A 3-Year, Multicenter, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of Intra-articular Lorecivivint in Subjects With Osteoarthritis of the Knee in a Real-World Setting (STRIDES-EXTRA)
Phase: PHASE3
Conditions: Osteoarthritis of the Knee
Sponsor: Biosplice Therapeutics, Inc.

 
 
 
 
 
 
 
 
 
A 3-Year, Multicenter, Open-Label Study Evaluating the 
Safety, Tolerability, and Efficacy of Intra-articular 
Lorecivivint in Subjects with Osteoarthritis of the Knee in a 
Real-World Setting 
 
 
Study Number: SM04690-OA-17 
IND Sponsor: Biosplice Therapeutics, Inc. (a subsidiary of Samumed, LLC) 
Version Number: Amendment 00 Version 00 
Date:  16 April 2021 
 
 
 
 
 
 
 
This document is the sole property of Biosplice Therapeutics, Inc. This document and any and all 
information contained herein must be considered and treated as strictly confidential. This 
document shall be used only for the purpose of the disclosure herein provided. No disclosure or 
publication shall be made without the prior written consent of Biosplice Therapeutics, Inc. 
  
  
  

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SPONSOR SIGNATURE PAGE 
A 3-Year, Multicenter, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of 
Intra-articular Lorecivivint in Subjects with Osteoarthritis of the Knee in a Real-World Setting 
 
Protocol Number: 
SM04690-OA-17 AM00V00 
Date:  
 
16 April 2021 
 
Name & Title 
Signature 
 Date 
Mark Fineman, PhD 
Senior Vice President, 
Clinical Development 
Document has been electronically signed. Please see the final 
page of the viewable rendition for electronic signature(s). 
Christopher Swearingen, PhD 
Vice President, Biometrics 
Document has been electronically signed. Please see the final 
page of the viewable rendition for electronic signature(s). 
Ismail Simsek, MD 
Medical Director 
Document has been electronically signed. Please see the final 
page of the viewable rendition for electronic signature(s). 
 
Biosplice Therapeutics, Inc. commits to satisfying the requirements of the International Council for 
Harmonisation guideline for Good Clinical Practice (ICH-GCP) E6 (R2) regarding the responsibilities of 
the Sponsor, the United States (US) Code of Federal Regulations (CFR) 21 Title CFR Parts 50, 54, 56, 
312, and 314, and GCP Guidelines, as applicable. 
 
 

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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................................ II 
TABLE OF CONTENTS ............................................................................................................. 2 
LIST OF ABBREVIATIONS ...................................................................................................... 6 
STATEMENT OF COMPLIANCE ............................................................................................ 9 
1. 
PROTOCOL SUMMARY ................................................................................................. 10 
1.1 
SYNOPSIS ....................................................................................................................... 10 
2. 
INTRODUCTION ............................................................................................................... 18 
2.1 
STUDY RATIONALE ........................................................................................................ 18 
2.2 
BACKGROUND INFORMATION ........................................................................................ 18 
2.3 
POTENTIAL RISKS AND BENEFITS................................................................................... 19 
2.3.1 Known Potential Risks .............................................................................................. 19 
2.3.2 Known Potential Benefits ......................................................................................... 20 
2.3.3 Assessment of Potential Risks and Benefits ............................................................. 20 
3. 
OBJECTIVES AND ENDPOINTS ................................................................................... 20 
3.1 
OBJECTIVES ................................................................................................................... 20 
3.2 
STUDY ENDPOINTS ......................................................................................................... 21 
3.2.1 Safety Endpoints ....................................................................................................... 21 
3.2.2 Efficacy Endpoints .................................................................................................... 21 
4. 
STUDY DESIGN ................................................................................................................. 21 
4.1 
DESCRIPTION OF THE STUDY DESIGN ............................................................................. 21 
4.1.1 OA Treatment Algorithm .......................................................................................... 22 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN .................................................................. 23 
4.3 
JUSTIFICATION FOR DOSE............................................................................................... 23 
4.4 
END OF STUDY DEFINITION............................................................................................ 23 
5. 
STUDY POPULATION ..................................................................................................... 23 
5.1 
PARTICIPANT INCLUSION CRITERIA ............................................................................... 23 
5.2 
PARTICIPANT EXCLUSION CRITERIA .............................................................................. 24 
5.3 
LIFESTYLE GUIDELINES ................................................................................................. 25 
5.3.1 Contraception ............................................................................................................ 25 
5.4 
SCREEN FAILURES.......................................................................................................... 26 
5.4.1 Screen Failures .......................................................................................................... 26 
5.4.2 Subject Rescreening .................................................................................................. 26 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION ......................................................... 26 
5.6 
PARTICIPANT WITHDRAWAL OR TERMINATION ............................................................. 26 
5.6.1 Reasons for Withdrawal or Termination................................................................... 26 
5.6.2 Handling of Participant Withdrawals or Termination .............................................. 27 

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5.7 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ................................................. 27 
6. 
STUDY AGENT .................................................................................................................. 27 
6.1 
STUDY AGENT DESCRIPTION ......................................................................................... 28 
6.1.1 Acquisition ................................................................................................................ 28 
6.1.2 Formulation, Appearance, Packaging, and Labeling ................................................ 28 
6.1.3 Product Storage and Stability.................................................................................... 28 
6.1.4 Preparation ................................................................................................................ 28 
6.1.5 Dosing and Administration ....................................................................................... 28 
6.1.6 Route of Administration ........................................................................................... 29 
6.1.7 Starting Dose and Dose Escalation Schedule ........................................................... 29 
6.1.8 Dose Adjustments/Modifications/Delays ................................................................. 29 
6.1.9 Duration of Therapy .................................................................................................. 29 
6.1.10 Study Intervention Compliance ................................................................................ 29 
6.1.11 Device Specific Considerations ................................................................................ 29 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................ 29 
7. 
STUDY PROCEDURES AND SCHEDULE .................................................................... 30 
7.1 
STUDY PROCEDURES/EVALUATIONS .............................................................................. 30 
7.1.1 Study Specific Procedures ........................................................................................ 30 
7.1.2 Standard of Care Study Procedures .......................................................................... 33 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................... 34 
7.2.1 Clinical Laboratory Evaluations ............................................................................... 34 
7.2.2 Other Assays or Procedures ...................................................................................... 34 
7.2.3 Specimen Preparation, Handling, and Storage ......................................................... 35 
7.2.4 Specimen Shipment .................................................................................................. 35 
7.3 
STUDY SCHEDULE .......................................................................................................... 35 
7.3.1 Screening................................................................................................................... 35 
7.3.2 Enrollment................................................................................................................. 36 
7.3.3 Follow-Up ................................................................................................................. 37 
7.3.4 Additional Visits ....................................................................................................... 38 
7.3.5 Final Study Visit ....................................................................................................... 39 
7.3.6 Early Termination Visit ............................................................................................ 39 
7.3.7 Schedule of Events Table .......................................................................................... 41 
7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES ................................................................. 43 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................................. 43 
7.5.1 Precautionary Medications, Treatments, and Procedures ......................................... 43 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ...................................... 43 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ................................. 43 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ............................................. 43 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ....................................... 43 
8. 
ASSESSMENT OF SAFETY ............................................................................................. 44 

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8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................... 44 
8.1.1 Definition of Adverse Events (AE)........................................................................... 44 
8.1.2 Definition of Serious Adverse Events (SAE) ........................................................... 44 
8.1.3 Definition of Unanticipated Problems (UP) ............................................................. 45 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ...................................................................... 45 
8.2.1 Severity of Event....................................................................................................... 45 
8.2.2 Relationship to Study Agent ..................................................................................... 46 
8.2.3 Expectedness ............................................................................................................. 46 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ................. 47 
8.4 
REPORTING PROCEDURES .............................................................................................. 47 
8.4.1 Adverse Event Reporting .......................................................................................... 47 
8.4.2 Serious Adverse Event Reporting ............................................................................. 47 
8.4.3 Unanticipated Problem Reporting............................................................................. 48 
8.4.4 Events of Special Interest.......................................................................................... 48 
8.4.5 Reporting of Pregnancy ............................................................................................ 48 
8.5 
STUDY HALTING RULES ................................................................................................. 49 
8.6 
SAFETY OVERSIGHT ....................................................................................................... 49 
9. 
CLINICAL MONITORING .............................................................................................. 49 
10. STATISTICAL CONSIDERATIONS .............................................................................. 49 
10.1 
STATISTICAL AND ANALYTICAL PLANS ......................................................................... 49 
10.2 
STATISTICAL HYPOTHESES ............................................................................................ 49 
10.3 
ANALYSIS DATASETS ..................................................................................................... 49 
10.4 
DESCRIPTION OF STATISTICAL METHODS ...................................................................... 50 
10.4.1 General Approach ..................................................................................................... 50 
10.4.2 Analysis of the Safety Endpoints .............................................................................. 50 
10.4.3 Analysis of the Efficacy Endpoints........................................................................... 50 
10.4.4 Safety Analyses ......................................................................................................... 50 
10.4.5 Baseline Descriptive Statistics .................................................................................. 50 
10.4.6 Planned Interim Analyses ......................................................................................... 50 
10.4.7 Exploratory Analyses ................................................................................................ 51 
10.4.8 Sub-Group Analyses ................................................................................................. 51 
10.5 
SAMPLE SIZE .................................................................................................................. 51 
10.6 
MEASURES TO MINIMIZE BIAS ....................................................................................... 51 
10.6.1 Blinding Procedures .................................................................................................. 51 
10.6.2 Evaluation of Success of Blinding ............................................................................ 51 
10.6.3 Breaking the Study Blind/Participant Code .............................................................. 51 
11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ......... 51 
12. QUALITY ASSURANCE AND QUALITY CONTROL ................................................ 52 
13. ETHICS/PROTECTION OF HUMAN SUBJECTS ....................................................... 52 
13.1 
ETHICAL STANDARD ...................................................................................................... 52 

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13.2 
INSTITUTIONAL REVIEW BOARD .................................................................................... 52 
13.3 
INFORMED CONSENT PROCESS ....................................................................................... 53 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants ....... 53 
13.3.2 Consent Procedures and Documentation .................................................................. 53 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................. 53 
13.5 
FUTURE USE OF STORED SPECIMENS AND DATA ........................................................... 54 
14. DATA HANDLING AND RECORD KEEPING ............................................................. 54 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ........................................... 54 
14.2 
STUDY RECORDS RETENTION ........................................................................................ 54 
14.3 
PROTOCOL DEVIATIONS ................................................................................................. 55 
14.4 
PUBLICATION AND DATA SHARING POLICY ................................................................... 55 
15. STUDY ADMINISTRATION ............................................................................................ 56 
15.1 
STUDY LEADERSHIP ....................................................................................................... 56 
15.2 
KEY ROLES .................................................................................................................... 56 
16. LITERATURE REFERENCES ........................................................................................ 57 
APPENDIX 1. 
AMERICAN COLLEGE OF RHEUMATOLOGY CLINICAL AND 
RADIOGRAPHIC CRITERIA FOR CLASSIFICATION OF OSTEOARTHRITIS OF 
THE KNEE 
....................................................................................................................... 59 
APPENDIX 2. 
KELLGREN-LAWRENCE GRADING SCALE .................................... 60 
 
 
 

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LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
ACR 
American College of Rheumatology 
AE  
Adverse event 
AESEV 
Severity/Intensity Scale for Adverse Events 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 
ER 
Emergency room 
ET 
Early termination 
FAS 
Full analysis set 
FDA 
(US) Food and Drug Administration 
GCP 
Good Clinical Practice 
HA 
Hyaluronic acid 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HRQoL 
Health-related quality of life 
IA 
Intra-articular 

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Abbreviation 
Term 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IP 
Investigational product 
IQRMP 
Integrated Quality and Risk Management Plan 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
KL 
Kellgren-Lawrence  
KOOS 
Knee Injury and Osteoarthritis Outcome Score 
LDH 
Lactate dehydrogenase 
LOR 
Lorecivivint 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not clinically significant 
NRS 
Numeric rating scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
OA 
Osteoarthritis 
PASS 
Patient Acceptable Symptom State 
PCP 
Phencyclidine 
PRO(s) 
Patient reported outcome(s) 
PRP 
Platelet rich plasma 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SD 
Standard deviation 

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Abbreviation 
Term 
SF-12 
12-Item Short Form Health Survey 
SOP 
Standard operating procedure 
TUG 
Timed Up and Go 
UP 
Unanticipated problem 
US 
United States 
USPI 
US prescribing information  
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WOMAC 
Western Ontario and McMaster Universities Arthritis Index 
WPAI 
Work Productivity and Activity Impairment 
WPI&SS 
Widespread Pain Index and Symptom Severity Form 
 
 
 

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STATEMENT OF COMPLIANCE 
Study Title 
A 3-Year, Multicenter, Open-Label Study Evaluating the Safety, 
Tolerability, and Efficacy of Intra-articular Lorecivivint in Subjects with 
Osteoarthritis of the Knee in a Real-World Setting  
Protocol Number 
SM04690-OA-17 
Protocol Date 
16 April 2021 
Protocol Version 
AM00V00 
I have read and understand the protocol and agree to implement the study in accordance with the 
procedures set forth in the protocol and in accordance with the Sponsor's guidelines, all 
applicable government regulations, and the International Council for Harmonisation Guideline 
for Good Clinical Practice (ICH-GCP) E6 (R2). 
I will obtain Institutional Review Board/Ethics Committee (IRB/EC) approval of the protocol 
and Informed Consent Form (ICF) prior to enrollment of subjects in the study. I understand that 
any modifications to the protocol made during the course of the study must first be approved by 
the IRB/EC prior to implementation except when such modification is made to remove an 
immediate hazard to the subject. 
I will ensure that a fully executed IRB/EC-approved ICF is obtained from each subject prior to 
initiation of any study procedures.  
I will allow the Sponsor, Biosplice Therapeutics, Inc., and its agents, as well as the United States 
(US) Food and Drug Administration (FDA) and other regulatory agencies, to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner, ensuring subject 
confidentiality. If I am notified that this study is to be inspected by a regulatory agency, I will 
notify the Sponsor as soon as possible thereafter (no later than 48 hours). 
This protocol contains information that is proprietary to Biosplice Therapeutics, Inc. The 
information contained herein is provided for the purpose of conducting a clinical trial for 
Biosplice Therapeutics, Inc. 
The contents of this protocol may only be disclosed to study personnel under my supervision and 
to my IRB/EC. The contents of this protocol may not be disclosed to any other parties (unless 
such disclosure is required by government regulations or laws) without the prior written approval 
of Biosplice Therapeutics, Inc. 
 
