 60M
Confirmatory IV
H0: Change in KOOS Symptoms (Agili-C™) at 60M   Change in KOOS Symptoms (SSOC) at 
60M
H1: Change in KOOS Symptoms (Agili-C™) at 60M  >  Change in KOOS Symptoms (SSOC) at 
60M
Confirmatory V
H0: Change in KOOS Sports (Agili-C™) at 60M   Change in KOOS Sports (SSOC) at 60M
H1: Change in KOOS Sports (Agili-C™) at 60M  >  Change in KOOS Sports (SSOC) at 60M
Confirmatory VI
H0: Response Rate (Agili-C™) at 60M   Response Rate (SSOC) at 60M
H1: Response Rate (Agili-C™) at 60M  >  Response Rate (SSOC) at 60M
10.7.3 Definition of Overall KOOS Responder Rate
a. Response = increase from baseline to 60 months of  30 points on overall KOOS
b. Non-response = otherwise. 
Type I error will be controlled hierarchically, such that testing will be done on each endpoint 
only if the null has been rejected for all preceding endpoints.
10.7.4 Secondary Endpoint Analysis
Secondary analysis will repeat the primary and confirmatory efficacy analyses in the FAS 
population.  The FAS and PP differ by one Agili-C subjects.  Therefore, these analysis are 

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nearly identical and so  additional secondary endpoints will only be tested in FAS in order to 
reduce the number of statistical tests performed. 
Change from baseline in average overall KOOS score (Pain, Symptoms, QOL, ADL & 
Sports) at 36 and 48 Months
Change from baseline in IKDC Subjective Knee Evaluation at 36, 48 and 60 Months
Change from baseline in Tegner score at 36, 48 and 60 Months
Change from baseline QOL as measured by SF-12 v2 at 36, 48 and 60 Months
Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in patients with chondral lesions
Change from baseline to 60 months in the average overall KOOS score(Pain, Symptoms, QOL, 
ADL & Sports) in patients with osteochondral lesions
Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in patients with single lesion  
Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in patients with multiple lesions  
Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in patients without osteoarthritis (K/L 0-1)  
Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in patients with osteoarthritis (K/L 2-3)  
Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in patients with total lesion(s) size 
  
Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in patients with total lesion(s) size >3cm²  
Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in patients with previous ligament reconstruction  
Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in patients without previous ligament reconstruction
Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in patients with intact meniscus   

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Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in patients with previous partial meniscectomy 
Change from baseline to 636, 48 and 0 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in patients with concomitant partial meniscectomy 
Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in active patients
Change from baseline to 36, 48 and 60 months in the average overall KOOS score(Pain, 
Symptoms, QOL, ADL & Sports) in non-active patients
10.8 Safety
Safety analyses will be conducted on the safety analysis set. All AEs, including all SAEs and 
device/procedure related events (including possibly and probably relted), will be 
summarized and tabulated. In addition, the following will be monitored:
Secondary surgery rate
Conversion to major knee procedure, such total/partial knee arthroplasty (TKA) and 
osteotomies
Overall Failure Rate
10.9 Covariate Analyses
Covariate analyses will be done in FAS for the primary and secondary confirmatory endpoints 
by including each covariate of interest in the MMRM model, for both study groups, with one 
MMRM model per covariate listed below. Each covariate will appear in one MMRM. The 
covariates are the same summarized in the pivotal trial: 
Age (21-<45 vs 45-<65 vs 
 and 
 vs <50)
Gender
BMI 
 vs <30)
Lesion type (Osteochondral vs Chondral) based on ICRS Grade (worst across lesions) = 
Grade 4b and ICRS Grade (worst across lesions) = Grade 3 or 4a, respectively

