A Long-Term Extension Study Evaluating the Safety and Efficacy of Lorecivivint in Subjects With Osteoarthritis of the Knee
Phase: PHASE3
Conditions: Osteoarthritis, Knee
Sponsor: Biosplice Therapeutics, Inc.

 
 
 
 
 
 
 
A Long-Term Extension Study Evaluating the Safety and 
Efficacy of Lorecivivint in Subjects with Osteoarthritis of 
the Knee 
 
 
Study Number: SM04690-OA-07 
IND Sponsor: Biosplice Therapeutics, Inc. (a subsidiary of Samumed, LLC) 
Version Number: Amendment 02 Version 00 
Date:  04 May 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. 
Original Protocol Date:  12 March 2020 
Amendment 00 Version 01: 15 April 2020 
Amendment 00 Version 02: 16 April 2020 
Amendment 01 Version 00: 22 July 2020 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07  
Biosplice Therapeutics, Inc. 
 
 
AM02V00 
04 May 2021 
 
Confidential 
 
ii 
SPONSOR SIGNATURE PAGE 
A Long-Term Extension Study Evaluating the Safety and Efficacy of Lorecivivint in Subjects 
with Osteoarthritis of the Knee 
Protocol Number: 
SM04690-OA-07 AM02V00 
Date:  
 
04 May 2021 
 
Name & Title 
Signature 
 Date 
Mark Fineman, PhD 
Senior Vice President, 
Clinical Affairs  
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 US Code of Federal Regulations (CFR) 21 CFR Parts 50, 54, 56, 312, and 314, and GCP 
Guidelines, as applicable. 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07  
Biosplice Therapeutics, Inc. 
 
 
AM02V00 
04 May 2021 
 
Confidential 
 
1 
 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................................ II 
TABLE OF CONTENTS ............................................................................................................. 1 
LIST OF ABBREVIATIONS ...................................................................................................... 5 
STATEMENT OF COMPLIANCE ............................................................................................ 7 
1. 
PROTOCOL SUMMARY ................................................................................................... 8 
1.1 
SYNOPSIS ......................................................................................................................... 8 
2. 
INTRODUCTION ............................................................................................................... 14 
2.1 
STUDY RATIONALE ........................................................................................................ 14 
2.2 
BACKGROUND INFORMATION ........................................................................................ 14 
2.3 
POTENTIAL RISKS AND BENEFITS................................................................................... 15 
2.3.1 Known Potential Risks .............................................................................................. 15 
2.3.2 Known Potential Benefits ......................................................................................... 15 
2.3.3 Assessment of Potential Risks and Benefits ............................................................. 16 
3. 
OBJECTIVES AND ENDPOINTS ................................................................................... 16 
3.1 
OBJECTIVES ................................................................................................................... 16 
3.2 
STUDY ENDPOINTS ......................................................................................................... 16 
3.2.1 Safety Endpoints ....................................................................................................... 16 
3.2.2 Efficacy Endpoints .................................................................................................... 17 
4. 
STUDY DESIGN ................................................................................................................. 17 
4.1 
DESCRIPTION OF THE STUDY DESIGN ............................................................................. 17 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN .................................................................. 18 
4.3 
JUSTIFICATION FOR DOSE............................................................................................... 18 
4.4 
END OF STUDY DEFINITION............................................................................................ 18 
5. 
STUDY POPULATION ..................................................................................................... 18 
5.1 
PARTICIPANT INCLUSION CRITERIA ............................................................................... 18 
5.2 
PARTICIPANT EXCLUSION CRITERIA .............................................................................. 18 
5.3 
LIFESTYLE GUIDELINES ................................................................................................. 19 
5.3.1 Contraception ............................................................................................................ 19 
5.4 
SCREEN FAILURES.......................................................................................................... 20 
5.4.1 Screen Failures .......................................................................................................... 20 
5.4.2 Subject Rescreening .................................................................................................. 20 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION ......................................................... 20 
5.6 
PARTICIPANT WITHDRAWAL OR TERMINATION ............................................................. 20 
5.6.1 Reasons for Withdrawal or Termination................................................................... 20 
5.6.2 Handling of Participant Withdrawals or Termination .............................................. 21 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07  
Biosplice Therapeutics, Inc. 
 
 
AM02V00 
04 May 2021 
 
Confidential 
 
2 
5.7 
TERMINATION OR SUSPENSION OF STUDY ...................................................................... 21 
6. 
STUDY AGENT .................................................................................................................. 21 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION ............................................................. 21 
6.1.1 Acquisition ................................................................................................................ 21 
6.1.2 Formulation, Appearance, Packaging, and Labeling ................................................ 21 
6.1.3 Product Storage and Stability.................................................................................... 22 
6.1.4 Preparation ................................................................................................................ 22 
6.1.5 Dosing and Administration ....................................................................................... 22 
6.1.6 Route of Administration ........................................................................................... 23 
6.1.7 Starting Dose and Dose Escalation Schedule ........................................................... 23 
6.1.8 Dose Adjustments/Modifications/Delays ................................................................. 23 
6.1.9 Duration of Therapy .................................................................................................. 23 
6.1.10 Study Intervention Compliance ................................................................................ 23 
6.1.11 Device Specific Considerations ................................................................................ 23 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................ 23 
7. 
STUDY PROCEDURES AND SCHEDULE .................................................................... 24 
7.1 
STUDY PROCEDURES/EVALUATIONS .............................................................................. 24 
7.1.1 Study Specific Procedures ........................................................................................ 24 
7.1.2 Standard-of-Care Study Procedures .......................................................................... 27 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................... 28 
7.2.1 Clinical Laboratory Evaluations ............................................................................... 28 
7.2.2 Other Assays or Procedures ...................................................................................... 28 
7.2.3 Specimen Preparation, Handling, and Storage ......................................................... 29 
7.2.4 Specimen Shipment .................................................................................................. 29 
7.3 
STUDY SCHEDULE .......................................................................................................... 29 
7.3.1 Screening/Enrollment ............................................................................................... 29 
7.3.2 Study Visits ............................................................................................................... 29 
7.3.3 Termination Visit ...................................................................................................... 31 
7.3.4 Schedule of Events Table .......................................................................................... 33 
7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES ................................................................. 34 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................................. 34 
7.5.1 Precautionary Medications, Treatments, and Procedures ......................................... 34 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ...................................... 34 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ................................. 35 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ............................................. 35 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ....................................... 35 
8. 
ASSESSMENT OF SAFETY ............................................................................................. 35 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................... 35 
8.1.1 Definition of Adverse Events.................................................................................... 35 
8.1.2 Definition of Serious Adverse Events....................................................................... 36 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07  
Biosplice Therapeutics, Inc. 
 