__________________________________________ 
_______________________ 
Investigator’s Signature  
 
 
 
 
Date 
 
__________________________________________ 
 
Investigator’s Printed Name 
 

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1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
A 3-Year, Multicenter, Open-Label Study Evaluating the Safety, 
Tolerability, and Efficacy of Intra-articular Lorecivivint in Subjects with 
Osteoarthritis of the Knee in a Real-World Setting  
Objectives: 
 
Primary:  
The primary objective of this study is to assess the safety and tolerability 
of lorecivivint (LOR) alone and in addition to other standard of care intra-
articular (IA) treatments in subjects with knee osteoarthritis (OA). 
 
Secondary: 
The secondary objectives of the study are to evaluate: 
1. The efficacy of LOR assessed using patient reported outcomes (PROs) 
and functional measures 
2. The effects of LOR injections on health-related quality of life 
(HRQoL) and work productivity 
3. Treatment patterns of LOR, glucocorticoid, and hyaluronic acid (HA) 
injections in both knees of subjects with knee OA 
Endpoints: 
Safety Endpoints:  
1. Adverse events (AEs) and serious adverse events (SAEs) (incidence, 
severity, and relationship to LOR) 
2. Clinically significant changes in clinical laboratory measures and vital 
signs, as assessed by the Investigator 
 
Efficacy Endpoints: 
1. Change from baseline in pain numeric rating scale (NRS) score for the 
knee at Month 3 and annual visits, at each Unscheduled Injection Visit, 
and 3 months after each injection 
2. Change from baseline in Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) physical function subscore (WOMAC 
Function) at Month 3 and annual visits, at each Unscheduled Injection 
Visit, and 3 months after each injection  
3. Change from baseline in WOMAC total score and pain and stiffness 
subscores at Month 3 and annual visits, at each Unscheduled Injection 
Visit, and 3 months after each injection  
4. Change from baseline in the Knee Injury and Osteoarthritis Outcome 
Score (KOOS) subscales of Symptoms, Function (Sports), and Quality 
of Life at Month 3 and annual visits, at each Unscheduled Injection 
Visit, and 3 months after each injection  
5. Change from baseline in HRQoL (as measured using the 12-Item Short 
Form Health Survey [SF-12]) and Work Productivity and Activity 
Impairment (WPAI) at Month 3 and annual visits 

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6. Patient-Acceptable Symptom State (PASS) at Month 3 and annual 
visits 
7. Change from baseline in 40-meter walk test time at Month 3 and 
annual visits, at each Unscheduled Injection Visit, and 3 months after 
each injection (at a subset of sites) 
8. Change from baseline in the Timed Up and Go (TUG) test time at 
Month 3 and annual visits, at each Unscheduled Injection Visit, and 3 
months after each injection (at a subset of sites) 
9. Frequency of and interval between knee IA injections   
Methodology: 
This study will be a multicenter, open-label study. Up to 300 subjects will 
be enrolled. After a screening period of up to 14 days, subjects will receive 
an IA injection of 0.07 mg LOR into one or both knees, followed by a 36-
month evaluation period. Clinic visits will be scheduled at Day 1, and 
Months 3, 12, 24, and 36 (End of study [EOS]) or Early Termination (ET) 
for completion of all PRO measurements (WOMAC, KOOS, pain NRS, 
SF-12, PASS, WPAI), functional tests (40-meter walk test and TUG test at 
a subset of sites), and safety evaluations. On Day 1, the Charlson 
Comorbidity Index and Widespread Pain Index and Symptom Severity 
[WPI&SS] assessments will also be completed. A phone visit for safety 
follow-up will occur 4 weeks after the injection on Day 1. Refer to Figure 
1 for an overview of the study design. Subjects may also have 
Unscheduled Injection Visits for additional injections of LOR, 
glucocorticoid, or HA, as described in the OA Treatment Algorithm 
section below. Following each injection, subjects will return to the clinic 
for 3-Month Post-Injection Follow-Up Visits, unless another visit has 
occurred between the injection and the 3-month post injection date. At 
these injection visits and 3-Month Post-Injection Follow-Up Visits, 
subjects will complete PRO measurements and functional tests (at a subset 
of sites). 
Mode of Administration: Direct IA injection into one or both knee joints. 
LOR injections into the same knee must be separated by at least 6 months; 
glucocorticoid and HA injections must be performed in accordance with 
US prescribing information (USPI). 
OA Treatment 
Algorithm: 
LOR Injections: 
• On Day 1, after subject eligibility has been confirmed and subjects 
complete all PRO measurements and functional tests (at applicable 
sites), subjects will receive an IA injection of 0.07 mg LOR into 
one or both knees. Bilateral injections of 0.07 mg LOR are 
allowed.   
• Subjects may receive additional injections of LOR into one or both 
knees, as clinically indicated, at any time between Day 1 and 
Month 33 with the restriction that LOR injections into the same 
knee must be separated by at least 6 months; these injections can 

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occur at Unscheduled Injection Visits, 3-Month Post-Injection 
Follow-Up Visits, or at the Months 3, 12, or 24 visits after the 
completion of visit assessments. 
• For LOR injections after Day 1: Within 6 months of any knee 
surgery, LOR may not be injected in the affected knee without 
consultation with and documented approval from the Medical 
Monitor.  
Glucocorticoid and HA Injections: 
• Between Day 1 and Month 3, subjects are prohibited from 
receiving any injections other than LOR into either knee. 
• Subjects may receive injections of glucocorticoid or HA into one or 
both knees, as clinically indicated, at any time between Month 3 
and Month 33 with the restriction that glucocorticoid and HA 
injections must be performed in accordance with USPI; these 
injections can occur at Unscheduled Injection Visits, 3-Month Post-
Injection Follow-Up Visits, or at the Months 3, 12, or 24 visits after 
the completion of visit assessments. 
o For subjects who receive HA as a series of injections, the 
first injection can occur at an Unscheduled Injection Visit, 
3-Month Post-Injection Follow-Up Visit, or at the Months 
3, 12, or 24 visits after the completion of visit assessments. 
The subsequent injections in the series should be entered 
into the database as Unscheduled Visits (PRO 
measurements and functional tests do not need to be 
performed at these visits).  
General Injection Guidelines: 
• If receiving an injection for the indication of OA, subjects may 
only be injected in the knee(s) for which OA diagnosis has been 
confirmed based on ACR criteria (Appendix 1). If one of the 
subject’s knees did not fulfill ACR criteria at Screening, knee OA 
based on these criteria must be confirmed in that knee prior to the 
first injection at any time in the study.  
• Following each injection that occurs at or after the Month 3 visit, 
subjects will return to the clinic for a 3-Month Post-Injection 
Follow-Up Visit unless another visit has occurred between the 
injection and the 3-month post-injection date.  
o If a subject receives a glucocorticoid or HA injection for the 
indication of OA at a location different than the study site, a 
3-Month Post-Injection Follow-Up Visit should be 
scheduled unless another visit has occurred between the 
injection and the 3-month post-injection date. 

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o For subjects who receive HA as a series of injections, the 
first visit will be used to determine when the 3-Month Post-
Injection Follow-Up Visit should occur.  
• Bilateral injections are allowed and may occur at the same visit, but 
only one injection per knee can occur at any visit. 
• Prior to the injection(s), the Investigator should evaluate the subject 
for suitability to receive the injection(s). The subject should not 
have any condition that, in the opinion of the Investigator, 
constitutes a risk or contraindication for the injection(s). 
• Any knee that has undergone a partial or total knee replacement 
should not be injected.  

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Figure 1. Overview of study design  
 
 
Abbreviations: HA = hyaluronic acid; LOR = lorecivivint; PRN = pro re nata (when necessary)

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Inclusion/ 
Exclusion 
Criteria: 
Criteria for Inclusion: 
1. Males and females between 40 and 80 years of age, inclusive, in 
general good health apart from their knee OA 
2. Femorotibial OA by standard American College of Rheumatology 
(ACR) criteria (Appendix 1); knee OA is not to be secondary to 
any rheumatologic conditions (e.g., rheumatoid arthritis). 
3. Pain compatible with knee OA for at least 26 weeks prior to the 
Screening Visit 
4. Negative drug test for amphetamine, buprenorphine, cocaine, 
methadone, opiates, phencyclidine (PCP), propoxyphene, 
barbiturates, and benzodiazepine, unless any of these drugs are 
prescribed by a physician to treat a specific condition   
5. Subjects with depression or anxiety must be clinically stable for at 
least 12 weeks prior to the Screening Visit and, if on treatment for 
depression or anxiety, be on at least 12 weeks of stable therapy  
6. Full understanding of the requirements of the study and willingness 
to comply with all study visits and assessments 
7. Subjects must have read and understood the informed consent form 
(ICF), and must have signed and dated it prior to any study-related 
procedure being performed 
 
Criteria for Exclusion: 
1. Pregnant women, breastfeeding women, and women who are not 
post-menopausal (defined as 12 months with no menses without an 
alternative medical cause) or permanently surgically sterile 
(includes hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy) who have a positive or indeterminate pregnancy 
test result at Screening and Day 1  
2. Women who are not post-menopausal or permanently surgically 
sterile who are sexually active, and who are not willing to use birth 
control as outlined in Section 5.3.1 during the study period 
3. Any surgery (e.g., arthroscopy) in either knee within 26 weeks 
prior to Day 1 
4. Intra-articular (IA) injection into either knee with a therapeutic aim 
including, but not limited to, hyaluronic acid (HA), platelet-rich 
plasma (PRP), and stem cell therapies within 26 weeks prior to 
Day 1 or IA glucocorticoids within 12 weeks prior to Day 1 
5. Previous treatment with lorecivivint 
6. Participation in a clinical research trial that included the receipt of 
an investigational product (IP) or any experimental therapeutic 
procedure within 4 weeks or 5 half-lives, whichever is greater, 
prior to the Screening Visit, or planned participation in any such 
trial 

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7. Planned surgery scheduled during the study period that, in the 
Investigator’s opinion, would interfere with study conduct or 
evaluation, not including non-surgical invasive procedures 
conducted for a diagnostic or therapeutic purpose scheduled during 
the study period (refer to Section 7.6) 
8. Any condition that, in the opinion of the Investigator, constitutes a 
risk or contraindication for participation in the study or that could 
interfere with the study objectives, conduct, or evaluation 
9. Any comorbid condition that could affect study endpoint 
assessments of the knee, including, but not limited to, rheumatoid 
arthritis, psoriatic arthritis, systemic lupus erythematosus, gout or 
pseudogout, and fibromyalgia  
10. Any contraindications for an IA injection in the knee(s) to be 
injected at Day 1 in the opinion of the Investigator 
11. History of mania, bipolar disorder, psychotic disorder, 
schizophrenia, or schizoaffective disorder 
12. Any known active infections, including urinary tract infection, 
upper respiratory tract infection, sinusitis, suspicion of IA 
infection, hepatitis B or hepatitis C infection, and/or infections that 
may compromise the immune system such as human 
immunodeficiency virus (HIV) at Day 1 
13. Subjects who have a current or pending disability claim, workers’ 
compensation, or litigation(s) that may compromise response to 
treatment  
14. Subjects who are immediate family members (spouse, parent, child, 
or sibling; biological or legally adopted) of personnel directly 
affiliated with the study at any investigative site, or are directly 
affiliated with the study at any investigative site 
15. Subjects employed by Biosplice Therapeutics, Inc., or any of its 
affiliates or development partners (that is, an employee, temporary 
contract worker, or designee) responsible for the conduct of the 
study, or who are immediate family members (spouse, parent, 
child, or sibling; biological or legally adopted) of said employees 
responsible for the conduct of the study 
Population: 
Approximately 300 subjects with knee OA 
Phase: 
3b 
Number of Sites 
enrolling 
participants: 
Approximately 30 investigational centers 
 
 

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Description of 
Study Agent: 
LOR is a small-molecule Wnt pathway modulator that inhibits CLK2 and 
DYRK1A intranuclear kinases and thereby potentially (a) reduces signs 
and symptoms of knee OA via an anti-inflammatory mechanism and (b) 
inhibits breakdown and enhances formation of cartilage through effects on 
progenitor cells and chondrocytes resident in the joint. 
Study Duration: Approximately 5 years  
Estimated date first subject consented: June 2021 
Estimated date last subject completed: June 2026 
Participant 
Duration: 
Approximately 3 years  
Statistical 
Methods: 
Sample Size:   
The sample size is not based on statistical considerations. A sample size of 
300 subjects is a reasonable sample size to observe patterns of use of LOR 
and other IA injections. 
General approach: 
For continuous variables, number of subjects in the analysis, mean, 
standard deviation (SD), median, minimum, and maximum will be 
reported. All categorical endpoints will be summarized using frequencies 
and percentages.  
Safety Analysis: 
Safety assessments include physical examinations, vital signs, clinical 
laboratory tests, collection of AEs and concomitant medications, and 
general medical evaluations. No formal statistical analyses are planned. 
Safety will be evaluated based on the incidence, seriousness, and severity 
of AEs, and by changes in clinical laboratory parameters and vital signs, 
relative to pre-injection. 
Efficacy Analysis: 
Treatment response over time will be characterized. Response will be 
defined as both actual change as well as meeting response criteria. 
Additionally, outcomes will be characterized across time for those subjects 
seeking additional injections. Frequency of injections will also be 
summarized. 
 