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Single vs multiple lesions
Kellgren/Lawrence grade (0-1 vs 2-3)
Lesion size  (total area >3 mm2 vs <=3 mm2)
Previous ligament reconstruction (with or without)
Meniscus status (intact, previous partial meniscectomy, concomitant meniscectomy)
Pre-Injury Activity Status (active or inactive)
Smoking History (Current, Past, Never)  
Lesion Location (Femoral Condyle, Trochlea, Mixed)
US vs OUS Status
Note that the effect of interest is the Treatment x Covariate interaction term in the MMRM 
model. The tests will be conducted using a 0.15 significance level. Additionally, descriptive 
statistics will be provided by covariate level.
10.10 Sensitivity Analyses
As noted, the Bayesian and MMRM analyses implicitly impute missing data over time. 
These implicit imputations are valid under the missing at random (MAR) assumptions. The 
following sensitivity analyses will be performed to evaluate the if primary results depend on 
this assumption. 
Worst-Case Scenario assumes all missing values among Agili-C are equal to most 
negative observed change score, if feasible, else equal to 0 - [baseline value] and all 
missing values among SSOC are equal to most positive observed change score, if 
feasible, else equal to 100 - [baseline value].
If the superiority finding is lost in the Worst-Case Scenario, a tipping point analysis will 
be performed.  In this analysis, for each value X from the worst observed control 
subject to the best observed control subject, and for each value Y from the worse 
observed Agili-C subject to the best Agili-C subject, the primary analysis will be 
calculated imputing all missing Control subjects as X and all Agili-C subjects as Y, 
producing a grid over all plausible values for the control and Agili-C subjects. This grid 

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includes a worst case scenario, where all control subjects are imputed with the best 
observed control value and all Agili-C patients imputed as the worst observed Agili-C 
patient. The grid also includes a best case scenario, imputing controls as the worst 
control patient and Agili-C patients as the best observed Agili-C patients. The tipping 
point curve can be observed looking in the grid for the required values of (X,Y) that 
result in primary analysis success.
10.11 Poolability analyses
MMRM will beused to evaluate poolability and heterogeneity of treatment effects across 
subgroups. The following fixed factors will be included:
Covariate by group
Covariate by visit
Covariate by visit by group
The effect of interest is the Treatment x Covariate interaction term in the MMRM model, 
which will be tested using a 0.15 significance level.  The interpretation of this interaction is a 
treatment group difference in the mean improvement over time averaging across follow-up 
visits.  The significance of the three-way interaction is also summarized.  The three-way 
interaction reflects covariate differences in the way group differences vary over time.
11.0 Interim Analysis
Information regarding interim study progress and results, including: number of study sites, 
number of patients, and effectiveness (primary & confirmatory secondary endpoints on FAS 
population) and safety endpoints results, will be posted on the FDA PAS webpage after each 
interim progress report:
Milestone
Expected Date of Completion
1. Follow-up is completed for all study 
participants
February 2025
2. Interim Reports
October 2022

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October 2023
October 2024
3. Final study report
Q2 2025
12.0 Compliance with IRB/EC Regulations  
This study will be conducted in accordance with applicable regulations (U.S. 21 CFR for all 
centers and country specific regulations). The PI must obtain approval from a properly 
constituted IRB/EC prior to initiating the study and re-approval or review as required. The 
Sponsor is to be notified immediately if the responsible IRB/EC has been disqualified or if 
proceedings leading to disqualification have begun. Copies of all IRB/EC correspondence with 
the PI should be provided to the Sponsor.
13.0  Compliance with Electronic Records; Electronic Signatures Regulations 
This study will be conducted in compliance with the regulations on electronic records and 
electronic signature. 
14.0  Changes to the Protocol 
If it becomes necessary to amend the Clinical Investigation, the nature of the amendment will 
be agreed between the Sponsor and the Principal Investigator(s) and this will be recorded 
with a justification for the amendment. The appropriate IRB/EC and other applicable 
oversight committee as required will be informed of any amendments prior to 
implementation.
15.0  Subject Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities, but the subject’s names will not be disclosed in these documents. Appropriate 

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precautions will be taken to maintain confidentiality of medical records and personal 
information. 
16.0 Subject Privacy 
Written authorization will be obtained from each subject prior to enrollment into the study 
in accordance with the applicable privacy requirements (e.g., the Health Insurance Portability 
and Accountability Act Standards for HIPAA) and any local national regulations.
17.0 Documentation 
The PI will maintain a confidential Subject Contact List with the names and contact 
information for all subjects recruited for participation in the study, whether s/he enrolled, 
and reason(s) for those who do not enroll. Each subject will receive a unique Subject Number. 
The Subject Contact List will link the subject by name and Subject Number to this study. The 
PI will track the participation of enrolled subjects on a Study Visit Log, which identifies subjects 
by number and initials only. 
18.0 Source Documents 
Individual Subject records will be maintained in the PI’s Source Documents (SDs). Source 
documentation is generally considered to be the document on which the information or data 
point was first recorded. SDs may include a subject's medical records, hospital charts, clinic 
charts, and the PI’s study files as well as the results of diagnostic tests. Pertinent records 
related to the study, e.g., the subject’s medical chart, will be made available to the Sponsor 
representative on request with due precaution to protect the privacy of the subject. Personal 
identifying information (except subject initials) will be removed from any photocopies of 
relevant medical records and replaced with the unique Subject Number before submission to 
the Sponsor. The PI will protect the confidentiality of all subjects’ records within applicable 
laws. 