 
AM02V00 
04 May 2021 
 
Confidential 
 
3 
8.1.3 Definition of Unanticipated Problems ...................................................................... 36 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ...................................................................... 37 
8.2.1 Severity of Event....................................................................................................... 37 
8.2.2 Relationship to Study Agent ..................................................................................... 38 
8.2.3 Expectedness ............................................................................................................. 38 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ................. 38 
8.4 
REPORTING PROCEDURES .............................................................................................. 39 
8.4.1 Adverse Event Reporting .......................................................................................... 39 
8.4.2 Serious Adverse Event Reporting ............................................................................. 39 
8.4.3 Unanticipated Problem Reporting............................................................................. 40 
8.4.4 Events of Special Interest.......................................................................................... 40 
8.4.5 Reporting of Pregnancy ............................................................................................ 40 
8.5 
STUDY HALTING RULES ................................................................................................. 40 
8.6 
SAFETY OVERSIGHT ....................................................................................................... 40 
9. 
CLINICAL MONITORING .............................................................................................. 40 
10. STATISTICAL CONSIDERATIONS .............................................................................. 41 
10.1 
STATISTICAL AND ANALYTICAL PLANS ......................................................................... 41 
10.2 
STATISTICAL HYPOTHESES ............................................................................................ 41 
10.3 
ANALYSIS DATASETS ..................................................................................................... 41 
10.4 
DESCRIPTION OF STATISTICAL METHODS ...................................................................... 41 
10.4.1 General Approach ..................................................................................................... 41 
10.4.2 Analysis of Safety Endpoint(s) ................................................................................. 42 
10.4.3 Analysis of Efficacy Endpoint(s) .............................................................................. 42 
10.4.4 Baseline Descriptive Statistics .................................................................................. 42 
10.4.5 Planned Interim Analyses ......................................................................................... 43 
10.4.6 Exploratory Analyses ................................................................................................ 43 
10.4.7 Sub-Group Analyses ................................................................................................. 43 
10.5 
SAMPLE SIZE .................................................................................................................. 43 
10.6 
MEASURES TO MINIMIZE BIAS ....................................................................................... 43 
10.6.1 Blinding Procedures .................................................................................................. 43 
10.6.2 Breaking the Study Blind/Participant Code .............................................................. 43 
11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ......... 44 
12. QUALITY ASSURANCE AND QUALITY CONTROL ................................................ 44 
13. ETHICS/PROTECTION OF HUMAN SUBJECTS ....................................................... 45 
13.1 
ETHICAL STANDARD ...................................................................................................... 45 
13.2 
INSTITUTIONAL REVIEW BOARD .................................................................................... 45 
13.3 
INFORMED CONSENT PROCESS ....................................................................................... 45 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants ....... 45 
13.3.2 Consent Procedures and Documentation .................................................................. 45 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07  
Biosplice Therapeutics, Inc. 
 
 
AM02V00 
04 May 2021 
 
Confidential 
 
4 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................. 46 
13.4.1 Research Use of Stored Human Samples, Specimens, or Data ................................ 46 
13.5 
FUTURE USE OF STORED SPECIMENS ............................................................................. 46 
14. DATA HANDLING AND RECORD KEEPING ............................................................. 46 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ........................................... 46 
14.2 
STUDY RECORDS RETENTION ........................................................................................ 47 
14.3 
PROTOCOL DEVIATIONS ................................................................................................. 48 
14.4 
PUBLICATION AND DATA SHARING POLICY ................................................................... 48 
15. STUDY ADMINISTRATION ............................................................................................ 49 
15.1 
STUDY LEADERSHIP ....................................................................................................... 49 
15.2 
KEY ROLES .................................................................................................................... 49 
16. LITERATURE REFERENCES ........................................................................................ 50 
APPENDIX 1. 
PROHIBITED CONCOMITANT MEDICATIONS AND 
PROCEDURES (SUPPLEMENT) ............................................................................................ 51 
APPENDIX 2. 
AMENDMENTS ......................................................................................... 52 
 
 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07  
Biosplice Therapeutics, Inc. 
 
 
AM02V00 
04 May 2021 
 
Confidential 
 
5 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
AE  
Adverse event 
AESEV 
Severity/Intensity Scale for Adverse Events 
ANCOVA 
Analysis of covariance 
β-CTX 
β-C-terminal telopeptide 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CLK2 
CDC-like kinase 2  
COMP 
Cartilage oligomeric matrix protein 
CRF 
Case report form 
DYRK1A 
Dual‐specificity tyrosine phosphorylation‐regulated kinase 1A 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 
FAS 
Full analysis set 
FDA 
(US) Food and Drug Administration 
GCP 
Good Clinical Practice 
HRQOL 
Health-related quality of life 
IA 
Intra-articular(ly) 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IP 
Investigational product 
IRB 
Institutional Review Board 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07  
Biosplice Therapeutics, Inc. 
 
 
AM02V00 
04 May 2021 
 
Confidential 
 
6 
Abbreviation 
Term 
IUD 
Intrauterine device 
mJSW 
Medial joint space width 
NRS 
Numeric rating scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
OA 
Osteoarthritis 
PA 
Posterior-anterior 
PASS 
Patient Acceptable Symptom State 
P1NP 
N-terminal propeptides of procollagen type I 
PPAS 
Per-protocol analysis set 
SAE 
Serious adverse event 
SAS 
Safety analysis set 
SF-36 
36-Item Short Form Health Survey 
SOP 
Standard operating procedure 
UP 
Unanticipated problem 
US 
United States 
WOCBP 
Women of childbearing potential 
WOMAC 
Western Ontario and McMaster Universities Arthritis Index 
 
 
 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07  
Biosplice Therapeutics, Inc. 
 
 
AM02V00 
04 May 2021 
 
Confidential 
 
7 
STATEMENT OF COMPLIANCE 
Study Title 
A Long-Term Extension Study Evaluating the Safety and Efficacy of 
Lorecivivint in Subjects with Osteoarthritis of the Knee 
Protocol Number 
SM04690-OA-07 
Protocol Date 
04 May 2021 
Protocol Version 
AM02V00 
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 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 
 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07  
Biosplice Therapeutics, Inc. 
 
 
AM02V00 
04 May 2021 
 
Confidential 
 
8 
1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
A Long-Term Extension Study Evaluating the Safety and Efficacy of 
Lorecivivint in Subjects with Osteoarthritis of the Knee 
Objectives: 
 
Primary:  
The primary objective of this study is to evaluate the safety and efficacy of a 
second year of use of lorecivivint (LOR) in subjects with knee osteoarthritis 
(OA). 
Secondary: 
The secondary objective of this study is to evaluate the safety and efficacy of 
long-term use of LOR in subjects with knee OA. 
Endpoints: 
Safety:  
• Adverse events (AEs) and serious adverse events (SAEs) (incidence, 
severity, and relationship to study drug) over the course of the study 
• Clinically significant changes from parent-study-baseline clinical 
laboratory measures and vital signs, as assessed by the Investigator, over 
the course of the study 
• Change in serum bone biomarkers (N-terminal propeptides of procollagen 
type I [P1NP] and β-C-terminal telopeptide [β-CTX]) from parent-study 
baseline, and change in a serum cartilage biomarker (cartilage oligomeric 
matrix protein [COMP]) from parent-study baseline at Visit 3E 
Efficacy: 
• Change from parent-study-baseline medial joint space width (mJSW) in 
the target knee as evaluated by radiograph over the course of the study 
• Change from parent-study-baseline OA pain in the target knee as assessed 
by pain NRS over the course of the study  
• Change from parent-study-baseline OA pain in the target knee as assessed 
by WOMAC Pain over the course of the study  
• Change from parent-study-baseline OA function in the target knee as 
assessed by WOMAC Function over the course of the study  
• Change from parent-study-baseline OA pain, function, and stiffness as a 
composite outcome measure as assessed by WOMAC total score 
(WOMAC Total) over the course of the study 
• Change from parent-study-baseline health-related quality of life 
(HRQOL) as assessed by the 36-Item Short Form Health Survey (SF-36) 
over the course of the study  
• Percentage of subjects who consider themselves to be in a Patient 
Acceptable Symptom State (PASS) over the course of the study  
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07  
Biosplice Therapeutics, Inc. 
 