 
 

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2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
Clinical studies of LOR to date have only administered LOR into one knee (the “target knee”) 
and on a fixed schedule (given once, given once every 6 months, or given every 12 months). In 
addition, in previous safety and efficacy studies, other injectable agents, specifically 
glucocorticoids and hyaluronic acid (HA), were prohibited. This study is being conducted to gain 
an understanding of how LOR is used when the previous clinical trial restrictions (i.e., unilateral 
use only, fixed injection schedule, and use with other agents) are removed, which should be more 
representative of real-life clinical practice if LOR were to be approved. This study will also 
provide information about safety and efficacy with longer-term use, as LOR has not previously 
been used in studies of more than 2 years in duration. 
2.2 
BACKGROUND INFORMATION  
OA is the most common form of arthritis and chronic joint disorder in man (Katz, Arant, and 
Loeser 2021). The exact causes of OA are unknown, but it is recognized as a disruption of 
homeostasis affecting the whole joint (Loeser et al. 2012). OA is characterized by the destruction 
of the articular cartilage, subchondral bone alterations, and synovitis. Patients present with pain 
and stiffness in the joints, with the joints becoming stiffer and more immobile over time 
(Lawrence, Felson et al. 2008).   
An estimated 10% to 15% of all adults aged over 60 have some degree of OA, with prevalence 
higher among women than men (WHO Department of Chronic Diseases and Health Promotion). 
The prevalence of OA is increasing due to population aging and an increase in related factors 
such as obesity. According to the United Nations, by 2050 people aged over 60 will account for 
more than 20% of the world’s population (World population to 2300). Of that 20%, a 
conservative estimate of 15% will have symptomatic OA, and one-third of these people will be 
severely disabled. This means that by 2050, 130 million people will suffer from OA worldwide 
(Maiese 2016). The prevalence of knee OA in US adults was an estimated 10.2%, totaling 24.7 
million individuals in 2019 (IHME 2021). Movement limitations are present in about 80% of 
persons with OA, and 25% are unable to perform major activities of daily living (Neogi 2013).  
Non-pharmacological management of OA (e.g., education, exercise, weight reduction) is 
considered core to OA management, but improvements may not provide sufficient relief and can 
be difficult to sustain (Gelse, Ekici et al. 2012). Pharmacological management, specifically 
nonsteroidal anti-inflammatory drug (NSAID) use, has shown only modest benefits on clinical 
outcomes and are not recommended for those who are frail or with cardiac or gastrointestinal 
comorbidities (Bannuru et al. 2019). Oral and transdermal opioid use are not recommended for 
the treatment of OA, due both to the limited therapeutic benefit and the potential for dependency 
(Hochberg et al. 2012). Finally, IA injections of corticosteroids may offer short-term pain relief, 
but may have detrimental long-term effects. IA hyaluronic acids have questionable efficacy in 
treatment of knee OA.  
One area of significant unmet need in the treatment of OA is the lack of pharmacological agents 
with disease-modifying properties. The development of agents with measurable, reliable disease-
modifying effects that also provide safe symptom relief has been identified as a significant need 

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in the treatment of OA (Gelse et al. 2012). Such agents could also potentially delay or reduce the 
need for joint replacement surgery, an end-stage option that may not be suitable for OA patients 
in whom surgical risk is deemed too high.  
The Wnt pathway is crucial in joint homeostasis and plays a central role in the initiation and 
progression of OA pathology (Monteagudo and Lories 2017). Mechanical stress/trauma on the 
joint has been shown to increase Wnt pathway signaling (Thomas et al. 2011) which, in turn, 
promotes cartilage degradation, tissue remodeling, and inflammation (Conaghan et al. 2019; Zhu 
et al. 2008; Zhu et al. 2009). These effects are associated with initiation and progression of 
disease in animal models of OA (Zhou et al. 2017). Moreover, Wnt signaling is upregulated in 
the joint tissue of patients with OA (Luyten, Tylzanowski, and Lories 2009). Thus, modulation 
of the Wnt pathway offers a potential disease modifying approach for OA treatment.  
LOR is a small-molecule inhibitor of cdc-like kinases (CLKs) and dual-specificity tyrosine 
kinases (DYRKs), delivered as an injection into the affected joint, where it locally reduces Wnt 
signaling and inflammation to ameliorate OA progression and symptoms, and protect joint 
health. Preclinical studies indicate that therapeutic modulation of Wnt signaling by LOR is a 
consequence of direct inhibition of CLK2-dependent alternative splicing of Wnt pathway genes. 
This leads to cartilage protection and chondrocyte differentiation in multiple laboratory models 
of OA. Concomitant inhibition of DYRK1A both enhances Wnt pathway modulation and 
reduces inflammatory cytokine production. Together, these observations indicate a mechanism of 
action whereby direct inhibition of CLK2 and DYRK1A activity by LOR leads to combined 
modulation of both inflammation and the Wnt pathway to provide symptom improvement and 
cartilage protection, and potentially promote chondrogenesis. 
LOR has been tested in a number of nonclinical and clinical studies. The results of those studies 
are included in the Investigator’s Brochure (IB). 
2.3 
POTENTIAL RISKS AND BENEFITS  
2.3.1 KNOWN POTENTIAL RISKS  
Lorecivivint  
The study drug LOR has risks and discomforts. The study drug LOR modulates the Wnt 
pathway. Refer to the IB for the known potential risks associated with LOR.  
Risks of Injection 
Risks associated with knee joint injection include infection and local site reactions such as 
erythema, irritation, and edema. 
Risks of Topical Anesthetics 
Reactions to the topical anesthetic drug that may be applied to the subjects’ skin are rare and 
may consist of cutaneous lesions (patches of skin that contrast with surrounding skin due to 
differences in texture, thickness, and color), or urticaria (red, raised itchy bumps). In addition to 
the local reactions, systemic reactions, although much rarer than the local ones, can be seen and 
include edema, bradycardia, dizziness, drowsiness, paresthesia, nausea, vomiting, or 
anaphylactoid reactions (generalized itching and hives, swelling, wheezing and difficulty 

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breathing, fainting, and/or other allergy symptoms). 
Blood Sampling 
There is some risk of pain or local bruising and infection at the site where blood is drawn for 
laboratory tests. There is also a small risk of a fainting episode, which can occur as a reaction to 
giving blood. 
2.3.2 KNOWN POTENTIAL BENEFITS  
Taking part in this study may or may not provide any benefit to the subject. Information from 
this study may help doctors learn more about treatments for OA and this information may help 
future patients, even if it may not help the subjects in this study. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
LOR is being considered as a new option for the treatment of knee OA. The safety assessments 
of LOR rely on data from product development and previous clinical trials. Based on nonclinical 
and clinical data, the conduct of the trial is regarded as justifiable at the planned dose and 
duration. Previous clinical trials (SM04690-01, SM04690-OA-02, SM04690-OA-04) involving 
over 1000 subjects identified no SAEs that were considered related to study medication. In 
previous trials, LOR was safe and well tolerated at single doses of 0.23 mg per injection, 
exceeding the 0.07 mg single dose used in the current study. Additional information about safety 
data from nonclinical and clinical studies of LOR is in the IB. 
Risks to subjects will be minimized by clinical safety oversight performed by centralized review 
and conducted by Medical Monitors per the Medical Monitoring Plan. In addition, appropriate 
review of data will be conducted by Clinical Research Associates. 
Taking the above information into account, an assessment of risks and benefits supports the 
current study designed to investigate LOR as a potential therapy for patients with knee OA. 
3. 
OBJECTIVES AND ENDPOINTS 
3.1 
OBJECTIVES 
Primary:  
The primary objective of this study is to assess the safety and tolerability of lorecivivint (LOR) 
alone and in addition to other standard of care intra-articular (IA) treatments in subjects with 
knee osteoarthritis (OA). 
 
Secondary: 
The secondary objectives of the study are to evaluate: 
1. The efficacy of LOR assessed using patient reported outcomes (PROs) and functional 
measures 
2. The effects of LOR injections on health-related quality of life (HRQoL) and work 
productivity 
3. Treatment patterns of LOR, glucocorticoid, and hyaluronic acid (HA) injections in both 
knees of subjects with knee OA 

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3.2 
STUDY ENDPOINTS 
3.2.1 SAFETY ENDPOINTS 
1. Adverse events (AEs) and serious adverse events (SAEs) (incidence, severity, and 
relationship to LOR) 
2. Clinically significant changes in clinical laboratory measures and vital signs, as assessed by 
the Investigator 
3.2.2 EFFICACY ENDPOINTS 
1. Change from baseline in pain numeric rating scale (NRS) score for the knee at Month 3 and 
annual visits, at each Unscheduled Injection Visit, and 3 months after each injection 
2. Change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) physical function subscore (WOMAC Function) at Month 3 and annual visits, at 
each Unscheduled Injection Visit, and 3 months after each injection  
3. Change from baseline in WOMAC total score and pain and stiffness subscores at Month 3 
and annual visits, at each Unscheduled Injection Visit, and 3 months after each injection  
4. Change from baseline in the Knee Injury and Osteoarthritis Outcome Score (KOOS) 
subscales of Symptoms, Function (Sports), and Quality of Life at Month 3 and annual visits, 
at each Unscheduled Injection Visit, and 3 months after each injection  
5. Change from baseline in HRQoL (as measured using the 12-Item Short Form Health Survey 
[SF-12]) and Work Productivity and Activity Impairment (WPAI) at Month 3 and annual 
visits 
6. Patient-Acceptable Symptom State (PASS) at Month 3 and annual visits 
7. Change from baseline in 40-meter walk test time at Month 3 and annual visits, at each 
Unscheduled Injection Visit, and 3 months after each injection (at a subset of sites) 
8. Change from baseline in the Timed Up and Go (TUG) test time at Month 3 and annual visits, 
at each Unscheduled Injection Visit, and 3 months after each injection (at a subset of sites) 
9. Frequency of and interval between knee IA injections 
4. 
STUDY DESIGN  
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This study will be a multicenter, open-label study. Up to 300 subjects will be enrolled. After a 
screening period of up to 14 days, subjects will receive an IA injection of 0.07 mg LOR into one 
or both knees, followed by a 36-month evaluation period. Clinic visits will be scheduled at Day 
1, and Months 3, 12, 24, and 36 (End of study [EOS]) or Early Termination (ET) for completion 
of all PRO measurements (WOMAC, KOOS, pain NRS, SF-12, PASS, WPAI), functional tests 
(40-meter walk test and TUG test at a subset of sites), and safety evaluations. On Day 1, the 
Charlson Comorbidity Index and Widespread Pain Index and Symptom Severity [WPI&SS] 
assessments will also be completed. A phone visit for safety follow-up will occur 4 weeks after 
the injection on Day 1. Refer to Figure 1 for an overview of the study design. Subjects may also 
have Unscheduled Injection Visits for additional injections of LOR, glucocorticoid, or HA, as 
described in the OA Treatment Algorithm section below. Following each injection, subjects will 
return to the clinic for 3-Month Post-Injection Follow-Up Visits, unless another visit has 

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occurred between the injection and the 3-month post injection date. At these injection visits and 
3-Month Post-Injection Follow-Up Visits, subjects will complete PRO measurements and 
functional tests (at a subset of sites). Specific timing of protocol procedures is described in the 
Schedule of Events Table (Section 7.3.7). 
This study will be conducted at approximately 30 investigational centers.  
Recording of AEs will start following study injection on Day 1 and continue at all subsequent in-
person and phone visits until the subject completes Month 36 (EOS)/ET. All AEs, whether 
volunteered, elicited, or noted during examination, will be recorded throughout the study. 
4.1.1 OA TREATMENT ALGORITHM 
LOR Injections: 
• On Day 1, after subject eligibility has been confirmed and subjects complete all PRO 
measurements and functional tests (at applicable sites), subjects will receive an IA 
injection of 0.07 mg LOR into one or both knees. Bilateral injections of 0.07 mg LOR are 
allowed.   
• Subjects may receive additional injections of LOR into one or both knees, as clinically 
indicated, at any time between Day 1 and Month 33 with the restriction that LOR 
injections into the same knee must be separated by at least 6 months; these injections can 
occur at Unscheduled Injection Visits, 3-Month Post-Injection Follow-Up Visits, or at the 
Months 3, 12, or 24 visits after the completion of visit assessments. 
• For LOR injections after Day 1: Within 6 months of any knee surgery, LOR may not be 
injected in the affected knee without consultation with and documented approval from the 
Medical Monitor.  
Glucocorticoid and HA Injections: 
• Between Day 1 and Month 3, subjects are prohibited from receiving any injections other 
than LOR into either knee. 
• Subjects may receive injections of glucocorticoid or HA into one or both knees, as 
clinically indicated, at any time between Month 3 and Month 33 with the restriction that 
glucocorticoid and HA injections must be performed in accordance with US prescribing 
information (USPI); these injections can occur at Unscheduled Injection Visits, 3-Month 
Post-Injection Follow-Up Visits, or at the Months 3, 12, or 24 visits after the completion 
of visit assessments. 
o For subjects who receive HA as a series of injections, the first injection can occur 
at an Unscheduled Injection Visit, 3-Month Post-Injection Follow-Up Visit, or at 
the Months 3, 12, or 24 visits after the completion of visit assessments. The 
subsequent injections in the series should be entered into the database as 
Unscheduled Visits (PRO measurements and functional tests do not need to be 
performed at these visits).  
General Injection Guidelines: 
• If receiving an injection for the indication of OA, subjects may only be injected in the 
knee(s) for which OA diagnosis has been confirmed based on ACR criteria (Appendix 1). 
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these criteria must be confirmed in that knee prior to the first injection at any time in the 
study.  
• Following each injection that occurs at or after the Month 3 visit, subjects will return to 
the clinic for a 3-Month Post-Injection Follow-Up Visit unless another visit has occurred 
between the injection and the 3-month post-injection date.  
o If a subject receives a glucocorticoid or HA injection for the indication of OA at a 
location different than the study site, a 3-Month Post-Injection Follow-Up Visit 
should be scheduled unless another visit has occurred between the injection and 
the 3-month post-injection date. 
o For subjects who receive HA as a series of injections, the first visit will be used to 
determine when the 3-Month Post-Injection Follow-Up Visit should occur. 
• Bilateral injections are allowed and may occur at the same visit, but only one injection 
per knee can occur at any visit. 
• Prior to the injection(s), the Investigator should evaluate the subject for suitability to 
receive the injection(s). The subject should not have any condition that, in the opinion of 
the Investigator, constitutes a risk or contraindication for the injection(s). 
• Any knee that has undergone a partial or total knee replacement should not be injected.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This Phase 3b study, SM04690-OA-17, is a multicenter, open-label study of a single 
concentration of 0.07 mg LOR per 2 mL injection injected into the knee joint(s) of OA subjects 
at Day 1. Subjects and Investigators will be able to choose to give additional injections of LOR 
(between Day 1 and Month 33) or glucocorticoids or HA (between Month 3 and Month 33) into 
either knee, as clinically warranted, with both safety and efficacy follow-up visits performed. 
This is being conducted as an open-label study with limited restrictions on how LOR is to be 
used to more closely represent how LOR would be used in clinical practice post-approval.  
4.3 
JUSTIFICATION FOR DOSE 
The dose of 0.07 mg LOR was selected for this study based on evidence available from 
nonclinical studies and 3 completed clinical studies (SM04690-01, SM04690-OA-02, and 
SM04690-OA-04). Administration of the 0.07 mg dose resulted in the most consistently positive 
responses compared to control when the outcome measures of pain NRS, WOMAC Function, 
and medial joint space width were assessed. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit shown in the Schedule of Events Table (Section 7.3.7). 
5. 
STUDY POPULATION 
Eligibility of subjects will be determined by the following inclusion and exclusion criteria. 
Subjects should meet all the inclusion criteria and none of the exclusion criteria. 
5.1 
PARTICIPANT INCLUSION CRITERIA 
In order to be eligible for the study, subjects must fulfill all of the following criteria: 