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18.1 Case Report Form (CRF) Completion 
The PI is responsible for ensuring that data are properly recorded on each subject's CRFs and 
related documents.  Source data must exist for all data entered in the CRF. 
18.2 Retention of Documentation
 Essential documents are any records that demonstrate the compliance of the subject, PI, 
Sponsor, and Monitor with the study protocol, with standards of GCP, and with all applicable 
regulatory requirements. Essential documents (including but not limited to study-related 
correspondence, subject records, subject privacy documentation, records of the distribution 
and use of all investigational devices, and copies of CRFs) should be retained and available for 
audit by the Sponsor’s auditor and regulatory authorities According to applicable  FDA and 
specific country regulation. These documents should be retained for a longer period, 
however, if mandated by the applicable regulatory requirements, by conditions imposed by 
the IRB/EC, or by an agreement with the Sponsor. It is the responsibility of the Sponsor to 
inform the PI when these documents no longer need to be retained.  The Sponsor requires 
that it be notified in writing if the PI chooses to store the records at a different physical 
address than the site address or if the PI wishes to relinquish ownership of the data so that 
mutually agreed-upon arrangements can be made for transfer of ownership to a suitably 
qualified, responsible person. 
19.0 Monitoring Procedure 
Appropriately trained representatives of the Sponsor will monitor the conduct of the trial at 
each investigational site, including visits to the site to review, audit, and retrieve copies of 
study-related documents. It is the responsibility of the PI to be present or available for 
consultation and to ensure that the Monitor has access to all study-related records during 
scheduled monitoring visits. The Monitor will review device accountability records and 
completed CRFs to ensure completeness and consistency with the source records and 
compliance with the protocol requirements. Study monitoring will be performed by a certified 

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CRO, in compliance with recognized GCP, FDA’s IDE guidance documents. On-site monitoring 
visits will ensure SDV and will include at least an initiation visit and any other visits that might 
be required during the study, and a final visit at the close of the study.
20.0 Regulatory and Health Authority Audits
The FDA, European Union authorities or local state health authorities (where applicable) may 
request access to all study records, including source documents for inspection. The PI and 
hospital staff are required to cooperate with these audits. The PI must notify the Sponsor of 
any health authority audit as soon as notification of such audit is made. A representative or 
designee of the Sponsor may also conduct similar audits and may be present during health 
authority audit.
21.0 Handling of Biological Specimens 
Tissue biopsy(ies) might be obtained if clinically indicated.  Biopsies can include: implants or 
parts of implants, synovial tissue, synovial fluid, cartilage, bone etc. Biopsies will be sent to an 
independent laboratory approved by the Sponsor, for analysis, as per the laboratory 
instructions. The specimens will be sent via an over-night delivery service. Routine biopsies 
are not recommended in this study. Biopsy samples for histological evaluation will be placed 
in formalin, securely sealed, and shipped to an independent laboratory for processing using 
established techniques and stains, such as hematoxylin and eosin (H&E), tri-chrome, or 
Safranin-O stain. A single board-certified pathologist who is experienced in histological 
evaluation of joint repair procedures will evaluate all slides from the study and will comment 
on the types and relative quantities of cells observed, the presence and status of the implant, 
the overall level of inflammation and any other interesting features. At the conclusion of the 
study, the laboratory and the pathologist will submit all tissue samples and slides to the 
Sponsor for retention with other essential study records (Section 18.2). The tissue samples 
and slides will not be used for any other purpose. Subject privacy concerns and biohazard 