 
AM02V00 
04 May 2021 
 
Confidential 
 
9 
Methodology: 
This study will be a multicenter study in subjects previously enrolled in study 
SM04690-OA-11. The first 48 weeks will be single-blind and placebo-
controlled while the remainder of the study will be open-label and 
uncontrolled. The study is planned to continue at least until commercial 
availability of LOR. Based on previous studies, up to approximately 500 
subjects will be enrolled, but there is no set cap on enrollment. Subjects must 
enroll no later than 6 weeks following completion of study SM04690-OA-11. 
Clinic visits will be scheduled at Visit 1E (Day 1), Visit 2E (Week 24), Visit 
3E (Week 48), Visit 4E (Week 52 phone visit), Visit 5E (Week 74), and 
every 26 weeks thereafter until the Termination Visit. Refer to Figure 1 for an 
overview of study design and endpoints. 
At the first visit in this study (Visit 1E), all subjects will complete PASS and 
pain NRS assessments and then receive a blinded study injection into their 
target knee (the same target knee injected in the parent study), with subjects 
receiving the same treatment (either 0.07 mg LOR or placebo) as they 
received in the parent study. Subjects will have clinic visits for pain and 
function assessments, collection of AEs, and knee radiographs. At Visit 3E, 
subjects will have plasma samples collected for assessment of biomarkers of 
bone and cartilage turnover, and all subjects, regardless of previous treatment, 
will receive an injection of 0.07 mg LOR into their target knee. Subjects will 
receive injections of 0.07 mg LOR into their target knee every 52 weeks 
thereafter.  
Subjects are allowed to use non-steroidal anti-inflammatory drugs (NSAIDs) 
and/or acetaminophen for pain relief as needed. If a subject has a partial or 
total knee replacement of the target knee, the subject will be discontinued 
from the study. 
Mode of Administration: At Visit 1E, injection of LOR or placebo into the 
target knee joint will be performed by an unblinded injector who does not 
participate in other subject evaluations. At Visit 3E and for any subsequent 
injections, injection of LOR into the target knee joint does not need to be 
performed by an unblinded injector due to the open-label nature of the 
remaining portion of the study.  
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07  
Biosplice Therapeutics, Inc. 
 
 
                                     AM02V00 
04 May 2021 
 
Confidential 
 
10 
Figure 1. Overview of SM04690-OA-07 Study Design and Endpoints 
 
 
Abbreviations: EOS = End of Study; LOR = lorecivivint; OA = osteoarthritis; PBO = placebo. 
 
 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
11 
Inclusion/ 
Exclusion 
Criteria: 
Criteria for Inclusion: 
1. Completion of study SM04690-OA-11 
2. Compliance with procedures in study SM04690-OA-11, in the 
opinion of the Investigator  
3. Fully understanding study requirements and willingness to comply 
with study visits and assessments 
4. Understanding and signing of the informed consent form (ICF) 
prior to any study-related procedures 
Criteria for Exclusion: 
1. 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 
2. Any contraindications for an intra-articular (IA) injection in the 
target knee in the opinion of the Investigator 
3. Any known reason identified by the Investigator or Sponsor that the 
subject may not be compliant with study visits or may no longer be 
an appropriate candidate for the study (e.g., planned surgery of the 
pelvis/hip, knee, ankle, or foot, knee replacement during the parent 
study, planning to move away from the research site, or initiation of 
a prohibited concomitant medication including, but not limited to, 
IA injection of glucocorticoids, hyaluronic acid derivatives, 
platelet-rich plasma, stem cell therapies, or other agents with 
therapeutic intent into the target knee) 
4. Participation in a clinical research trial (other than the prior 
SM04690-OA-11 study) that included the receipt of an 
investigational product (IP) or any experimental therapeutic 
procedure within 12 weeks before any study injection, or planned 
participation in any such trial 
5. Current or pending disability claim, workers’ compensation, or 
litigation(s) that may compromise response to treatment 
6. 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 Visit 1E  
7. 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 
Population: 
Up to approximately 500 subjects with no cap on enrollment  
Phase: 
3 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
12 
Number of Sites 
Enrolling 
Participants: 
Approximately 50 
  
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 degradation and enhances formation of cartilage through effects on 
progenitor cells and chondrocytes resident in the joint. 
Study Duration: Approximately 4 years (based on potential commercial availability of 
LOR) 
Estimated date first subject consented: August 2020 
Estimated date last subject completed: September 2024 
Participant 
Duration: 
Subjects are anticipated to stay in the study until conduct completion 
unless they are withdrawn or choose to withdraw from the study (refer to 
Section 5.6.1). 
Statistical 
Methods: 
Sample Size:   
The sample size of up to approximately 500 subjects was estimated based 
on practical considerations, such as the number of subjects anticipated to 
complete study SM04690-OA-11 but there is no set cap on enrollment. 
General approach: 
For continuous variables, number of subjects in the analysis, mean, 
standard deviation, median, minimum, and maximum will be reported. All 
categorical endpoints will be summarized using frequencies and 
percentages. Baseline values are defined as assessments occurring before 
the first blinded study injection in the parent study. 
Safety Analysis: 
Safety assessments include physical examinations, vital signs, clinical 
laboratory tests, solicitation of AEs and concomitant medications, and 
general medical evaluations. No formal statistical analyses are planned. 
Safety will be evaluated based on the incidence, seriousness, severity, and 
relationship of AEs, by changes in clinical laboratory parameters and vital 
signs, relative to parent-study baseline. For subjects who cross over from 
placebo to LOR, subsequent changes in laboratory parameters and vital 
signs will be relative to Visit 3E. 
Efficacy Analysis: 
Change over time in mJSW, pain NRS, WOMAC Pain, WOMAC 
Function, and WOMAC Total will be characterized using mixed-effects 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
13 
models for repeated measures (MMRM). The models will estimate change 
from parent-study baseline with treatment, visit, treatment × visit 
interaction, and parent-study-baseline value as covariates.  
Percentage of subjects in a PASS state will be analyzed by logistic 
regression. Analysis of covariance (ANCOVA) will be used to analyze the 
change in SF-36 domain scores and summary component scores.  
 