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1. Males and females between 40 and 80 years of age, inclusive, in general good health 
apart from their knee OA 
2. Femorotibial OA by standard American College of Rheumatology (ACR) criteria 
(Appendix 1); knee OA is not to be secondary to any rheumatologic conditions (e.g., 
rheumatoid arthritis). 
3. Pain compatible with knee OA for at least 26 weeks prior to the Screening Visit 
4. Negative drug test for amphetamine, buprenorphine, cocaine, methadone, opiates, 
phencyclidine (PCP), propoxyphene, barbiturates, and benzodiazepine, unless any of 
these drugs are prescribed by a physician to treat a specific condition   
5. Subjects with depression or anxiety must be clinically stable for at least 12 weeks prior to 
the Screening Visit and, if on treatment for depression or anxiety, be on at least 12 weeks 
of stable therapy  
6. Full understanding of the requirements of the study and willingness to comply with all 
study visits and assessments 
7. Subjects must have read and understood the informed consent form (ICF), and must have 
signed and dated it prior to any study-related procedure being performed 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
Any potential subject who meets one or more of the following criteria will not be included in this 
study: 
1. Pregnant women, breastfeeding women, and women who are not post-menopausal 
(defined as 12 months with no menses without an alternative medical cause) or 
permanently surgically sterile (includes hysterectomy, bilateral salpingectomy, and 
bilateral oophorectomy) who have a positive or indeterminate pregnancy test result at 
Screening and Day 1  
2. Women who are not post-menopausal or permanently surgically sterile who are sexually 
active, and who are not willing to use birth control as outlined in Section 5.3.1 during the 
study period 
3. Any surgery (e.g., arthroscopy) in either knee within 26 weeks prior to Day 1 
4. Intra-articular (IA) injection into either knee with a therapeutic aim including, but not 
limited to, hyaluronic acid (HA), platelet-rich plasma (PRP), and stem cell therapies 
within 26 weeks prior to Day 1 or IA glucocorticoids within 12 weeks prior to Day 1 
5. Previous treatment with lorecivivint 
6. Participation in a clinical research trial that included the receipt of an investigational 
product (IP) or any experimental therapeutic procedure within 4 weeks or 5 half-lives, 
whichever is greater, prior to the Screening Visit, or planned participation in any such 
trial 
7. Planned surgery scheduled during the study period that, in the Investigator’s opinion, 
would interfere with study conduct or evaluation, not including non-surgical invasive 
procedures conducted for a diagnostic or therapeutic purpose scheduled during the study 
period (refer to Section 7.6) 
8. Any condition that, in the opinion of the Investigator, constitutes a risk or 
contraindication for participation in the study or that could interfere with the study 

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objectives, conduct, or evaluation 
9. Any comorbid condition that could affect study endpoint assessments of the knee, 
including, but not limited to, rheumatoid arthritis, psoriatic arthritis, systemic lupus 
erythematosus, gout or pseudogout, and fibromyalgia  
10. Any contraindications for an IA injection in the knee(s) to be injected at Day 1 in the 
opinion of the Investigator 
11. History of mania, bipolar disorder, psychotic disorder, schizophrenia, or schizoaffective 
disorder 
12. Any known active infections, including urinary tract infection, upper respiratory tract 
infection, sinusitis, suspicion of IA infection, hepatitis B or hepatitis C infection, and/or 
infections that may compromise the immune system such as human immunodeficiency 
virus (HIV) at Day 1 
13. Subjects who have a current or pending disability claim, workers’ compensation, or 
litigation(s) that may compromise response to treatment  
14. Subjects who are immediate family members (spouse, parent, child, or sibling; biological 
or legally adopted) of personnel directly affiliated with the study at any investigative site, 
or are directly affiliated with the study at any investigative site 
15. Subjects employed by Biosplice Therapeutics, Inc., or any of its affiliates or development 
partners (that is, an employee, temporary contract worker, or designee) responsible for 
the conduct of the study, or who are immediate family members (spouse, parent, child, or 
sibling; biological or legally adopted) of said employees responsible for the conduct of 
the study 
5.3 
LIFESTYLE GUIDELINES 
5.3.1 CONTRACEPTION 
WOMEN OF CHILDBEARING POTENTIAL 
Women of childbearing potential (WOCBP) refers to women who are not post-menopausal 
(defined as 12 months with no menses without an alternative medical cause) or permanently 
surgically sterile (includes hysterectomy, bilateral salpingectomy, and bilateral oophorectomy).  
From the Screening Visit until Month 36 (EOS)/ET, sexually active WOCBP must agree to use 
an acceptable form of contraception. Acceptable forms of contraception are:  
1. Intrauterine device (IUD) 
2. Implantable rod  
3. Established hormonal contraceptive methods. This includes combined (estrogen and 
progestogen containing) hormonal contraception associated with inhibition of ovulation 
(oral, intravaginal, or transdermal); progestogen only hormonal contraception associated 
with inhibition of ovulation (oral, injectable, or implantable). Females who are using 
hormonal contraceptives must have had consistent use of the same hormonal 
contraceptive product for at least 4 weeks.  
4. Bilateral tubal ligation/occlusion/division  

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5. Male partner who had a vasectomy provided that the partner is the sole sexual partner of 
the WOCBP, and that the vasectomized partner has received medical assessment of the 
success of the surgical procedure or had the vasectomy for at least 6 months 
Sexually active WOCBP who withdraw from the study after receiving study medication should 
remain on an acceptable form of contraception for 1 month after their last LOR injection.  
MEN  
For men, no contraception measures are required.  
 
5.4 
SCREEN FAILURES 
5.4.1 SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently enrolled in the study. 
5.4.2 SUBJECT RESCREENING 
Subjects are allowed to be rescreened once for this protocol and, if the subject is affected by an 
amendment(s) that changes the inclusion/exclusion criteria, they are additionally allowed to 
rescreen. Rescreens are limited to subjects who did not meet inclusion/exclusion criteria due to a 
transient reason or if the inclusion/exclusion criteria have changed. Transient refers to 
self-limiting and predictably resolving conditions or acute events (e.g., common cold or otitis 
media), reversible medical conditions that are successfully treated (e.g., resolved anemia), being 
unable to comply with study procedures due to administrative convenience (e.g., family issues or 
attending to a private matter), and/or being within the exclusion window for past medications 
and/or procedures, as outlined in Section 5.2.  
Subjects who failed any entry criteria for which no further treatment or spontaneous resolution is 
expected are not allowed to be rescreened. 
Any rescreened subject must be reconsented and will be issued a new subject number. All 
screening procedures and assessments must be performed at rescreen; no results or data may be 
used from the previous screen.  
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
A detailed recruitment and retention plan will be maintained by the Sponsor.  
5.6 
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.6.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Subjects will be informed they are free to withdraw from the study at any time and for any 
reason. A premature discontinuation from the study will occur when a subject who was enrolled 
ceases participation in this study, regardless of circumstances, prior to completion of the defined 
study period.  

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Reasons for premature discontinuation from the study might include:  
• AE 
• Total or partial knee replacement of the knee diagnosed with OA in unilateral OA 
subjects or of both knees in bilateral OA subjects 
• Lost to follow-up after a minimum of 3 attempts have been made to contact the 
subject, including sending a registered letter 
• Withdrawal by subject for reason other than lack of efficacy 
• Subject non-compliance 
• Physician decision for reason other than lack of efficacy  
• Study terminated by Sponsor 
• Site terminated by Sponsor 
• Request by regulatory authority 
• Lack of efficacy 
• Pregnancy 
• Death 
• Other 
5.6.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
In case of premature discontinuation of study participation, ET procedures should be conducted 
within 14 days of discontinuation for any subject who was enrolled in the study, if possible. The 
date the subject is withdrawn from the study and the reason for the discontinuation should be 
recorded on the electronic case report form (eCRF). The Investigator or designee must complete 
all applicable eCRF pages for subjects who discontinue from the study prematurely.  
Replacement of subjects who withdraw or discontinue prematurely is not allowed. 
Total or Partial Knee Replacement Follow-Up  
A subject who has had total or partial knee replacement of the knee diagnosed with OA in 
unilateral OA or of both knees in bilateral OA should be discontinued from the study. In 
addition to ET procedures as described above, sites should follow up with these subjects 
approximately 6 months after the total or partial knee replacement surgery as described in 
Section 7.1.1. 
5.7 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
The Sponsor reserves the right to prematurely terminate the study at any time for administrative 
or safety reasons. Written notification, documenting the reason for study suspension or 
termination, will be provided to the Investigator, Sponsor, and regulatory authorities as 
appropriate. If the study is prematurely terminated or suspended, the Investigator will promptly 
inform the IRB and will provide the reason(s) for the termination or suspension.  
6. 
STUDY AGENT 
For glucocorticoid and/or HA injections, specific products to be used are at the discretion of the 

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Investigator. Refer to USPIs for product descriptions, storage conditions, and method of 
administration. Sites are to inform subjects of risks associated with use of the selected product(s).  
6.1 
STUDY AGENT DESCRIPTION 
6.1.1 ACQUISITION 
The Sponsor will be responsible for the manufacturing, labeling, packaging, distribution, and 
reconciliation of LOR, and the ultimate destruction of unused LOR. 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
LOR drug product is a sterile suspension in diluent containing 0.5% carboxymethylcellulose 
sodium and 0.05% polysorbate 80 in pH 7.4 phosphate buffered saline. LOR drug product is 
supplied as vials of 2.4 mL of formulated suspension.  
LOR will be supplied as single-use vials and labeled according to the applicable local and 
national regulations. For dispensing, dose preparation, and labeling instructions, refer to the 
Pharmacy Manual. 
6.1.3 PRODUCT STORAGE AND STABILITY 
LOR should be stored at the appropriate temperature (15-30 °C [59-86 °F]) and in a restricted 
area with limited access. Temperature excursions are to be evaluated on a case-by-case basis by 
the Sponsor.  
6.1.4 PREPARATION 
Each dose of LOR should be well mixed (the drug product is a suspension) before injection. 
Refer to the Pharmacy Manual for detailed instructions on LOR preparation.  
6.1.5 DOSING AND ADMINISTRATION 
LOR will be administered as a 2 mL injection containing 0.07 mg LOR. The Investigator will 
administer the injection into one or both knee joints once at Day 1. Between Day 1 and Month 
33, subjects may have unscheduled visits at any time for additional injections of LOR into either 
knee as clinically indicated, with the restriction that LOR injections into the same knee must be 
separated by at least 6 months. 
The IA LOR injections can be done through lateral or medial (including superior/suprapatellar, 
midpatellar, and inferior/anterior) approaches, based on the standard practice of the Investigator 
and the knee examination of the subject. Although not required, the injections may be guided by 
ultrasound or fluoroscopy without contrast if it is the standard practice of the Investigator.   
Only topical anesthetics are allowed before any IA LOR injection. Local anesthetic injections are 
prohibited before or concurrent with any IA LOR injection. 
The injector should place the needle into the joint and the total volume contained in the syringe 
is to be injected into the joint space. Because LOR drug product is a suspension, prior aspiration 

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of synovial fluid into the syringe containing the injectate should be avoided to prevent trapping 
of particles within synovial aspirate/cellular content residues. Aspiration of a small amount (0.3-
0.5 mL) of joint fluid is allowed if it is the standard practice of the injector to confirm correct 
needle placement. For subjects with moderate to large effusion in the target knee, aspiration of 
the effusion prior to injection of study medication is recommended. Aspirations should be done 
with an empty sterile syringe. Using the same needle, the study medication should then be 
injected with a separate syringe. The approximate volume of fluid aspirated should be recorded 
in the eCRF.   
The Sponsor will provide sterile needles and syringes that should be used for IA LOR injections. 
Refer to the Pharmacy Manual for further information. 
6.1.6 ROUTE OF ADMINISTRATION 
LOR is to be administered as an IA injection into the knee joint. 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
Not applicable to this study. 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
No dose modifications of LOR are allowed. 
6.1.9 DURATION OF THERAPY 
LOR is to be administered as an IA injection into one or both knee joints once at Day 1. Subjects 
may have unscheduled visits at any time for additional injections of LOR (between Day 1 and 
Month 33) or glucocorticoid or HA (between Month 3 and Month 33) into either knee as 
clinically indicated, with the restrictions that 1) LOR injections into the same knee must be 
separated by at least 6 months, and 2) glucocorticoid and HA injections must be performed in 
accordance with their USPIs. The subject should not have any condition that, in the opinion of 
the Investigator, constitutes a risk or contraindication for the injection. 
6.1.10 STUDY INTERVENTION COMPLIANCE  
Not applicable to this study. 
6.1.11 DEVICE SPECIFIC CONSIDERATIONS 
Not applicable to this study. 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
All used and unused vials of LOR received must be accounted for. All injections prepared and 
dispensed must also be logged. The log includes the following: 
• Subject number and initials 
• Date that LOR was injected 