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handling precautions will be paramount. All evaluation shall be conducted according to 
GCP/GLP.
22.0 Publications 
The Sponsor has a proprietary interest in this study. Authorship and manuscript composition 
will reflect joint cooperation among multiple investigators and sites and the Sponsor 
personnel. Authorship will be established prior to the writing of the manuscript. As this study 
involves multiple centers, no individual publications will be allowed prior to completion of the 
final report of the multicenter study except as agreed with the Sponsor.
23.0 Relevant publications 
1. Dell'accio F, Vincent TL. Joint surface defects: clinical course and cellular response in 
spontaneous and experimental lesions. Eur Cell Mater. 2010 Sep 28;20:210-7.
2. Curl WW, Krome J, Gordon ES, Rushing J, Smith BP, Poehling GG (1997) Cartilage 
injuries: a review of 31,516 knee arthroscopies. Arthroscopy 13: 456-460.
3. Hjelle K, Solheim E, Strand T, Muri R, Brittberg M (2002) Articular cartilage defects in 
1,000 knee arthroscopies. Arthroscopy 18: 730-734.
4. Ding C, Cicuttini F, Jones G (2008) How important is MRI for detecting early 
osteoarthritis? Nat Clin Pract Rheumatol 4: 4-5.
5. Davies-Tuck M, Wluka AE, Wang Y, Teichtahl AJ, Jones G, Ding C, Cicuttini FM (2008) 
The natural history of cartilage defects in people with knee osteoarthritis. 
Osteoarthritis Cartilage 16: 337-342.
6. Wluka AE, Ding C, Jones G, Cicuttini FM (2005) The clinical correlates of articular 
cartilage defects in symptomatic knee osteoarthritis: a prospective study. 
Rheumatology (Oxford) 44: 1311-1316.
7. Demers C, Hamdy CR, Corsi K, Chellat F, Tabrizian M, Yahia L: Natural coral exoskeleton 
as a bone graft substitute: a review. Biomed Mater Eng 2002, 12: 15-35.

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8. Le Graverand MP, Mazzuca,S, Lassere,M, Guermazi,A, Pickering,E, Brandt,K, Peterfy,C, 
Cline,G, Nevitt,M, Woodworth,T, Conaghan,P, and Vignon,E. Assessment of the 
radioanatomic positioning of the osteoarthritic knee in serial radiographs: comparison 
of three acquisition techniques. Osteoarthritis.Cartilage. 2006;14 Suppl A:A37-A43.
9. Botha-Scheepers S, Kloppenburg M, Kroon HM, Hellio Le Graverand MP, Breedveld 
FC, Ravaud P, Dougados M. Fixed-flexion knee radiography: the sensitivity to 
detect knee joint space narrowing in osteoarthritis. Osteoarthritis Cartilage. 2007 
Mar;15(3):350-3.
10. Broglio KR, Connor JT, Berry SM. Not too big, not too small: a goldilocks approach to 
sample size selection. Journal of Biopharmaceutical Statistics. 2014;24(3):685-705.

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24.0 Appendixes
1. Appendix 1: MRI protocol 
2. Appendix 2: MRI Defect Fill Assessment Method
3. Appendix 3: Weight bearing X-Ray Protocol
4. Appendix 4: Osteoarthritis Kellgren and Lawrence score
5. Appendix 5: Agili-C™Surgical Technique
6. Appendix 6: Recommended Rehabilitation Protocol 

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Appendix 1: MRI protocol 
Purpose: Optimal imaging of cartilage repair tissue of femoral condyles including the trochlea. 
MR Imaging (general protocol for 1.5T):
For all scans:  Field of view (FOV) 14cm; slice thickness 3-3.5mm; matrix 512 x 256(or 384);
Receiver bandwidth:  80-120Hx/pixel 
Coronal IW FSE no fatsat; TR 
 TE = 30-40ms
Coronal PDW FSE with fatsat; TR 
 TE = 10-20ms 
Sagittal IW FSE no fatsat; TR 
 TE = 30-40ms
Sagittal PDW FSE with fatsat; TR 
 TE = 10-20ms
Axial IW FSE no fatsat; TR 
 TE = 30-40ms
Axial T2W FSE with fatsat; TR 
 TE = 
Sagittal T1W no fatsat; TR = 600-800; TE = 10-20ms
Oblique PDW FSE with fatsat; TR 
 TE = 10-20ms oriented orthogonal to scaffold.
Slice orientations:
Coronal- parallel to a line drawn between the posterior femoral condyles on an axial image:  