 
 
 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
14 
2. 
INTRODUCTION 
2.1 
STUDY RATIONALE 
Osteoarthritis (OA) is the most common form of arthritis and chronic joint disorder in humans 
(Dougados et al. 2011). The exact cause of OA is unknown, but it is associated with aging and 
normal wear on a joint. 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 more stiff and immobile over time (Dougados et al. 2011). OA is a 
leading cause of physical disability in the United States (US) (Lawrence et al. 2008).  
The Wnt pathway plays a central role in the initiation and progression of OA pathology and is 
crucial in normal joint metabolism (Hochberg et al. 2012). Wnt is a major regulator of joint 
development and is involved in the formation of bone, cartilage, and synovium. The transcription 
of Wnt pathway target genes causes an increase in catabolic processes during the development of 
OA, and increased Wnt signaling may contribute to cartilage loss (Gelse et al. 2012). 
Polymorphisms in genes involved in Wnt signaling are associated with an increased 
susceptibility to OA development (Wu et al. 2012). Established research suggests that 
modulation of Wnt signaling is an attractive target mechanism for treatment of OA. 
To address the need for effective pharmaceutical agents to treat OA, Biosplice Therapeutics, Inc. 
(Biosplice) has used structure-based drug design to synthesize a small molecule modulator of the 
Wnt pathway, lorecivivint (LOR), as a potential OA therapeutic to be administered as a local 
injection into the affected joint. This study is being conducted to assess the long-term safety of 
repeated LOR injections, as well as the effects of repeated LOR injections on knee OA pain, 
function, and structural progression over a total of 2 years. 
2.2 
BACKGROUND INFORMATION  
OA is the most common form of arthritis and the major cause of activity limitation and physical 
disability in older people. Today, 35 million people (13% of the US population) are 65 and older, 
and more than half of them have radiological evidence of OA in at least 1 joint. By 2030, 20% of 
Americans (about 70 million people) will have passed their 65th birthday and will be at risk for 
OA (Nevitt et al. 2006). 
Therapies available to treat OA are limited. Most current treatments are designed only to relieve 
pain and reduce or prevent the disability caused by bone and cartilage degeneration. Drug 
therapies target the symptoms but not the cause of this disease; no treatment inhibits or reverses 
the degenerative structural changes that are responsible for its progression (Nevitt et al. 2006). 
Biosplice is developing LOR for the treatment of OA. 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.  
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). 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
15 
2.3 
POTENTIAL RISKS AND BENEFITS  
2.3.1 KNOWN POTENTIAL RISKS  
Study Medication LOR 
The study drug LOR, which modulates the Wnt pathway, has risks and discomforts. Refer to the 
IB for the known potential risks associated with LOR.  
Study Placebo 
The placebo injection in this study will be 2 mL of vehicle, which is carboxymethylcellulose 
sodium and polysorbate 80 in phosphate buffered saline. Carboxymethylcellulose sodium and 
polysorbate 80 are inactive substances often used as food additives or drug excipients. There is a 
small risk of allergic reaction or hypersensitivity to these components.     
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 
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. 
Radiograph (X-ray) 
This study involves radiation exposure from multiple radiographs of the knee joints, with 
possibly up to 3 retakes for each radiograph. As part of everyday living, everyone is exposed to a 
small amount of background radiation that comes from soil, rocks, outer space, and within the 
body itself. The radiation dose for each radiograph that the subject will receive in this study is 
expected to be about 0.005 millisievert (mSv) or equivalent to approximately <0.5 day of 
background radiation in the US. The risk from this dose is small. This radiation exposure may 
not be necessary for the subjects’ medical care, but it is necessary to obtain the research 
information desired.  
2.3.2 KNOWN POTENTIAL BENEFITS  
Taking part in this study may or may not provide any benefit to the subject. Information from 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
16 
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 serious adverse events (SAEs) considered related to study 
medication. In previous trials, LOR was safe and well tolerated at single doses of up to 0.23 mg 
per injection, exceeding the 0.07 mg dose used in the current study. At the time of protocol 
development, no completed studies have examined the safety or efficacy of repeated injections of 
LOR, although a double-blind study is ongoing in which subjects will receive up to 4 injections 
of LOR with 6 months between each injection. 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 Monitor(s) per the Medical Monitoring Plan. In addition, on-site 
review 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 evaluate the safety and efficacy of a second year of use 
of lorecivivint (LOR) in subjects with knee osteoarthritis (OA). 
Secondary: 
The secondary objective of this study is to evaluate the safety and efficacy of long-term use of 
LOR in subjects with knee OA. 
3.2 
STUDY ENDPOINTS 
3.2.1 SAFETY ENDPOINTS 
• Adverse events (AEs) and serious adverse events (SAEs) (incidence, severity, and 
relationship to study drug) over the course of the study 
• Clinically significant changes from parent-study-baseline clinical laboratory measures and 
vital signs, as assessed by the Investigator, over the course of the study 
• Change in serum bone biomarkers (N-terminal propeptides of procollagen type I [P1NP] and 
β-C-terminal telopeptide [β-CTX]) from parent-study baseline, and change in a serum 
cartilage biomarker (cartilage oligomeric matrix protein [COMP]) from parent-study baseline 
at Visit 3E 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
17 
3.2.2 EFFICACY ENDPOINTS 
• Change from parent-study-baseline medial joint space width (mJSW) in the target knee as 
evaluated by radiograph over the course of the study 
• Change from parent-study-baseline OA pain in the target knee as assessed by pain NRS over 
the course of the study  
• Change from parent-study-baseline OA pain in the target knee as assessed by WOMAC Pain 
over the course of the study  
• Change from parent-study-baseline OA function in the target knee as assessed by WOMAC 
Function over the course of the study  
• Change from parent-study-baseline OA pain, function, and stiffness as a composite outcome 
measure as assessed by WOMAC total score (WOMAC Total) over the course of the study 
• Change from parent-study-baseline health-related quality of life (HRQOL) as assessed by the 
36-Item Short Form Health Survey (SF-36) over the course of the study  
• Percentage of subjects who consider themselves to be in a Patient Acceptable Symptom State 
(PASS) over the course of the study 
4. 
STUDY DESIGN  
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This study will be a multicenter study in subjects previously enrolled in study SM04690-OA-11. 
The first 48 weeks will be single-blind and placebo-controlled while the remainder of the study 
will be open-label and uncontrolled. The study is planned to continue at least until commercial 
availability of LOR. Based on previous studies, up to approximately 500 subjects will be 
enrolled, but there is no set cap on enrollment. Subjects must enroll no later than 6 weeks 
following completion of study SM04690-OA-11. Clinic visits will be scheduled at Visit 1E (Day 
1), Visit 2E (Week 24), Visit 3E (Week 48), Visit 4E (Week 52 phone visit), Visit 5E (Week 74), 
and every 26 weeks thereafter until the Termination Visit. Refer to Figure 1 for an overview of 
study design and endpoints.  
At the first visit in this study (Visit 1E), all subjects will complete PASS and pain NRS 
assessments and then receive a blinded study injection into their target knee (the same target 
knee injected in the parent study), with subjects receiving the same treatment (either 0.07 mg 
LOR or placebo) as they received in the parent study. Subjects will have clinic visits for pain and 
function assessments, collection of AEs, and knee radiographs. At Visit 3E, subjects will have 
plasma samples collected for assessment of biomarkers of bone and cartilage turnover, and all 
subjects, regardless of previous treatment, will receive an injection of 0.07 mg LOR into their 
target knee. Subjects will receive injections of 0.07 mg LOR into their target knee every 52 
weeks thereafter. Specific timing of protocol procedures is described in the Schedule of Events 
Table (Section 7.3.4). 
Subjects are allowed to use non-steroidal anti-inflammatory drugs (NSAIDs) and/or 
acetaminophen for pain relief as needed. If a subject has a partial or total knee replacement of the 
target knee, the subject will be discontinued from the study. 
Recording of signs and symptoms of study medication intolerability and AE reporting will start 
immediately following the parent-study EOS (End of Study) visit and continue at all subsequent 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
18 
visits until the subject completes the Termination Visit. All AEs, whether volunteered, elicited, 
or noted during examination, will be recorded throughout the study. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
SM04690-OA-07 is a long-term study designed to evaluate the safety and efficacy of a second 
year and long-term use of LOR in subjects with OA of the knee. The placebo used in this study is 
the same vehicle used to formulate LOR but without the active ingredient. A vehicle-controlled 