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• Quantity dispensed (LOR vial) 
• Quantity returned/used (LOR vial) 
All LOR vials dispensed by the Investigator and/or designee will be inventoried and accounted 
for throughout the study. The Investigator and/or designee must maintain an accurate, up-to-date 
dispensing log for all LOR supplied by the Sponsor. LOR dispensed for all subjects must be 
recorded on the drug accountability forms. The dispensing log and remaining drug inventory will 
be reviewed by the Sponsor-designated clinical monitor. 
LOR supplied for this study is for use only in subjects properly consented and randomized into 
this protocol. LOR must be kept in a secure location physically separated from standard clinic or 
office drug supplies, and with access limited to the Investigator and/or designee. Procedures for 
return or destruction of used and unused vials of LOR will be provided in the Pharmacy Manual.   
Details regarding accountability procedures for glucocorticoid and HA supplied by the Sponsor 
will be provided in the Pharmacy Manual.  
7. 
STUDY PROCEDURES AND SCHEDULE 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 STUDY SPECIFIC PROCEDURES  
Collection of Adverse Events Data 
Data regarding AEs will be collected in this study. AEs are events that occur during the study 
that are not present before the Day 1 study injection(s), or, if present at the time of the Day 1 
study injection(s), have worsened in severity during the study. AEs will be assessed at each in-
person and phone visit from the time of study injection(s) on Day 1 through Month 36 
(EOS)/ET.  
Each subject will be observed and queried by the Investigator or designee at each study visit for 
any continuing AEs or new AEs since the previous visit. The subject may be asked to return to 
the site for an unscheduled visit if an AE occurs between study visits, and if, in the opinion of the 
Investigator, the AE requires a study visit for full evaluation. The following information will be 
recorded within the eCRF for each AE: Description of the event, date of onset and resolution, 
etiology, and severity as assessed by the Investigator according to the Clinical Data Interchange 
Standards Consortium (CDISC) Severity/Intensity Scale for Adverse Events (AESEV) (Table 1), 
causal relationship to LOR or LOR injection, outcome, and any action taken.  
In this protocol, signs and symptoms of exacerbation or worsening of knee OA will be captured 
in the context of efficacy assessments and recorded on specific pages of the eCRF. Anticipated 
fluctuations or anticipated deterioration (in the opinion of the Investigator) of the underlying 
disease (knee OA) will not be considered as AEs nor captured on the AE page of the eCRF. 
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series of 
symptoms relating to a diagnosis. Fluctuations of pre-existing conditions that do not represent a 
clinically significant exacerbation or worsening need not be considered AEs. 
AEs will be followed until the subject’s last visit or resolution, whichever comes first. Non-

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serious AEs that are ongoing at the subject’s last visit will be followed for 30 days after their last 
study injection or until resolution, whichever comes first. Resolution is defined as the return to 
baseline status or stabilization of the condition. At the discretion of the Medical Monitor and in 
consultation with the Investigator, certain non-serious AEs may be followed beyond 30 days. All 
SAEs will be followed until resolution. 
Medical History 
A medical history will be obtained at the Screening Visit with a follow-up at Month 36 
(EOS)/ET to capture End Dates of any ongoing medical history collected at the Screening Visit. 
Medical history at the Screening Visit will include demographic data (e.g., age, race, ethnicity, 
payer/insurance type). In addition, medical information will also be recorded, including all 
(1) medical conditions and disease states that require current or ongoing therapy and (2) other 
medical conditions and disease states that, in the opinion of the Investigator, are relevant to the 
subject’s study participation. Examples of medical conditions and disease states that should be 
considered relevant to the subject’s study participation include history of current disease, 
medical history that confirms the eligibility criteria of the subject, and asymptomatic medical 
history that could become symptomatic while on the study.  
Past Treatments for Knee OA Pain 
Subjects will be asked at the Screening Visit about their previous or current use of the following 
treatments for their knee OA pain: NSAIDs, acetaminophen, opioids, IA steroids, and IA HA. 
For medications that have been used in the past but are no longer being used, the reason for 
discontinuation will also be collected on the eCRF.  
Physical Examination  
A general physical examination will be conducted at the Screening Visit, Day 1, and Months 12, 
24, and 36 (EOS)/ET. Results of the physical examination will be noted in the source documents. 
Any clinically significant finding noted after the Day 1 study injection(s) should be reported as 
an AE.  
Knee Examination 
A knee examination of both knees will be conducted at the Screening Visit, Day 1, Months 3, 12, 
24, and 36 (EOS)/ET, and at each Unscheduled Injection Visit and 3-Month Post-Injection 
Follow-Up Visit. Results of the knee examination will be noted in the source documents. Any 
clinically significant finding noted after the Day 1 study injection(s) should be reported as an 
AE.  
Presence of unilateral or bilateral symptomatic knee OA will be recorded in the eCRF at the 
Screening Visit. Following confirmation of knee OA based on ACR criteria (Appendix 1) at the 
Screening Visit and any Unscheduled Injection Visit, as necessary, the date of the radiograph and 
the Investigator-assessed Kellgren-Lawrence (KL) grade will be recorded in the eCRF. Refer to 
Appendix 2 for KL Grading Scale.  
Vital Signs 
Vital signs will be measured by a qualified staff member at all in-person visits. 
At each visit, the following vital signs will be measured: 

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• Body temperature 
• Pulse rate 
• Blood pressure (systolic and diastolic)  
Any measurement that is, in the opinion of the Investigator, abnormal AND clinically significant 
must be recorded as an AE if found after the Day 1 study injection(s).  
Height and Weight 
A height measurement will be taken at the Screening Visit. Weight measurements will be taken 
at the Screening Visit and Months 12, 24, and 36 (EOS)/ET. 
Charlson Comorbidity Index 
The Charlson Comorbidity Index will be completed by the Investigator at Day 1. The Charlson 
Comorbidity Index is a method of assessing and categorizing a subject’s comorbid conditions. 
The index provides a weighted score that can be used to predict short- and long-term outcomes 
(e.g., resource use, mortality rates).  
Instructions for completion of the Charlson Comorbidity Index will be provided to sites prior to 
initiation of subject enrollment. Upon completion of the Charlson Comorbidity Index, the 
Investigator will sign or initial, then date the source document.  
Patient Reported Outcome Measures 
All PRO measures will be completed on paper, will be provided by the Sponsor, and may not be 
reproduced. Upon completion of each assessment and questionnaire, the subject will sign or 
initial, then date the source documents to indicate that they were reported accurately.  
The following PRO measure will be completed by the subject at the Day 1 visit only: 
• Widespread Pain Index and Symptom Severity Form - The WPI&SS assessment 
consists of a body map that determines a subject’s areas of pain or tenderness (WPI) and 
symptom severity (SS) questions. The WPI&SS assessment used in this study is modified 
from that described in (Clauw 2014).  
The following PRO measures will be completed by the subject at Day 1 and Months 3, 12, 24, 
and 36 (EOS)/ET: 
• 12-Item Short Form Health Survey - The SF-12 is a widely used questionnaire that 
relies upon subject self-reporting to measure the subject’s health-related quality of life.  
• Patient Acceptable Symptom State Questionnaire - Subjects will be asked the 
following, using a paper questionnaire: “Taking into account all the activities you have 
during your daily life, your level of pain, and also your functional impairment, do you 
consider that your current state is satisfactory?” Subjects are able to choose the answers 
of “Yes” or “No.”    
• Work Productivity and Activity Impairment Questionnaire - The WPAI 
questionnaire is a validated instrument to assess the impact of disease on paid work and 
activities.  

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The following PRO measures will be completed by the subject at Day 1, Months 3, 12, 24, and 
36 (EOS)/ET, and at each Unscheduled Injection Visit and 3-Month Post-Injection Follow-Up 
Visit: 
• Western Ontario and McMaster Universities Arthritis Index - The WOMAC is a 
widely used, proprietary outcome measurement tool used by health professionals to 
evaluate the condition of patients with OA of the knee and hip, including pain, stiffness, 
and physical functioning of a target joint. The WOMAC Version NRS 3.1 questionnaire 
will be completed by the subject for both knees.  
• Knee Injury and Osteoarthritis Outcome Score - KOOS is used to assess a subject’s 
opinion about their knee and associated problems. Subjects will complete the KOOS 
subscales for Symptoms, Function (Sports), and knee-related Quality of Life. The KOOS 
subscales will be completed by the subject for both knees. 
• Pain Numeric Rating Scale - The pain NRS is an 11-point scale [0–10] for subject self-
reporting of average knee pain in the last 24 hours. The NRS will be anchored by 
descriptors at each end (“No Pain” on the left and “Pain as bad as you can imagine” on the 
right). The pain NRS will be completed by the subject for both knees. 
Functional Tests 
At a subset of sites, the following functional tests will be administered to subjects by a qualified 
staff member at Day 1, Months 3, 12, 24, and 36 (EOS)/ET, and at each Unscheduled Injection 
Visit and each 3-Month Post-Injection Follow-Up Visit:  
• 40-meter Walk Test - The 40-meter walk test is a performance-based measure used to 
assess walking speed over the distance of 40 meters.  
• Timed Up and Go Test - The TUG test is a performance-based measure of mobility, 
balance, walking ability, and fall risk.  
The results of each test will be recorded in the eCRF. Refer to the functional test guide for details 
regarding test performance and scoring (provided to select sites). 
Total or Partial Knee Replacement Follow-Up  
For any subjects who have a total or partial knee replacement of the knee diagnosed with OA in 
unilateral OA or of either knee in bilateral OA, sites should follow up with these subjects 
approximately 6 months after the total or partial knee replacement surgery is completed to assess 
outcomes of the surgery.  
Note: A subject who has had total or partial knee replacement of the knee diagnosed with OA in 
unilateral OA or of both knees in bilateral OA should be discontinued from the study. See 
Section 5.6 for additional information. 
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
All Investigators are to provide appropriate care to their subjects as they deem necessary, 
including prescribing the use of NSAIDs/acetaminophen and/or glucocorticoid and HA 
injections as needed; however, additional standard of care study procedures are not required by 
this protocol.  

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7.2 
LABORATORY PROCEDURES/EVALUATIONS 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
Samples for clinical laboratory analysis by the central laboratory will be collected by a qualified 
staff member at the Screening Visit and Months 12, 24, and 36 (EOS)/ET. Refer to the 
Laboratory Manual for details about collection of specimens. At a minimum, the following tests 
will be conducted: 
• Chemistry panel: Albumin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), blood urea nitrogen, bicarbonate, calcium, 
calcium (corrected total), chloride, creatinine, glucose, lactate dehydrogenase (LDH), 
potassium, sodium, bilirubin (total), and uric acid 
• Hematology: Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell 
(WBC) count with differential, and platelet count 
• Urinalysis: Clarity, specific gravity, pH, protein, glucose, ketones, nitrite, leukocyte 
esterase, and occult blood  
Urine microscopy will be performed if urinalysis urine protein, leukocyte esterase (WBC 
esterase), occult blood, or nitrite values are out of range, or if the Investigator deems that the 
microscopy is clinically warranted. 
The Investigator or designee must review the results of each subject’s Screening Visit clinical 
laboratory test results prior to the Day 1 visit. The subject must not be enrolled on Day 1 if any 
of the Screening Visit results are outside the normal range for the laboratory AND, in the opinion 
of the Investigator, are indicative of a condition that should prevent the subject from 
participating.  
The results of the clinical laboratory tests will be reported on the laboratory’s standard reports. 
The Investigator must review all laboratory reports in a timely manner, noting “not clinically 
significant” (NCS) or comment on the clinical significance of any result that is outside the 
normal range for the laboratory, then date and initial the report. The Investigator must report all 
laboratory results that are BOTH outside the normal range for the laboratory AND, in the 
opinion of the Investigator, are clinically significant. If any abnormal, clinically significant 
laboratory measure is found before study injection on Day 1 that, in the opinion of the 
Investigator, is not indicative of a condition that should prevent the subject from participating in 
the study, it should be reported as medical history. Any abnormal, clinically significant AE that 
is found after Day 1 study injection should be reported as an AE. 
7.2.2 OTHER ASSAYS OR PROCEDURES 
Pregnancy Test 
A serum-based pregnancy test will be performed on WOCBP at the Screening Visit and a 
urine-based pregnancy test will be performed on WOCBP at Day 1 and Month 36 (EOS)/ET. 
Results from the Screening Visit and Day 1 pregnancy tests will be utilized to determine subject 
eligibility.   

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WOCBP are women who are not post-menopausal (defined as 12 months with no menses 
without an alternative medical cause) or permanently surgically sterile (includes hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy). 
Drug Test 
A urine sample for drug testing will be collected at the Screening Visit. The urine drug test will 
identify amphetamine, buprenorphine, cocaine, methadone, opiates, PCP, propoxyphene, 
barbiturates, and benzodiazepine. Results from the drug test will be utilized to determine subject 
eligibility. 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
Refer to the Laboratory Manual for the central laboratory.  
7.2.4 SPECIMEN SHIPMENT 
Refer to the Laboratory Manual for the central laboratory. 
7.3 
STUDY SCHEDULE 
7.3.1 SCREENING 
Screening Visit  
The Screening Visit must occur within 14 days prior to Day 1. The screening visit window 
begins with participant signature of the study informed consent. 
The Investigator or designee must explain the nature of the study protocol and associated risks to 
the potential study participant. The potential participant must be allowed to review the study 
information and to ask questions before being asked to sign and date the ICF. Written informed 
consent must be provided, signed, and dated by the potential study participant prior to initiation 
of any screening evaluations or other study-related procedures. The signature, date, and the name 
of the individual at the site who obtained the informed consent will be recorded. After written 
informed consent is obtained, the subject will be assigned a subject number.  
The following procedures and assessments will be performed initially during the Screening Visit: 
• Documentation of demographic information, including date of birth, sex, race, 
ethnicity, and payer/insurance type 
• Documentation of current and past medical history including prior procedures and 
non-drug therapies, documentation of current medications, and review of prior 
medications excluded by the protocol 
• Documentation of past treatments for knee OA pain 
• Assessment/confirmation of diagnosis of knee OA based on ACR criteria (Appendix 
1) for both knees 
• Physical examination, including knee examination of both knees  
• Height and weight measurements 

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• Pregnancy test (serum-based) for WOCBP 
• Vital sign measurements (temperature, pulse rate, and blood pressure) 
• Urine drug test 
• Collection of samples for clinical laboratory tests  
Investigators will maintain a confidential log of all subjects who have been screened for 
participation in the study whether or not the subject was eligible for study participation. 
7.3.2 ENROLLMENT 
Day 1 
This visit must occur within 14 days of the Screening Visit. 
The following procedures and assessments will be performed at Day 1 prior to enrollment: 
• Documentation of current medications, and review of prior medication excluded by 
the protocol 
• Pregnancy test (urine-based) for WOCBP 
Results from the Screening Visit and Day 1 evaluations will be compared with 
inclusion/exclusion criteria to determine subject eligibility. Eligible subjects will then be enrolled 
in the study. The following procedures and assessments will be performed at Day 1 following 
enrollment: 
• Physical examination, including knee examination of both knees 
• Vital sign measurements (temperature, pulse rate, and blood pressure) 
• WPI&SS assessment 
• Charlson Comorbidity Index assessment 
• WOMAC questionnaire  
• KOOS questionnaire  
• Pain NRS 
• SF-12 questionnaire  
• PASS questionnaire 
• WPAI questionnaire  
• 40-meter walk test (at a subset of sites) 
• TUG test (at a subset of sites) 
• IA injection of LOR into one or both knees  
• Collection of AE and concomitant procedures/medication data 
 