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Sagittal- orthogonal to the line connecting the posterior condyles:
Oblique to scaffold- orthogonal to the articular surface at the repair site. Note, if there are 2 
or more scaffolds, more angled images may be required (2 examples shown below):  Only 
enough slices to cover the repair area are needed.
posterior femoral condyle  
  
Repair Site
*
*

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anterior femoral condyle
A
P
Repair Site*
*

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Appendix 2:  MRI Defect Fill Assessment Method
Defect Fill Assessment Method
Defect Fill (in both groups) immediately following the procedure is defined as zero. 
In the SSOC group, Defect Fill in each lesion will be measured separately and the patients 
Defect Fill score will be the averaged result of all lesions.
In the Agili-C™ group, Defect Fill for each implantation site (i.e. lesion), will be measured 
separately and the patients Defect Fill score will be the averaged result of all lesions.
Assessment Personnel 
The MRI images will be assessed in a blinded fashion off-site.  Two certified radiologists 
experienced in MRI evaluation of cartilage repair will assess each imaging study 
independently.  The degree of cartilage defect volume fill will be semi-quantitatively assessed 
by each radiologist separately in increments of 25% fill on a scale grade of 1-5 (i.e 0-24% fill 
[1], 25-49% fill [2], 50-74% fill [3], 75%-99% fill [4], and 100% fill [5]). When the radiologist's 
averaged scores differ by up to two grades, the two scores are averaged. When the 
radiologist's scores differ by two or more grades, a third blinded radiologist will assess the 
specific imaging study and then the three scores will be averaged.
Assessment Score
On each MRI scan, 2-3 slices located within the implant/lesion on a sagittal scan and 2-3 slices 
located within the implant/lesion on a coronal scan will be assessed by each examiner. To 
enable for accurate assessment, the radiologists will be provided an information regarding 
the number, size and location of the lesions. Each slice will be scored in 25% increments 
(Figure 6).  Results of these slices will be averaged.  Thus, each score is a composite average 
of 4-6 slices in both sagittal and coronal orientation. In certain notch lesions and trochlear 
lesions axial cuts allow better evaluation of the defect and thus will be used. In addition to 
average defect fill, minimum and maximum defect fill scores will be recorded (Figure 6). 

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1.
MRI date:
|__|__|__|
|__|__|
20|__|__|*
Month 
Day
Year
2.
Time Point:     
 12M   
 
 24M   
 Other _________ 
3.
Location*:
 Lateral Femoral Condyle 
(Anterior/Central/Posterior)  
 Medial Femoral Condyle 
(Anterior/Central/Posterior)  
 Central Trochlea
 Lateral Trochlea
 Medial Trochlea
 Other __________________
* In case of multiple implants/lesions in the same area, specify the location of each lesion/implant
4.
Defect Fill**: Degree of defect fill in comparison to adjacent cartilage
** In case of multiple implants/lesions, average the score of all implants/lesions 
Volume (excluding hypertrophy)
 1: 0-24% 
 2: 25-49%
 3: 50-74 %
 4: 75-99 %
 5: 100 %
Performed by: 
Signature
Date
_________________________      ______________________       _______________ (MMM/DD/YY)
Figure 6: Example of Defect Fill Assessment Form

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Appendix 3: Weight bearing X-Ray Protocol
The MTP method is used as it does not require fluoroscopic control.
The MTP protocol uses a horizontal X-ray beam and positions the first MTP joints beneath the front 
surface of the film cassette, the patellae in contact with the cassette and aligned vertically with the 
first MTP joints resulting in a knee angulation of approximately 7–10° flexion8.
Figure 7: Metatarsophalangeal PA view
Standing semiflexed knee or MTP position (posteroanterior view). The x-ray tube is positioned so 
that the central ray of the x-ray beam is horizontal, parallel to the floor and perpendicular to the x-
ray film. The radiographic technician identifies the position of the tibiofemoral joint space located 
midway between the inferior borders of the patella and the superior margin of the tibial tuberosity. 
The line of the joint space is traced around to the side of the knee and the skin marked with a felt tip 
pen. This mark is used to help align the center of the x-ray beam with joint space. The patient stands 
with both knees facing the film cassette, the feet slightly externally rotated at about 15°, as 
recommended by Botha-Scheepers et al (2007)9 in their assessment of the optimum foot position for 
knee radiography. The joint of the first MTP joint of each foot is positioned immediately below and 
in line with the front edge of the film cassette. The patient bends their knees so that the anterior 
surface of each knee touches the middle and front of the film cassette. The tube is positioned so that 
the X-ray beam is directed midway between the popliteal surface of the knees, and the tube’s 
positioning light is aligned with the horizontal plane of the joint space (as described above). This 
plane lies above the horizontal skin crease of the popliteal fossa.