single-blind design is considered appropriate for year one of this study as it allows for evaluation 
of the safety and efficacy of the LOR molecule alone through an unbiased comparison of the 
active and vehicle injections over a total of 2 years. Beyond 2 years (including parent-study 
SM04690-OA-11 participation), crossing subjects on placebo over to LOR will provide 
additional long-term safety information in a group of subjects not previously treated with LOR. 
4.3 
JUSTIFICATION FOR DOSE 
The dose of 0.07 mg LOR was selected for this study to remain consistent with the dose used in 
the parent study. Administration of the 0.07 mg LOR dose resulted in the most consistently 
positive responses compared to control when the outcome measures of pain NRS, WOMAC 
Function, and mJSW were assessed in 3 completed clinical studies (SM04690-01, SM04690-
OA-02, and SM04690-OA-04). 
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 Termination Visit (Section 7.3.4). 
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 the following criteria: 
1. Completion of study SM04690-OA-11 
2. Compliance with procedures in study SM04690-OA-11, in the opinion of the Investigator  
3. Fully understanding study requirements and willingness to comply with study visits and 
assessments 
4. Understanding and signing of the informed consent form (ICF) prior to any study-related 
procedures 
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. 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 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
19 
objectives, conduct, or evaluation 
2. Any contraindications for an intra-articular (IA) injection in the target knee in the opinion 
of the Investigator 
3. Any known reason identified by the Investigator or Sponsor that the subject may not be 
compliant with study visits or may no longer be an appropriate candidate for the study 
(e.g., planned surgery of the pelvis/hip, knee, ankle, or foot, knee replacement during the 
parent study, planning to move away from the research site, or initiation of a prohibited 
concomitant medication including, but not limited to, IA injection of glucocorticoids, 
hyaluronic acid derivatives, platelet-rich plasma, stem cell therapies, or other agents with 
therapeutic intent into the target knee) 
4. Participation in a clinical research trial (other than the prior SM04690-OA-11 study) that 
included the receipt of an investigational product (IP) or any experimental therapeutic 
procedure within 12 weeks before any study injection, or planned participation in any 
such trial 
5. Current or pending disability claim, workers’ compensation, or litigation(s) that may 
compromise response to treatment 
6. 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 
Visit 1E  
7. 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 
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 Visit 1E until the Termination Visit, 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.  
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
20 
4. Bilateral tubal ligation/occlusion/division  
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 within 30 days after receiving a study 
injection should remain on an acceptable form of contraception for 30 days after the last study 
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 dosed or entered into the study. 
5.4.2 SUBJECT RESCREENING 
Screen failures are not allowed to rescreen for this study. 
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 
Best efforts will be made to encourage subjects to attend all study visits. Subjects will be 
informed that they are free to withdraw from the study at any time and for any reason. A 
discontinuation from the study will occur when a subject who signed informed consent and was 
dosed ceases participation in this study, regardless of circumstances.  
Subjects can be discontinued from the study for one of the following reasons:  
• AE 
• Total or partial knee replacement of the target knee 
• 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 noncompliance 
• Physician decision for reason other than lack of efficacy  
• Study terminated by Sponsor 
• Site terminated by Sponsor 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
21 
• Request by regulatory authority 
• Lack of efficacy 
• Pregnancy 
• Death 
• Other 
5.6.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
All Termination Visit procedures and assessments should be performed on subjects who are 
withdrawn or who voluntarily withdraw, including subjects who withdraw due to partial or total 
knee replacement. 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 eCRFs for subjects who discontinue from the study.  
Replacement of subjects who withdraw or discontinue is not allowed. 
Total or Partial Knee Replacement Follow-Up  
A subject who has had total or partial knee replacement of the target knee should be discontinued 
from the study. In addition to Termination Visit procedures, sites should make every attempt to 
follow up with these subjects approximately 6 months after the total or partial knee replacement 
surgery is completed to assess outcomes of the surgery.  
5.7 
TERMINATION OR SUSPENSION OF STUDY 
The Sponsor reserves the right to 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 and regulatory authorities as appropriate. If the study is 
terminated or suspended, the Investigator will promptly inform the Institutional Review Board 
(IRB) and will provide the reason(s) for the termination or suspension.  
6. 
STUDY AGENT 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
6.1.1 ACQUISITION 
The Sponsor will be responsible for the manufacturing, labeling, packaging, distribution, and 
reconciliation of study medication, and ultimate destruction of unused study medication (both 
LOR drug product and placebo product). 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
LOR drug substance is an off-white powder. 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 and placebo products are supplied as vials of 2.4 mL of formulated 
suspension. Placebo product contains 0.5% carboxymethylcellulose sodium and 0.05% 
polysorbate 80 in pH 7.4 phosphate buffered saline.  
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
22 
LOR drug and placebo products will be supplied as single-use vials to the study pharmacist 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 drug and placebo products 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 
At Visit 1E, study medication should be well mixed by the Unblinded Investigator (the drug 
product is a suspension) before injecting 2 mL intra-articularly into the target knee.  
At Visit 3E and for any subsequent injections, study drug preparation and injection do not need 
to be performed by a designated unblinded individual due to the open-label nature of the 
remaining portion of the study.  
Refer to the Pharmacy Manual for detailed instructions on study injection preparation.  
6.1.5 DOSING AND ADMINISTRATION 
LOR will be administered in the following dosage strengths:  
• 0.07 mg LOR in 2 mL injectable suspension 
• 0 mg LOR; 2 mL vehicle-only injection (placebo) 
Each subject will maintain the same treatment assignment of LOR or placebo as in the parent 
study at Visit 1E. At Visit 3E and for any subsequent injections until the Termination Visit, all 
subjects will receive a LOR injection. Subjects should not have any condition that, in the opinion 
of the Investigator, constitutes a risk or contraindication for the injections.   
At Visit 1E, the injectable drug product or placebo product is to be administered by the 
Unblinded Investigator as a single injection into the target knee joint. Before administration of 
the IA knee injection, the subject should be blinded to observation of the study medication and 
injection procedure according to the processes specified in the Site-Specific Blinding Plan. The 
Unblinded Investigator must minimize any contact with the subject aside from the injections and 
may not perform any study assessments throughout the duration of the study. All other subject 
contact is limited to the Blinded Investigator and other appropriate blinded study personnel. The 
Unblinded Investigator does not need to be the same person for the duration of the study. At 
Visit 3E and for any subsequent injections, the LOR injections do not need to be performed by a 
designated Unblinded Investigator due to the open-label nature of the remaining portion of the 
study.  
Only 1 knee will be treated for each subject in this study. The injection can be done either 
through lateral or medial (including superior/suprapatellar, midpatellar, and inferior/anterior) 
approaches, based on the standard practice of the Unblinded Investigator/injector or the knee 
examination of the subject. Although not required, the injection may be guided by ultrasound or 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
23 
fluoroscopy without contrast if it is the standard practice of the Unblinded Investigator/injector.   
Only topical anesthetics are allowed before the study injection. Local anesthetic injections are 
prohibited. 
The Unblinded Investigator/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 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 joint fluid into a separate empty syringe 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. 
The study medication should then subsequently be injected via syringe exchange. 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 the study 
injections. 
6.1.6 ROUTE OF ADMINISTRATION 
Injectable LOR drug product or placebo product is to be administered as an IA injection into the 
target knee joint. 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
Not applicable to this study.  
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