 

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7.3.3 FOLLOW-UP  
Month 1 (Phone Visit) 
The Month 1 phone visit should occur on Day 30 (with a window of ± 7 days). Sites will contact 
subjects to collect AE and concomitant procedures/therapies/medication data.  
Month 3 
The Month 3 visit should occur on Day 90 (with a window of ± 14 days).  
The following procedures and assessments will be performed at this visit: 
• Knee examination of both knees  
• Vital sign measurements (temperature, pulse rate, and blood pressure) 
• WOMAC questionnaire  
• KOOS questionnaire  
• Pain NRS 
• SF-12 questionnaire  
• PASS questionnaire 
• WPAI questionnaire  
• 40-meter walk test (at a subset of sites) 
• TUG test (at a subset of sites) 
• Collection of AE and concomitant procedures/therapies/medication data 
Once all study assessments are completed, and if clinically indicated, subjects may receive an 
injection of glucocorticoid, or HA into one or both knees, or an injection of LOR into the knee 
not injected on Day 1. Refer to Section 4.1.1 for restrictions and guidelines.  
Months 12 and 24 
The Month 12 visit should occur on Day 360 (with a window of ± 28 days) and the Month 24 
visit should occur on Day 720 (with a window of ± 28 days). 
The following procedures and assessments will be performed at these visits: 
• Collection of AE and concomitant procedures/therapies/medication data 
• Physical examination, including knee examination of both knees 
• Weight measurement 
• Vital sign measurements (temperature, pulse rate, and blood pressure) 
• WOMAC questionnaire  
• KOOS questionnaire  
• Pain NRS 
• SF-12 questionnaire  
• PASS questionnaire 

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• WPAI questionnaire  
• 40-meter walk test (at a subset of sites) 
• TUG test (at a subset of sites) 
• Collection of samples for clinical laboratory tests  
Once all study assessments are completed, and if clinically indicated, subjects may receive an 
injection of LOR, glucocorticoid, or HA into one or both knees. Refer to Section 4.1.1 for 
restrictions and guidelines.  
7.3.4 ADDITIONAL VISITS 
Unscheduled Injection Visit 
Subjects may have Unscheduled Injection Visits at any time for additional injections of LOR 
(between Day 1 and Month 33) or glucocorticoid or HA (between Month 3 and Month 33) into 
one or both knees as clinically indicated. Refer to Section 4.1.1 for restrictions and guidelines. 
The following procedures and assessments will be performed at this visit: 
• Collection of AE and concomitant procedures/therapies/medication data 
• Knee examination of both knees  
• Vital sign measurements (temperature, pulse rate, and blood pressure) 
• WOMAC questionnaire  
• KOOS questionnaire  
• Pain NRS 
• 40-meter walk test (at a subset of sites) 
• TUG test (at a subset of sites) 
• IA injection of LOR, glucocorticoid, or HA into the knee(s) 
Note: PRO measurements (WOMAC, KOOS, and pain NRS) and functional tests (40-meter 
walk test and TUG test) do not need to be completed at this visit if they were completed within 2 
weeks prior.  
3-Month Post-Injection Follow-Up Visit 
This visit should occur 90 days after any Unscheduled Injection Visit or after any IA 
glucocorticoid or HA injection occurring at a location different than the study site (with a 
window of ± 14 days) unless another visit has occurred between the injection and the 3-month 
post injection date.  
The following procedures and assessments will be performed at this visit: 
• Collection of AE and concomitant procedures/therapies/medication data 
• Knee examination of both knees  
• Vital sign measurements (temperature, pulse rate, and blood pressure) 
• WOMAC questionnaire  

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• KOOS questionnaire  
• Pain NRS 
• 40-meter walk test (at a subset of sites) 
• TUG test (at a subset of sites) 
Once all study assessments are completed, and if clinically indicated, subjects may receive an 
injection of LOR, glucocorticoid, or HA into one or both knees. Refer to Section 4.1.1 for 
restrictions and guidelines. 
7.3.5 FINAL STUDY VISIT 
Month 36 End of Study 
The Month 36 visit should occur on Day 1080 (with a window of ± 28 days). 
The following procedures and assessments will be performed at this visit: 
• Collection of AE and concomitant procedures/therapies/medication data 
• Physical examination, including knee examination of both knees 
• Weight measurement 
• Pregnancy test (urine-based) for WOCBP 
• Vital sign measurements (temperature, pulse rate, and blood pressure) 
• WOMAC questionnaire  
• KOOS questionnaire  
• Pain NRS 
• SF-12 questionnaire  
• PASS questionnaire 
• WPAI questionnaire  
• 40-meter walk test (at a subset of sites) 
• TUG test (at a subset of sites) 
• Collection of samples for clinical laboratory tests  
7.3.6 EARLY TERMINATION VISIT 
If possible, the following procedures and assessments should be performed within 14 days of 
subject premature withdrawal or termination.  
• Collection of AE and concomitant procedures/therapies/medication data 
• Physical examination, including knee examination of both knees 
• Weight measurement 
• Pregnancy test (urine-based) for WOCBP 
• Vital sign measurements (temperature, pulse rate, and blood pressure) 

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• WOMAC questionnaire  
• KOOS questionnaire  
• Pain NRS 
• SF-12 questionnaire  
• PASS questionnaire 
• WPAI questionnaire  
• 40-meter walk test (at a subset of sites) 
• TUG test (at a subset of sites) 
• Collection of samples for clinical laboratory tests  
Note: PRO measurements (WOMAC, KOOS, pain NRS, SF-12, PASS, WPAI) and functional 
tests (40-meter walk test and TUG test) do not need to be completed at this visit if they were 
completed within 2 weeks prior.  

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7.3.7 SCHEDULE OF EVENTS TABLE 
Schedule of Study Procedures 
Screening 
(Day -14 to 
Day -1) 
Day 1a 
Month 1 
(Phone) 
(Day 30 ± 
7 days) 
Month 3 
(Day 90 ± 
14 days) 
Months 12 
and 24 
(Days 360 
and 720 ± 
28 days) 
Unscheduled 
Injection 
Visitb 
3-Month Post-
Injection 
Follow-Up 
Visitc 
(± 14 days) 
Month 36 
(EOS)  
(Day 1080 ± 
28 days)/ 
ETd 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion & exclusion criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Xe 
Current and prior 
procedures/medications 
X 
X 
 
 
 
 
 
 
Past treatments for knee OA pain 
X 
 
 
 
 
 
 
 
Pregnancy testf 
X 
X 
 
 
 
 
 
X 
Urine drug test 
X 
 
 
 
 
 
 
 
Injection into kneeg 
 
Xh 
 
 
 
X 
 
 
Physical examination 
X 
X 
 
 
X 
 
 
X 
Knee examination 
X 
X 
 
X 
X 
X 
X 
X 
Weight 
X 
 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
Clinical laboratory sampling 
X 
 
 
 
X 
 
 
X 
WPI&SS 
 
X 
 
 
 
 
 
 
Charlson Comorbidity Index 
 
X 
 
 
 
 
 
 
WOMAC 
 
X 
 
X 
X 
X 
X 
X 
KOOS 
 
X 
 
X 
X 
X 
X 
X 
Pain NRS 
 
X 
 
X 
X 
X 
X 
X 

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Schedule of Study Procedures 
Screening 
(Day -14 to 
Day -1) 
Day 1a 
Month 1 
(Phone) 
(Day 30 ± 
7 days) 
Month 3 
(Day 90 ± 
14 days) 
Months 12 
and 24 
(Days 360 
and 720 ± 
28 days) 
Unscheduled 
Injection 
Visitb 
3-Month Post-
Injection 
Follow-Up 
Visitc 
(± 14 days) 
Month 36 
(EOS)  
(Day 1080 ± 
28 days)/ 
ETd 
SF-12 
 
X 
 
X 
X 
 
 
X 
PASS Question 
 
X 
 
X 
X 
 
 
X 
WPAI 
 
X 
 
X 
X 
 
 
X 
40-meter walk testi 
 
X 
 
X 
X 
X 
X 
X 
TUG testi 
 
X 
 
X 
X 
X 
X 
X 
AEs & concomitant proceduresj/ 
therapies/medications 
 
X 
X 
X 
X 
X 
X 
X 
 
a  All Day 1 procedures should be performed prior to study medication injection except for collection of AE and concomitant procedures/medication data.  
b  The Unscheduled Injection Visit may only occur between Day 1 and Month 33 if the subject is receiving an IA LOR injection, or between Month 3 and Month 
33 if the subject is receiving an IA glucocorticoid or HA injection. PRO measurements (WOMAC, KOOS, and pain NRS) and functional tests (40-meter walk 
test and TUG test) do not need to be completed at the Unscheduled Injection Visit if they were completed within 2 weeks prior. 
c This visit should occur 90 days after the Unscheduled Injection Visit or any IA glucocorticoid or HA injection occurring at a location different than the study 
site (with a window of ± 14 days) unless another visit has occurred between the injection and the 3-month post injection date.  
 
d If possible, the ET visit should be performed within 14 days of subject premature withdrawal or termination. PRO measurements (WOMAC, KOOS, pain 
NRS, SF-12, PASS, WPAI) and functional tests (40-meter walk test and TUG test) do not need to be completed at the ET visit if they were completed within 2 
weeks prior. 
e  Review medical history to capture End Date(s), if applicable, of any ongoing medical history(ies) collected at the Screening Visit. 
f  A serum pregnancy test will be performed on WOCBP at the Screening visit and a urine pregnancy test will be performed on WOCBP at Day 1 and Month 36 
(EOS)/ET. 
g  At Unscheduled Injection Visits, 3-Month Post-Injection Follow-Up Visits, or at Months 3, 12, or 24 (after completion of all visit assessments), subjects may 
receive LOR, glucocorticoid, or HA in either knee. Refer to the OA Treatment Algorithm in Section 4.1.1 for further details.  
h  Subjects are to receive an IA injection of LOR into one or both knees on Day 1.  
i Functional tests will only be performed at a subset of sites.  
j For any subjects who have a total or partial knee replacement of the knee diagnosed with OA in unilateral OA or of either knee in bilateral OA, sites should 
follow up with these subjects approximately 6 months after the total or partial knee replacement surgery is completed to assess outcomes of the surgery. 
 

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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Not applicable for this study. 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
Details regarding the name, indication, route of administration, dose, and frequency of all 
medications taken within 30 days prior to the Screening Visit through Month 36 (EOS)/ET will 
be recorded in the “Prior and Concomitant Medications” eCRF. “All medications” should 
include prescription, over-the-counter, supplements, and herbal or alternative medications, as 
well as glucocorticoid and HA injections for indications other than OA.  
Procedures or non-drug therapies that are ongoing, new, or modified at or after the Screening 
Visits must be recorded on the “Procedures and Non-Drug Therapies” eCRF. 
AE assessments should include consideration of any new or modified concomitant therapies 
administered to the subject.  
7.5.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
Not applicable to this study. 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
Prohibited Concomitant Medications and Procedures: 
• Any IA injection other than LOR, glucocorticoids, and HA including PRP, stem cell 
therapies, or other agents with therapeutic intent, into either knee is prohibited while the 
subject is on study; IA injection of glucocorticoids, HA derivatives, PRP, stem cells, or 
other therapeutic agents into joints other than the knee is allowed. 
• Drugs screened to assess eligibility (i.e., amphetamine, buprenorphine, cocaine, 
methadone, opiates, PCP, propoxyphene, barbiturates, and benzodiazepine) are prohibited 
while the subject is on study unless prescribed by a physician to treat a specific condition.  
• Subjects are prohibited from participating in any other clinical research trial that includes 
the receipt of an IP or any experimental therapeutic procedure.  
The Investigator should notify the Sponsor Medical Monitor if any prohibited therapies are 
required to ensure subject safety.  
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable to this study. 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable to this study. 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Not applicable to this study. 

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8. 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
Safety assessments include physical examinations, vital signs, clinical laboratory tests, collection 
of AEs and concomitant medications, and general medical evaluations.  
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
AEs in the eCRF will be classified according to the most recent US FDA definitions and in a 
manner consistent with ICH-GCP guidelines. As such the following definitions will be used: 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an IP or other protocol-imposed intervention, regardless of attribution. An AE may 
include intercurrent illnesses or injuries that represent an exacerbation (increase in frequency, 
severity, or specificity) of preexisting conditions (e.g., worsening of asthma).  
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series of 
symptoms relating to a diagnosis. Fluctuations of pre-existing conditions, including the disease 
under study that does not represent a clinically significant exacerbation or worsening, need not 
be considered AEs. In order to classify AEs and diseases, preferred terms will be assigned by the 
Sponsor to the original terms entered on the eCRF, using the Medical Dictionary for Regulatory 
Activities (MedDRA).   
In this protocol, signs and symptoms of exacerbation or worsening of knee OA will be captured 
in the context of efficacy assessments and recorded on specific pages of the eCRF. Anticipated 
fluctuations or anticipated deterioration (in the opinion of the Investigator) of the underlying 
disease (knee OA) will not be considered as AEs nor captured on the AE page of the eCRF. 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An SAE is an AE that meets one or more of the following criteria: 
• Results in death 
• Is life threatening  
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event, defined as an event that does not fit one of the other 
outcomes, but may jeopardize the subject and may require medical or surgical 
intervention (treatment) to prevent one of the other outcomes. Examples include 
allergic bronchospasm (a serious problem with breathing) requiring treatment in an 
emergency room (ER), serious blood dyscrasias (blood disorders), or 
seizure/convulsion that does not result in hospitalization. The development of drug 
dependence or drug abuse would be other examples of important medical events.  
The term "life-threatening" in the definition of "serious" refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe. 