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Appendix 4: Osteoarthritis Kellgren and Lawrence score
Source: http://radiopaedia.org/articles/kellgren-and-lawrence-system-for-classification-of-
osteoarthritis-of-knee, visited on January 21st, 2016
By Dr Tim Luijkx and Dr Vivek Pai et al.
The Kellgren and Lawrence system is a method of classifying the severity OA using five 
grades: 
K/L grade 
Description
Grade 0 
No radiographic features of OA are present 
Grade 1 
Doubtful joint space narrowing (JSN) and possible osteophytic 
lipping
Grade 2 
Definite osteophytes and possible JSN on anteroposterior weight-
bearing radiograph
Grade 3 
Multiple osteophytes, definite JSN, sclerosis, possible bony 
deformity
Grade 4 
Large osteophytes, marked JSN, severe sclerosis and definite bony 
deformity

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X-Ray date:
|__|__|__|
|__|__|
20|__|__|*
Month Day
Day
Year
Was AP x-ray available for analysis? 
Yes
No
Was lateral x-ray available for analysis?
Yes
No
Kelgren Lawrence Grade:                 
0      
1        
2       
3      
4
Patient Stratification:
    
 NO OA (K/L grades 0-1)    
 Mild to moderate OA (K/L grades 2-3) 
 Severe OA (K/L grades 4) - Patient is excluded
____________________           ___________________                      
Figure 8: X-ray Kellgren-Lawrence Evaluation at Screening

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Appendix 5: Agili-C™ Surgical Technique

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Appendix 6: Rehabilitation Recommendations (modified from Ebert et al. 2012) 
Immediately after surgery: 
Exercise: Quadriceps isometric sets
Up to 48 hours:
Physical treatment: Standard cryotherapy (ice packing)
Ambulation: Flat Foot weight-bearing as tolerated (WBAT) with crutches 
Up to 96 hours:
Exercise: Continuous passive motion (CPM) from 48 hours after the procedure
From 96 hours to 2 weeks: 
Exercise: During physiotherapy Knee ROM: passive & active ROM as tolerated
Exercise: isometric contractions & circulation exercises, CPM & cryotherapy
Week 3-6:
Exercise: Knee ROM: active ROM from 0-90° (week 3) to 0-125° (week 6)
Exercise: isometric/straight leg & passive/active knee flexion exercises, remedial 
massage, patella mobilization, CPM, cryotherapy & hydrotherapy
Exercise: Stationary cycling is introduced, provided that the patient had reached 
knee flexion of 100 degrees
Ambulation: Protected WBAT using crutches
Ambulation: Progressive load increase to full weight-bearing 
Week 7-12:
Exercise: Knee ROM: full active ROM (week 7)
Exercise: introduction of proprioceptive/balance activities, stationary cycling, 
walking, resistance & CKC activities
3-6 months:
Exercise: Introduction of more demanding OKC (terminal leg
extension) & CKC (inner range quadriceps and modified leg press) 
Exercise: Upright cycling, rowing ergometry & elliptical trainers

Page  80 of 80
A Post Approval Multicenter Open-label 
Randomized Controlled Trial of Agili-C™  vs. 
Surgical Standard of Care (SSOC) for the 
Treatment of Joint Surface Lesions of the Knee
CLN0021-US
 Rev. 8 
March 29, 2022
6-9 months:
Exercise: Increase difficulty of proprioceptive/balance, OKC & CKC exercises (ie. step 
ups/downs, squats)
Exercise: Introduce controlled mini trampoline
9-12 months: 
Exercise: Increase difficulty of CKC exercises (ie. lunge and squat activities on 
unstable surfaces)
Exercise: Introduction of agility drills relevant to patient’s sport
Exercise: Jogging
Return to competitive activity after 12 months