No modification in the specified dose concentration or volume (2 mL) of the study injection will 
be allowed. 
6.1.9 DURATION OF THERAPY 
Injectable LOR drug product or placebo product is to be administered as a single IA injection 
into the target knee joint at Visit 1E. LOR is to be administered as an IA injection in the target 
knee joint every 52 weeks starting at Visit 3E until the Termination Visit.  
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 
The study medications supplied for this study are for use only in subjects properly consented and 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
24 
enrolled into this protocol. 
All used and unused vials of LOR drug and placebo products received must be returned and 
accounted for. All injections prepared and dispensed must also be logged. The log includes, but 
is not limited to, the following: 
• Subject number and initials 
• Date that study medication was injected 
• Quantity dispensed (drug product vials and placebo vials) 
• Quantity returned/used (drug product vials and placebo vials) 
All study medication dispensed by the Unblinded Investigator and/or unblinded designee will be 
inventoried and accounted for throughout the study until all subjects at each site complete Visit 
3E. The Unblinded Investigator and/or unblinded designee must maintain an accurate, up-to-date 
dispensing log for all study medications supplied by the Sponsor. Study medication dispensed for 
all subjects must be recorded on the drug accountability forms. The study medication dispensing 
log and remaining drug inventory will be reviewed by the Sponsor-designated unblinded clinical 
monitor. 
Starting at Visit 3E and for subsequent injections, subjects will receive open-labeled IP. 
Accountability will be documented on a new, separate accountability log with the same 
information as noted above. The open-labeled IP and the separate IP accountability log will be 
reviewed, and dosing will be verified by a Sponsor-designated clinical monitor (not the 
unblinded clinical monitor).  
For the Visit 1E injections, used and unused study medications must be kept in a secure, blinded 
location physically separated from standard clinic or office drug supplies, and with access 
limited to the Unblinded Investigator and/or unblinded designee. Once all subjects at a site have 
had their Visit 1E injection, IP will be accounted for by the unblinded clinical monitor, and the 
IP can be returned to the depot. Procedures for return or destruction of used and unused vials of 
the study medication will be provided in the Pharmacy Manual. Open-labeled IP to be used for 
Visit 3E and subsequent injections will need to be kept in a secure, temperature-controlled 
location separate from the blinded IP. Accountability for the initial blinded IP will be separate 
from the open-label IP and sites will need to maintain separate accountability records and 
pharmacy binders until all subjects at the site are receiving the open-labeled IP, the blind has 
been lifted, and the parent-study (SM04690-OA-11) database has been locked.  
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. As this is an extension trial, AE collection 
will continue from the parent study, ongoing AEs at the end of the parent study will continue to 
be monitored, and new AEs that occur during this study will be recorded. Changes to ongoing 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
25 
AEs that occur after the parent-study EOS visit will not be recorded in the parent study. AEs will 
be assessed through the Termination Visit.  
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, 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 study medication, outcome, and any action taken.  
In this protocol, signs and symptoms of exacerbation or worsening of target 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 (target knee OA) will not be considered as AEs nor captured on the AE 
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. For 
subjects who discontinue from the study within 30 days of their study injection, AEs that are 
ongoing at the subject’s last visit will be followed for 30 days after administration of the last 
dose or until resolution, whichever comes first. Resolution is defined as the return to baseline 
status or stabilization of the condition. SAEs and selected AEs identified by the Investigator or 
the Sponsor to warrant further follow-up that are ongoing at a subject’s last visit will be followed 
until resolution. 
Medical History 
A follow-up on Medical History (collected in the parent study) will be performed at the 
Termination Visit to capture End Dates of any ongoing medical history.   
Physical Examination  
A general physical examination will be conducted at Visit 3E and the Termination Visit. Results 
of the physical examination will be noted in the source documents. Any clinically significant 
finding should be reported as an AE. 
Knee Examination 
A knee examination of both knees will be conducted at all clinic visits after Visit 1E. Results of 
the knee examination will be noted in the source documents. Any clinically significant finding 
should be reported as an AE.  
Weight 
Weight measurements will be taken at Visit 2E, Visit 3E, every 52 weeks thereafter (e.g., Visits 
6E, 8E, etc.), and at the Termination Visit. 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
26 
Vital Signs 
Vital signs will be measured by a qualified staff member at Visit 2E, Visit 3E, every 52 weeks 
thereafter (e.g., Visits 6E, 8E, etc.), and at the Termination Visit.  
At each time point, the following vital signs will be measured: 
• Pulse rate 
• Blood pressure (systolic and diastolic) after the subject rests (sitting or supine) for at 
least 5 minutes  
At visits when the subject will receive an IA injection (e.g., Visits 3E, 6E, 8E, etc.), temperature 
will also be measured. 
Any measurement that is, in the opinion of the Investigator, abnormal AND clinically significant 
must be recorded as an AE.  
Radiograph of Knee Joints 
Radiograph of the knee joints will be taken at all clinic visits after Visit 1E.  
Detailed instructions for obtaining and managing the radiographs will be provided to the 
investigational center before subject enrollment. As described in the Image Review Charter – 
Image Acquisition Guidelines, radiographs should be obtained in the posterior-anterior (PA) 
view.  
Upon receipt of images, the central imaging vendor will assess the image quality as acceptable or 
unacceptable. It is recommended that the Investigator attempt up to 3 additional image captures 
in order to obtain an acceptable image.  
All radiographs will be submitted to an independent radiologist at the central imaging vendor 
who will document mJSW. The central imaging vendor does not provide medical advice, clinical 
diagnosis, or treatment recommendations. These imaging assessments and quantitative 
measurements provided to the Sponsor do not and shall not constitute a medical diagnosis, 
treatment recommendation, or medical advice, and are not intended to be used as a substitute for 
the study Investigator’s or other qualified health care professional’s medical diagnosis, 
treatment, or advice. If any unusual pathology is noted in the study images, the Sponsor will be 
notified of the finding and will promptly notify the Investigator. The Investigator will then assess 
the clinical significance as well as any follow-up procedures that need to be completed.   
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). A pain NRS assessment will be completed by the 
subjects at all clinic visits.  
Pain NRS questionnaires will be provided by the Sponsor. Upon completion of the pain NRS, 
subjects will sign or initial, then date the source document to indicate that the assessment is 
reported accurately. 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
27 
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 their target knee at all clinic visits after Visit 
1E.  
WOMAC questionnaires will be provided by the Sponsor and may not be reproduced. Upon 
completion of the WOMAC, subjects will sign or initial, then date the source document to 
indicate that the assessment is reported accurately. 
Patient Acceptable Symptom State Questionnaire 
At Visit 1E, Visit 3E, every 52 weeks thereafter (e.g., Visits 6E, 8E, etc.), and at the Termination 
Visit, 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.”    
PASS questionnaires will be provided by the Sponsor. Upon completion of the questionnaire, 
subjects will sign or initial, then date the source document to indicate that the assessment is 
reported accurately. 
36-Item Short Form Health Survey  
The SF-36 is a widely used questionnaire that relies upon subject self-reporting to measure the 
subject’s health-related quality of life. The SF-36 will be completed by the subject at Visit 3E, 
every 52 weeks thereafter (e.g., Visits 6E, 8E, etc.), and at the Termination Visit.  
The SF-36 is a paper questionnaire that will be provided by the Sponsor and may not be 
reproduced. Upon completion of the SF-36, the subject will sign or initial, then date the source 
document to indicate that the quality of life assessment is reported accurately. 
Assessment of NSAID/Acetaminophen Usage 
Information about NSAID and acetaminophen usage will be collected at all clinic visits after 
Visit 1E. Subjects will be asked to recall the name, indication, route of administration, usual total 
daily dose, and usual number of days taken per week of any NSAID or acetaminophen 
medications during the previous 4 weeks. Assessment of NSAID/acetaminophen usage will be 
documented on the “NSAID/Acetaminophen Usage” eCRF. 
7.1.2 STANDARD-OF-CARE STUDY PROCEDURES  
All Investigators are to provide appropriate care to their subjects as they deem necessary; 
however, additional standard-of-care study procedures are not required by this protocol. 
 