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“Inpatient hospitalization” is clarified as hospitalization lasting ≥ 24 hours. Admission to the 
hospital or prolongation of hospitalization qualifies as an SAE only if it is the result of an AE. 
All SAE information must be recorded on the SAE form approved by the Sponsor. Additional 
follow-up information (e.g., test results, autopsy, and discharge summary) may be requested to 
supplement the SAE report form and can be attached as de-identified records. 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
An AE observed during the conduct of a study should be considered an Unanticipated Problem 
(UP) involving risk to human subjects, and be reported to the IRB, only if it was unexpected, 
serious, and would have implications for the conduct of the study (e.g., requiring a significant, 
and usually safety-related, change in the protocol, such as revising inclusion/exclusion criteria or 
including a new monitoring requirement, informed consent, or IB). The occurrence of such an 
event would suggest that the research places study participants or others at a greater risk of harm.  
FDA recommends that there be careful consideration of whether an AE is a UP that must be 
reported to IRBs. In summary, FDA believes that only the following AEs should be considered 
as UPs that must be reported to the IRB:  
• A single occurrence of a serious, unexpected event that is uncommon and strongly 
associated with drug exposure (such as angioedema, agranulocytosis, hepatic injury, or 
Stevens-Johnson syndrome)  
• A single occurrence, or more often a small number of occurrences, of a serious, 
unexpected event that is not commonly associated with drug exposure, but uncommon in 
the study population (e.g., tendon rupture, progressive multifocal leukoencephalopathy)  
• An AE that is described or addressed in the IB, protocol, or informed consent documents, 
but occurs at a specificity or severity that is inconsistent with prior observations  
• An SAE that is described or addressed in the IB, protocol, or informed consent 
documents, but for which the rate of occurrence in the study represents a clinically 
significant increase in the expected rate of occurrence (ordinarily, reporting would only 
be triggered if there were a credible baseline rate for comparison)  
• Any other AE or safety finding (e.g., based on animal or epidemiologic data) that would 
cause the sponsor to modify the IB, study protocol, or informed consent documents, or 
would prompt other action by the IRB to ensure the protection of human subjects  
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 SEVERITY OF EVENT 
The Investigator will assess AEs for severity utilizing the CDISC AESEV, which classifies AEs 
as mild, moderate, or severe (Table 1). 
 
 

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Table 1: 
CDISC Definitions of Adverse Event Severity 
CDISC Submission 
Value 
CDISC Definition 
MILD 
A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living. 
MODERATE 
A type of adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
SEVERE 
A type of adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
8.2.2 RELATIONSHIP TO STUDY AGENT 
The relationship of LOR to an AE will be determined by the Investigator based on the following 
definitions: 
Not Related 
The AE is not related if (1) exposure to LOR or administration of the LOR study injection has 
not occurred or (2) the occurrence of the AE is not reasonably related in time or (3) the AE is 
considered related to another event, medical condition, or product not associated with LOR or 
the LOR study injection. 
Unlikely Related 
The AE is unlikely related if (1) the AE is unlikely related in time or (2) the AE is considered 
unlikely to be related to use of LOR or the LOR study injection (i.e., there are no facts 
[evidence] or arguments to suggest a causal relationship), or the AE is considered possibly 
related to another event, medical condition, or product not associated with LOR or the LOR 
study injection. 
Possibly Related 
The AE is possibly related if (1) LOR or the LOR study injection and AE are considered 
reasonably related in time and (2) the AE could equally be explained by causes other than 
exposure to LOR or the LOR study injection. 
Probably Related 
The AE is probably related if (1) LOR or the LOR study injection and AE are considered 
reasonably related in time and (2) LOR or the LOR study injection is more likely than other 
causes to be responsible for the AE or is the most likely cause of the AE. 
8.2.3 EXPECTEDNESS  
The Sponsor will be responsible for determining whether an AE/SAE is expected or unexpected. 
An AE/SAE will be considered unexpected if the nature, severity, or frequency of the event is 

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not consistent with the risk information previously described for the study agent in the IB or is 
not listed in the IB at the specificity or severity that has been observed.  
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
The reporting period for AEs starts after the Day 1 study injection(s) and ends after the final 
study visit. 
AEs will be followed until the subject’s last visit or resolution, whichever comes first. Non-
serious AEs that are ongoing at the subject’s last visit will be followed for 30 days after their last 
IA injection or until resolution, whichever comes first. Resolution is defined as the return to 
baseline status or stabilization of the condition. At the discretion of the Medical Monitor and in 
consultation with the Investigator, certain non-serious AEs may be followed beyond 30 days. All 
SAEs will be followed until resolution. 
8.4 
REPORTING PROCEDURES 
8.4.1 ADVERSE EVENT REPORTING  
The Investigator is responsible for reporting AEs to the Sponsor via the eCRF and to the IRB 
according to the protocol and 21 Code of Federal Regulations (CFR) Parts 50, 56, and 312. The 
Investigator is responsible for ensuring accurate AE information is reviewed and recorded in the 
subject source and the AE eCRF in a timely manner. The Sponsor is responsible for submitting 
reports of AEs associated with the use of LOR that are both serious and unexpected to the FDA 
according to 21 CFR 312.32. All Investigators participating in ongoing studies with LOR will 
receive copies of these reports from the Sponsor for prompt submission to their IRB/EC 
according to their institution’s requirements.  
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
The Investigator is responsible for reporting SAEs to the Sponsor and IRB according to 21 CFR 
Parts 50, 56, and 312.  
Using the SAE Report Form, SAEs must be reported within 24 hours of study site personnel’s 
knowledge of the event, regardless of the Investigator assessment of the relationship of the event 
to study drug. The Investigator should review the SAE information and sign the SAE report, and 
the Investigator or designee should submit the SAE report to the Sponsor Study SAE email 
address: sae@biosplice.com or FAX: +1 858 408 4470.  
The initial report should include, at a minimum, the following: 
• A description of the SAE (including event term and serious criteria)  
o If the subject died, the report should include the cause of death as the event term 
(with fatal outcome)   
• Causal relationship to the study drug 
• Subject number, sex, and age 
• Details of study drug administration  

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• The date of the report 
Follow-up information must be detailed in a follow-up SAE report and reported to the Sponsor 
Study SAE email address or fax number as it becomes available. The Investigator also must 
report all SAEs promptly to the appropriate IRB/EC as required by the institution. Sponsor 
contact information for questions regarding SAE reporting is provided in Table 2. 
Table 2: 
Sponsor Contact Information for Questions on SAE Reporting 
Primary Contact 
Alternative Contact 
Sherry Beckman, Associate Director, Drug 
Safety and Pharmacovigilance  
Famina Hemani, Executive Director, Drug 
Safety and Pharmacovigilance  
Cellular:  
(858) 500-6021 
 
 
Email:  sherry.beckman@biosplice.com 
Email:  famina.hemani@biosplice.com 
8.4.3 UNANTICIPATED PROBLEM REPORTING  
Incidents or events that meet the criteria for UP (see Section 8.1.3) require the creation and 
completion of an UP report. It is the site Investigator’s responsibility to report UPs to their IRB 
and to the Sponsor. The UP report will include the following information:  
• Protocol identifying information: protocol title and number, Investigator’s name, and 
the IRB project number;  
• A detailed description of the event, incident, experience, or outcome; and 
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP.  
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:  
• UPs that are SAEs will be reported to the Sponsor and the IRB within 24 hours of the 
Investigator becoming aware of the event on the SAE report form.  
• Any other UP will be reported to the IRB and to the Sponsor within the IRB-required 
reporting timeframe.  
8.4.4 EVENTS OF SPECIAL INTEREST  
Not applicable to this study. 
8.4.5 REPORTING OF PREGNANCY  
If a subject becomes pregnant, the pregnancy is to be followed until the outcome is known. An 
IRB-approved Pregnant Subject Data Release Form should be completed by the subject in order 
to obtain consent to follow the progress of the pregnancy and birth, and the health of the infant.  
Any subject pregnancy will be collected on a Pregnancy Report Form. Information will be 
collected for any pregnancy in a female subject which occurs during the study, including 

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perinatal and neonatal outcome. Infants resulting from such pregnancies should be followed for a 
minimum of 12 weeks.  
8.5 
STUDY HALTING RULES  
Not applicable to this study. 
8.6 
SAFETY OVERSIGHT 
Clinical safety oversight will be performed by centralized review conducted by Medical 
Monitors per the Medical Monitoring Plan. In addition, appropriate monitoring will be conducted 
by Clinical Research Associates. 
9. 
CLINICAL MONITORING 
All aspects of the study will be monitored by the Sponsor or the Sponsor’s designees with 
respect to current GCP and Standard Operating Procedures (SOPs) for compliance with 
applicable government regulations. It is the responsibility of the Investigator to provide all study 
records, including eCRFs and source documents among other records, for review and inspection 
by the clinical monitor. 
Clinical monitoring will be performed per the Clinical Monitoring Plan. Clinical monitors will 
periodically evaluate the progress of the study, including the verification of appropriate consent 
form procedures and the verification of the accuracy and completeness of eCRFs. Clinical 
monitors will also ensure that all protocol requirements, applicable US FDA regulations, other 
regulatory requirements, and the Investigator’s obligations are being fulfilled. 
Centralized data monitoring will be performed per the Centralized Data Monitoring Plan in order 
to periodically evaluate study progress and risks. A regular report of risks will be utilized 
together with centralized data monitoring to direct overall monitoring focus and activities to the 
areas of greatest risk which have the most potential to impact subject safety and data quality. 
The accuracy of the data will be verified by reviewing the documents described in Section 11. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
STATISTICAL AND ANALYTICAL PLANS 
This section describes the planned statistical analyses in general terms. A complete description of 
the statistical analyses will be specified in a statistical analysis plan (SAP), finalized prior to 
database lock.   
10.2 
STATISTICAL HYPOTHESES 
No formal hypotheses are being tested in this study.  
10.3 
ANALYSIS DATASETS 
Full Analysis Set (FAS): All subjects who receive a study injection.  
Safety Analysis Set (SAS): All subjects who receive a study injection. In this study, FAS and 
SAS will be identical. 

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Additional analysis sets may be defined and included in the SAP. 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
10.4.1 GENERAL APPROACH 
For continuous variables, the number of subjects in the analysis, mean, standard deviation (SD), 
median, minimum, and maximum will be reported. All categorical endpoints will be summarized 
using frequencies and percentages. 
10.4.2 ANALYSIS OF THE SAFETY ENDPOINTS 
Safety assessments will be performed on an ongoing basis throughout the study on all subjects in 
the SAS. Safety assessments include physical examinations, vital signs, clinical laboratory tests, 
collection of AEs and concomitant medications, and general medical evaluations.  
Safety will be evaluated based on the incidence, severity, and seriousness of AEs and by changes 
in clinical laboratory parameters and vital signs relative to pre-injection. AEs may be 
summarized separately by study medication injected and by the injected knee(s). No formal 
statistical analyses are planned. 
10.4.3 ANALYSIS OF THE EFFICACY ENDPOINTS 
Change over time in the efficacy endpoints will be characterized for each knee and each 
medication using a pre-injection adjusted analysis of covariance (ANCOVA) with time and pre-
injection value as covariates. Unadjusted 95% confidence intervals and P values will be reported 
for the estimated change over time from pre-injection. Percentage of subjects achieving 30%, 
50%, and 70% improvement will also be summarized over time from pre-injection. 
Frequency and interval of time between injections will be summarized by medication and 
subsequent number of injections. Efficacy will be characterized by study medication and 
injection number. 
10.4.4 SAFETY ANALYSES 
Refer to Section 10.4.2.  
10.4.5 BASELINE DESCRIPTIVE STATISTICS 
Baseline is defined as the last value recorded for any given parameter prior to the first study 
injection unless otherwise specified. If a subject never received a study injection, baseline is 
defined as the last value recorded prior to study termination. 
Baseline descriptive statistics will include age, sex, race, ethnicity, weight, BMI, the presence of 
symptomatic OA, KL grade, and insurer/payor. 
10.4.6 PLANNED INTERIM ANALYSES  
Not applicable to this study.  

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10.4.6.1 
SAFETY REVIEW 
Medical monitoring of study safety assessment data will be performed during periodic safety 
reviews detailed in the Medical Monitoring Plan. 
10.4.6.2 
EFFICACY REVIEW 
Not applicable to this study.  
10.4.7 EXPLORATORY ANALYSES 
Not applicable to this study.  
10.4.8 SUB-GROUP ANALYSES 
No subgroup analysis is planned for this study. 
10.5 
SAMPLE SIZE 
The sample size is not based on statistical considerations. A sample size of 300 subjects is a 
reasonable sample size to observe patterns of use of LOR and other IA injections. 
10.6 
MEASURES TO MINIMIZE BIAS 
10.6.1 BLINDING PROCEDURES 
This is an open-label study. 
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
Not applicable to this study. 
10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
Not applicable to this study. 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator must maintain required records for all study subjects. Source data are all 
information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial. Source data for this study will be 
recorded in the subject’s source documents and on the eCRFs, unless otherwise noted. All data 
on these eCRFs should be recorded completely and promptly. A copy of the completed eCRFs 
for each subject will be retained by the investigational center. 
The Investigator must maintain adequate and accurate source documents upon which eCRFs for 
each subject are based. They are to be separate and distinct from eCRFs, except for cases in 
which the Sponsor has predetermined that direct data entry into specified pages of the subject’s 
eCRF is appropriate. The source documents should include detailed notes on the following: 

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• The oral and written communication with the subject regarding the study (including the 
risks and benefits of the study), both at the site and by phone, and the date of informed 
consent(s) must be recorded in the source documentation 
• The subject’s medical and disease history before participation in the study 
• The subject’s basic identifying information, such as subject number, that links the 
subject’s source documents with the eCRFs 
• The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject 
• All AEs  
• The subject’s exposure to any concomitant therapy (including start and stop dates, route 
of administration, and dosage)  
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
site/Investigator training, and applicable regulations and guidelines. Clinical Investigator sites 
will be trained at the Investigator Meeting and/or individual visits. All aspects of the study will 
be monitored carefully by the Sponsor’s designees with respect to current GCP and SOPs for 
compliance with applicable government regulations. It is the responsibility of the Investigator to 
provide all study records, including case report forms (CRFs) and source documents, among 
other records, for review and inspection by the clinical monitor, representatives of the Sponsor, 
and regulatory authorities, as needed. 
The Integrated Quality and Risk Management Plan (IQRMP) details the trial specific quality 
management plans to indicate how risks are mitigated and data quality is addressed in the clinical 
trial.  
13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
13.1 
ETHICAL STANDARD  
The study will be conducted in accordance with the Declaration of Helsinki (1964), including all 
amendments up to and including the Brazil revision (2013). The Investigator will ensure that this 
study is conducted in full conformity with Regulations for the Protection of Human Subjects of 
Research set forth in US 21 CFR Part 50, 21 CFR Part 56, and/or the ICH-GCP E6 (R2). 
13.2 
INSTITUTIONAL REVIEW BOARD  
The Investigator agrees to provide the IRB/EC with all appropriate material, including a copy of 
the ICF. The study will not be initiated until the Investigator obtains written approval of the 
research plan and the ICF from the appropriate IRB/EC and copies of these documents are 
received by the Sponsor. Appropriate reports on the progress of this study will be made by the 
Investigator to the IRB/EC and Sponsor in accordance with applicable government regulations 
and in agreement with the policies established by the Sponsor and the IRB/EC. Any amendment 
to the protocol will require review and approval by the IRB before the changes are implemented 
to the study. All changes to the consent form will be IRB approved; a determination will be made 