 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
28 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
7.2.1 CLINICAL LABORATORY EVALUATIONS 
Specimens for clinical laboratory analysis by the central laboratory will be collected by a 
qualified staff member at Visit 2E, Visit 3E, every 52 weeks thereafter (e.g., Visits 6E, 8E, etc.), 
and at the Termination Visit. Subjects should fast prior to the Visit 3E clinical laboratory 
collection. 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) 
• 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 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, clinically significant. If any abnormal, clinically significant 
laboratory measure is found, it should be reported as an AE. 
7.2.2 OTHER ASSAYS OR PROCEDURES 
Pregnancy Test 
A urine-based pregnancy test will be performed on WOCBP at Visit 1E, Visit 3E, and every 52 
weeks thereafter (e.g., Visits 6E, 8E, etc.).  
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). 
Biomarkers 
Fasting blood samples for biomarker analysis will be collected by a qualified staff member at 
Visit 3E. Biomarkers that will be assessed include bone biomarkers, P1NP and β-CTX, and a 
cartilage biomarker, COMP. 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
29 
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/ENROLLMENT 
Visit 1E 
Visit 1E should occur at the subject’s parent-study EOS visit, with a window of + 6 weeks.   
Collection of NSAID/acetaminophen usage, physical and knee examination, weight 
measurement, vital sign measurements, and venipuncture and collection of samples for clinical 
laboratory tests and biomarker analysis will be performed at the parent-study Week 56 (EOS) 
visit and therefore do not need to be repeated at Visit 1E.  
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. Subjects will 
retain the same subject number as assigned in the parent study.    
Subjects who sign the ICF at Visit 1E will be considered consented. For WOCBP, a urine-based 
pregnancy test will then be performed.  
After the subject is deemed eligible for the study based on inclusion/exclusion criteria, the 
following procedures and assessments will be performed at Visit 1E: 
• PASS assessment 
• Pain NRS assessment  
• Collection of AE and concomitant procedures/therapies/medication data 
• IA injection of study medication by the Unblinded Investigator (injector) into the 
target knee; the target knee must be the same as the knee injected in the parent 
study. 
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 STUDY VISITS 
Visit 2E 
Visit 2E should occur 24 weeks after the Visit 1E injection with a window of ± 4 weeks. 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
30 
The following procedures and assessments will be performed at Visit 2E: 
• Pain NRS assessment  
• WOMAC questionnaire 
• Collection of AE and concomitant procedures/therapies/medication data 
• Assessment of NSAID/acetaminophen usage 
• Knee examination 
• Weight measurement  
• Vital sign measurements (pulse rate and blood pressure) 
• Venipuncture and collection of samples for clinical laboratory tests 
• Radiograph – bilateral in weight-bearing fixed flexion position, PA view X-ray 
Visit 3E  
Visit 3E should occur 48 weeks after the Visit 1E injection with a window of ± 4 weeks. 
Subjects should fast for 8 hours prior to this visit.   
The following procedures and assessments will be performed at Visit 3E: 
• Pain NRS assessment  
• WOMAC questionnaire 
• PASS assessment 
• SF-36 
• Collection of AE and concomitant procedures/therapies/medication data 
• Assessment of NSAID/acetaminophen usage 
• Pregnancy test (urine-based) in WOCBP 
• Physical examination  
• Knee examination 
• Weight measurement  
• Vital sign measurements (temperature, pulse rate, and blood pressure) 
• Venipuncture and collection of samples for clinical laboratory tests and biomarkers 
• Radiograph – bilateral in weight-bearing fixed flexion position, PA view X-ray 
• IA injection of LOR into the target knee; the target knee must be the same as the 
knee injected in the parent study. 
Visit 4E (Phone Visit) 
The Visit 4E phone visit should occur on Week 52 (with a window of ± 7 days). Sites will 
contact subjects to collect AE and concomitant procedures/therapies/medication data. 
Visit 5E, 7E, 9E, etc. 
These visits should occur on Weeks 74, 126, 178, etc. with a window of ± 4 weeks.  
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
31 
The following procedures and assessments will be performed at these visits: 
• Pain NRS assessment  
• WOMAC questionnaire 
• Collection of AE and concomitant procedures/therapies/medication data 
• Assessment of NSAID/acetaminophen usage 
• Knee examination 
• Radiograph – bilateral in weight-bearing fixed flexion position, PA view X-ray 
Visit 6E, 8E, 10E, etc. 
These visits should occur on Weeks 100, 152, 204, etc. with a window of ± 4 weeks. 
The following procedures and assessments will be performed at these visits: 
• Pain NRS assessment  
• WOMAC questionnaire 
• PASS assessment 
• SF-36 
• Collection of AE and concomitant procedures/therapies/medication data 
• Assessment of NSAID/acetaminophen usage 
• Pregnancy test (urine-based) in WOCBP 
• Knee examination 
• Weight measurement  
• Vital sign measurements (temperature, pulse rate, and blood pressure) 
• Venipuncture and collection of samples for clinical laboratory tests 
• Radiograph – bilateral in weight-bearing fixed flexion position, PA view X-ray 
• IA injection of LOR into the target knee; the target knee must be the same as the 
knee injected in the parent study. 
7.3.3 TERMINATION VISIT 
The following procedures and assessments should be performed on subjects who withdraw or are 
discontinued from the study.  
• Pain NRS assessment 
• WOMAC questionnaire 
• PASS assessment 
• SF-36 
• Collection of AE and concomitant procedures/therapies/medication data 
• Assessment of NSAID/acetaminophen usage 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
32 
• Review of medical history 
• Physical examination  
• Knee examination 
• Weight measurement  
• Vital sign measurements (pulse rate and blood pressure) 
• Venipuncture and collection of samples for clinical laboratory tests 
• Radiograph – bilateral in weight-bearing fixed flexion position, PA view X-ray (if not 
completed within 12 weeks before the Termination Visit) 
Note: Subjects who withdraw from the study after having a partial or total knee replacement are 
not required to complete the pain NRS assessment, WOMAC questionnaire, PASS assessment, 
SF-36, or radiograph. 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
33 
7.3.4 SCHEDULE OF EVENTS TABLE 
 