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regarding whether previously consented participants need to be re-consented. The Sponsor 
ensures that the IRB/EC complies with the requirements set forth in US 21 CFR Part 56.  
13.3 
INFORMED CONSENT PROCESS  
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED 
TO PARTICIPANTS 
Consent forms describing in detail the study procedures and risks will be given to the potential 
participant and written documentation of informed consent is required prior to starting any 
screening evaluations or other study-related procedures.   
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
The informed consent and consent process should be in accordance with the current Declaration 
of Helsinki, ICH, GCP, federal, state, and local regulations. The Investigator or designee must 
explain the nature of the study protocol and associated risks to the potential study participant. 
The potential participant must be allowed to review the study information and to ask questions 
before being asked to sign and date the ICF. Written informed consent must be provided (signed 
and dated) by the potential study participant prior to initiation of any screening evaluations or 
other study-related procedures. A copy of the ICF will be given to the participants for their 
records. The signature, date, and the name of the individual at the site who obtained the informed 
consent will be recorded.  
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
The Investigator(s) and the Sponsor or its authorized representative will preserve the 
confidentiality of all subjects participating in a study, in accordance with current GCP, federal, 
state, and local regulations, including, to the extent applicable, the Health Insurance Portability 
and Accountability Act of 1996 (HIPAA). 
In order to maintain subject confidentiality, all eCRFs, study reports, and communications 
relating to the study will identify subjects by initials and assigned subject numbers; subjects 
should not be identified by name. If a subject name appears on any document, it must be 
obliterated before a copy of the document is supplied to the Sponsor or its authorized 
representative. Study findings stored on a computer will be stored in accordance with federal, 
state, and local data protection laws. Subjects will be told that representatives of the Sponsor, its 
authorized representative, IRB or EC, or regulatory authorities may inspect their medical records 
to verify the information collected, and that all personal information will be held in strict 
confidence and in accordance with applicable data protection laws. The Investigator or designee 
will maintain a personal subject identification list (subject numbers with the corresponding 
subject names) to make it possible for records to be identified.  
Clinical information will not be released without written permission from the subject, except as 
necessary for monitoring by the IRB/EC, the FDA, or the study Sponsor.  
Any information, inventions, or discoveries (whether patentable or not), innovations, 
suggestions, ideas, and reports made or developed by the Investigator(s) as a result of conducting 
this study shall be promptly disclosed to the Sponsor and shall be the sole property of the 

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Sponsor. The Investigator agrees, upon the Sponsor’s request and at the Sponsor’s expense, to 
execute such documents and to take such other actions, as the Sponsor deems necessary or 
appropriate, to obtain patents in the Sponsor’s name covering any of the foregoing. 
13.5 
FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected in this study may be useful for other research studies. The Sponsor will only use 
protected health information in other research studies upon approval from the IRB/EC. If the 
IRB/EC determines it to be necessary, the Sponsor will obtain informed consent before starting 
the other research study(ies). Subjects may withdraw permission for use of their data for future 
research by notifying the site by letter. 
14. 
DATA HANDLING AND RECORD KEEPING  
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
As defined by ICH guidelines, the CRF is a printed, optical, or electronic document designed to 
record all protocol-required information to be reported to the Sponsor on each study subject. 
Data required by the protocol will either be collected within eCRFs of the study-specific 
Medidata Rave database or provided directly to the Sponsor via data transfers. Medidata Rave is 
a validated electronic data capture (EDC) system fully compliant with regulatory expectations 
for software developers and service providers within the global regulatory environment, 
including but not limited to ICH-GCP E6 (R2) and US 21 CFR Parts 312, 812, and 11. Data to 
be transferred external to Rave may include central laboratory data. 
Data collection on the eCRF will follow the instructions described in the eCRF Completion 
Guidelines. The Investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF. The Investigator or designee as identified on Form FDA 1572 
will electronically sign the completed eCRF to attest to its accuracy, authenticity, and 
completeness. Copies of the completed eCRFs will be retained by each investigational center as 
well as the Sponsor. 
Clinical data management activities will be conducted by the Sponsor as described in the 
study-specific Data Management Plan. 
14.2 
STUDY RECORDS RETENTION  
During this study, the Investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the investigation on each 
individual treated with the IP or entered as a control in the investigation. CRFs will be provided 
for each subject by the Sponsor. Data reported on the eCRFs and derived from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
completed eCRFs must be promptly reviewed, and electronically signed and dated in EDC by a 
qualified physician who is an Investigator on the study once all data is considered final. During 
this study, the Investigator must retain copies of eCRFs (or electronic files), and source 
documents for the maximum period required by (1) applicable regulations and guidelines or 
institution procedures or (2) for the period specified by the Sponsor, whichever is longer. The 
Investigator must contact the Sponsor prior to destroying any records associated with the study. 

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The Sponsor will notify the Investigator when the study records are no longer needed. 
In the event the Investigator withdraws from the study (e.g., relocation, retirement), the records 
shall be transferred to a mutually agreed-upon designee (e.g., another Investigator). Notice of 
such transfer will be given in writing to the Sponsor. 
The Investigator must ensure that clinical study records are retained according to national 
regulations, as documented in the Clinical Trial Agreement entered into with the Sponsor in 
connection with this study. For example, US federal laws require that an Investigator maintain all 
study records for the indication under investigation for 2 years following the date of a New Drug 
Application approval or, if no application is filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and the FDA is notified. 
The Sponsor will maintain correspondence with the Investigator after study closeout to ensure 
that study documentation is retained for the appropriate amount of time. Subject files and other 
source data must be kept for the maximum period of time permitted by the hospital, institution, 
or private practice and should be retained in accordance with applicable regulations. The 
Investigator must inform the Sponsor immediately if any documents are to be destroyed, to be 
transferred to a different facility, or to be transferred to a different owner. 
14.3 
PROTOCOL DEVIATIONS  
The Investigator and study staff will apply due diligence to avoid protocol deviations. If protocol 
deviations do occur, the Investigator or study staff must report them to the local IRB/EC per their 
guidelines.  
14.4 
PUBLICATION AND DATA SHARING POLICY 
The Sponsor encourages the scientific publication of data from clinical research studies. 
Investigators, however, may not present or publish partial or complete study results individually 
without the participation of the Sponsor. The Investigator(s) and the Sponsor may propose 
appropriate scientific manuscripts or abstracts from the study data. All proposed publications 
must be reviewed and commented on by the Sponsor before submission for publication. The 
detailed procedures for the review of publications are set out in the Clinical Trial Agreement 
entered into with the Sponsor in connection with this study. These procedures are in place to 
ensure coordination of study data publication and adequate review of data for publication against 
the validated study database for accuracy. International Committee of Medical Journal Editors 
(ICMJE) guidelines for authorship will be considered to determine authors for publications.   
 
 
 

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15. 
STUDY ADMINISTRATION 
15.1 
STUDY LEADERSHIP 
The study will be led and conducted by Biosplice Therapeutics, Inc.  
15.2 
KEY ROLES 
Medical monitor 
Ismail Simsek, MD - Medical Director 
Biosplice Therapeutics, Inc.  
9360 Towne Centre Drive 
San Diego, CA 92121 
(858) 926-2968 
ismail.simsek@biosplice.com 
 

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16. 
LITERATURE REFERENCES  
 
"WHO Department of Chronic Diseases and Health Promotion." from 
http://www.who.int/chp/topics/rheumatic/en/. 
"World Population to 2300." 
(IHME), I. f. H. M. a. E. (2021). "GBDx Results Tool."   Retrieved January 7, 2021 from 
http://ghdx.healthdata.org/gbd-results-tool  
Altman, R., E. Asch, D. Bloch, G. Bole, D. Borenstein, K. Brandt, W. Christy, T. D. Cooke, R. 
Greenwald, M. Hochberg and et al. (1986). "Development of criteria for the classification and 
reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and 
Therapeutic Criteria Committee of the American Rheumatism Association." Arthritis Rheum 
29(8): 1039-1049. 
Bannuru, R. R., M. C. Osani, E. E. Vaysbrot, N. K. Arden, K. Bennell, S. M. A. Bierma-
Zeinstra, V. B. Kraus, L. S. Lohmander, J. H. Abbott, M. Bhandari, F. J. Blanco, R. Espinosa, I. 
K. Haugen, J. Lin, L. A. Mandl, E. Moilanen, N. Nakamura, L. Snyder-Mackler, T. Trojian, M. 
Underwood and T. E. McAlindon (2019). "OARSI guidelines for the non-surgical management 
of knee, hip, and polyarticular osteoarthritis." Osteoarthritis Cartilage 27(11): 1578-1589. 
Clauw, D. J. (2014). "Fibromyalgia: a clinical review." JAMA 311(15): 1547-1555. 
Conaghan, P. G., A. D. Cook, J. A. Hamilton and P. P. Tak (2019). "Therapeutic options for 
targeting inflammatory osteoarthritis pain." Nat Rev Rheumatol 15(6): 355-363. 
Gelse, K., A. B. Ekici, F. Cipa, B. Swoboda, H. D. Carl, A. Olk, F. F. Hennig and P. Klinger 
(2012). "Molecular differentiation between osteophytic and articular cartilage--clues for a 
transient and permanent chondrocyte phenotype." Osteoarthritis Cartilage 20(2): 162-171. 
Hochberg, M. C., R. D. Altman, K. T. April, M. Benkhalti, G. Guyatt, J. McGowan, T. Towheed, 
V. Welch, G. Wells, P. Tugwell and R. American College of (2012). "American College of 
Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic 
therapies in osteoarthritis of the hand, hip, and knee." Arthritis Care Res (Hoboken) 64(4): 465-
474. 
Katz, J. N., K. R. Arant and R. F. Loeser (2021). "Diagnosis and Treatment of Hip and Knee 
Osteoarthritis: A Review." JAMA 325(6): 568-578. 
Lawrence, R. C., D. T. Felson, C. G. Helmick, L. M. Arnold, H. Choi, R. A. Deyo, S. Gabriel, R. 
Hirsch, M. C. Hochberg, G. G. Hunder, J. M. Jordan, J. N. Katz, H. M. Kremers, F. Wolfe and 
W. National Arthritis Data (2008). "Estimates of the prevalence of arthritis and other rheumatic 
conditions in the United States. Part II." Arthritis Rheum 58(1): 26-35. 
Loeser, R. F., S. R. Goldring, C. R. Scanzello and M. B. Goldring (2012). "Osteoarthritis: a 
disease of the joint as an organ." Arthritis Rheum 64(6): 1697-1707. 
Luyten, F. P., P. Tylzanowski and R. J. Lories (2009). "Wnt signaling and osteoarthritis." Bone 
44(4): 522-527. 
Maiese, K. (2016). "Picking a bone with WISP1 (CCN4): new strategies against degenerative 
joint disease." J Transl Sci 1(3): 83-85. 

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Monteagudo, S. and R. J. Lories (2017). "Cushioning the cartilage: a canonical Wnt restricting 
matter." Nat Rev Rheumatol 13(11): 670-681. 
Neogi, T. (2013). "The epidemiology and impact of pain in osteoarthritis." Osteoarthritis 
Cartilage 21(9): 1145-1153. 
Thomas, R. S., A. R. Clarke, V. C. Duance and E. J. Blain (2011). "Effects of Wnt3A and 
mechanical load on cartilage chondrocyte homeostasis." Arthritis Res Ther 13(6): R203. 
Zhou, Y., T. Wang, J. L. Hamilton and D. Chen (2017). "Wnt/beta-catenin Signaling in 
Osteoarthritis and in Other Forms of Arthritis." Curr Rheumatol Rep 19(9): 53. 
Zhu, M., M. Chen, M. Zuscik, Q. Wu, Y. J. Wang, R. N. Rosier, R. J. O'Keefe and D. Chen 
(2008). "Inhibition of beta-catenin signaling in articular chondrocytes results in articular 
cartilage destruction." Arthritis Rheum 58(7): 2053-2064. 
Zhu, M., D. Tang, Q. Wu, S. Hao, M. Chen, C. Xie, R. N. Rosier, R. J. O'Keefe, M. Zuscik and 
D. Chen (2009). "Activation of beta-catenin signaling in articular chondrocytes leads to 
osteoarthritis-like phenotype in adult beta-catenin conditional activation mice." J Bone Miner 
Res 24(1): 12-21. 
 
 
 

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APPENDIX 
Appendix 1. 
American College of Rheumatology Clinical and Radiographic Criteria for 
Classification of Osteoarthritis of the Knee  
Per American College of Rheumatology (ACR) clinical and radiographic classification criteria 
(Altman, Asch et al. 1986), the presence of all 3 of the following items classifies knee OA in 
patients: 
1. Knee pain,  
2. Osteophytes, AND 
3. At least 1 of 3:  
• Age > 50 years 
• Morning stiffness < 30 minutes duration 
• Crepitus on active motion 
 
 

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Appendix 2. 
Kellgren-Lawrence Grading Scale  
 
Grade 0:  Normal appearance of the knee 
Grade 1:  Doubtful narrowing of joint space and possible osteophyte lipping 
Grade 2:  Definite osteophytes and possible narrowing of joint space 
Grade 3:  Multiple osteophytes, definite narrowing of joint space, some sclerosis, and possible 
deformity of bone ends 
Grade 4:  Large osteophytes, marked narrowing of joint space, severe sclerosis, and definite 
deformity of bone ends