 
Visit 1E 
(Day 1) 
+ 6 weeks 
Visit 2E 
(Week 
24) 
± 4 weeks 
Visit 3E 
(Week 
48) 
± 4 weeks 
Visit 4E 
Phone 
visit 
(Week 
52) 
± 7 days 
Visit 5E, 
7E, 9E, 
etc. 
(Week 74, 
126, 178, 
etc.) 
± 4 weeks 
Visit 6E, 
8E, 10E, 
etc. 
(Week 
100, 152, 
204, etc.) 
± 4 weeks 
Termin-
ation 
Visitd 
Informed consent 
X 
 
 
 
 
 
 
Inclusion & exclusion 
criteria 
X 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
X 
Urine pregnancy testa 
X 
 
X 
 
 
X 
 
Injection into target kneeb 
X 
 
X 
 
 
X 
 
Physical examinationc 
 
 
X 
 
 
 
X 
Knee examinationc 
 
X 
X 
 
X 
X 
X 
Weightc 
 
X 
X 
 
 
X 
X 
Vital signsc 
 
X 
X 
 
 
X 
X 
Clinical laboratory 
samplingc 
 
X 
X 
 
 
X 
X 
Pain NRS 
X 
X 
X 
 
X 
X 
X 
WOMAC 
 
X 
X 
 
X 
X 
X 
PASS 
X 
 
X 
 
 
X 
X 
SF-36 
 
 
X 
 
 
X 
X 
Knee Radiograph 
 
X 
X 
 
X 
X 
Xe 
Collection of biomarker 
samplesc 
 
 
X 
 
 
 
 
AEs and concomitant 
procedures/therapies/ 
medications 
X 
X 
X 
X 
X 
X 
X 
Assessment of NSAID/ 
acetaminophen usagec 
 
X 
X 
 
X 
X 
X 
 
Abbreviations: AEs, adverse events; NRS, numeric rating scale; PASS, Patient Acceptable Symptom State; SF-36, 
36-Item Short Form Health Survey; WOMAC, Western Ontario and McMaster Universities Arthritis Index. 
a    Urine pregnancy tests are to be performed on WOCBP only. 
b Study injection should be the last procedure performed at injection visits (e.g., Visit 1E, 3E, 6E, etc.). 
c    Collection of NSAID/acetaminophen usage, physical and knee examination, weight measurement, vital sign 
measurements, and venipuncture and collection of samples for clinical laboratory tests and biomarker analysis 
will be performed at the parent-study Week 56 (EOS) visit and therefore do not need to be repeated at Visit 1E. 
d  Subjects who discontinue from the study after having a partial or total knee replacement are not required to 
complete the pain NRS assessment, WOMAC questionnaire, PASS assessment, SF-36, or radiograph at the 
Termination Visit.   
e  Radiograph is only to be performed at the Termination Visit, when applicable, if not performed within 12 weeks 
before the Termination Visit.
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
34 
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 parent-
study medications will be recorded in this study. Changes to medications ongoing at Visit 1E 
will be recorded in this study. Changes to ongoing medications that occur after the parent-study 
EOS visit will not be recorded in the parent study. All new medications, therapies, or procedures 
taken or received from Visit 1E through the Termination Visit will be recorded in the eCRF at 
each visit. Documented medications should include prescription, over the counter, supplements, 
as well as herbal or alternative medications. 
All new or modified concomitant medications must be recorded on the “Concomitant 
Medications” eCRF. 
Procedures or non-drug therapies that are ongoing, new, or modified at or after Visit 1E 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, including glucocorticoids, hyaluronic acid derivatives, 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, hyaluronic acid 
derivatives, PRP, stem cells, or other therapeutic agents into joints other than the knee 
is allowed. 
• The following medications are prohibited while the subject is in the study: 
− Opioids; short-term use of opioids as part of anesthesia or procedural sedation 
during the study period is permitted 
− Centrally acting analgesics (e.g., duloxetine) (refer to Appendix 1)  
− Topical local anesthetic agents; short-term use as part of anesthesia, including for 
study injections during the study period is permitted 
− Other anticonvulsants not listed in Appendix 1 
− Systemic glucocorticoids ≥10 mg of prednisone per day or the equivalent; 
epidural, inhaled, intranasal, and topical glucocorticoids are permitted  
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
35 
− Drugs screened to assess eligibility in the parent study, unless clinically indicated 
and allowed by the protocol: amphetamine, buprenorphine, cocaine, methadone, 
opiates, phencyclidine, propoxyphene, barbiturates, benzodiazepine, 
methaqualone, and tricyclic antidepressants  
• Electrotherapy (refer to Appendix 1), acupuncture, therapeutic ultrasound, and/or 
chiropractic treatments for knee OA are prohibited while the subject is on study. 
• Any new formalized (i.e., prescribed by a medical professional) physical therapy 
exercise programs for knee OA are prohibited while the subject is on study. 
• Elective surgery of the pelvis/hip, knee, ankle, or foot is prohibited while the subject 
is on the study.  
• Subjects are prohibited from participating in any other clinical research trial that 
includes the receipt of an IP or any experimental therapeutic procedure. Subjects are 
also prohibited from participating in any observational research trial while in the 
study. 
The Investigator should notify the Medical Monitor(s) immediately 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  
Subjects are allowed to use NSAIDs and/or acetaminophen for pain relief as needed. If a 
subject’s clinical condition significantly deteriorates (defined as experiencing significant pain 
that cannot be satisfactorily controlled using NSAIDs and/or acetaminophen), the Investigator 
should consult with the Medical Monitor(s).  
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Not applicable to this study. 
8. 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
Safety assessments include physical examinations, vital signs, clinical laboratory tests, collection 
of AEs and SAEs, concomitant medications, and general medical evaluations.  
8.1.1 DEFINITION OF ADVERSE EVENTS  
AEs in the eCRF will be classified according to the most recent US Food and Drug 
Administration (FDA) definitions and in a manner consistent with International Council for 
Harmonisation Guideline for Good Clinical Practice (ICH-GCP) guidelines. As such the 
following definitions will be used: 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
36 
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 preexisting 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 target 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 (target knee OA) will not be considered AEs nor captured on the AE eCRF. 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS  
According to the ICH-GCP Guidelines E6 (R2), an SAE is any untoward medical occurrence 
during a clinical investigation that is characterized by one or more of the following: 
• 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 which hypothetically 
might have caused death if it were more severe. 
“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  
An AE observed during the conduct of a study should be considered an Unanticipated Problem 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
37 
(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 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 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 not commonly associated with drug exposure, but uncommon in the 
study population (e.g., tendon rupture, progressive multifocal leukoencephalopathy)  
• An AE described or addressed in the IB, protocol, or informed consent documents, but 
occurs at a specificity or severity inconsistent with prior observations  
• An SAE 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 using the CDISC AESEV, which classifies AEs as 
mild, moderate, or severe (Table 1). 
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. 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
38 
8.2.2 RELATIONSHIP TO STUDY AGENT 
The relationship of the study treatment 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 the study medication or administration of the 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 
the study medication or the 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 the study medication or 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 the study medication. 
Possibly Related 
The AE is possibly related if (1) the study medication or the study injection and AE are 
considered reasonably related in time and (2) the AE could equally be explained by causes other 
than exposure to the study medication or the study injection. 
Probably Related 
The AE is probably related if (1) the study medication or study injection and AE are considered 
reasonably related in time and (2) the study medication or 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 
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 immediately following the parent-study EOS visit and ends 
after the final study visit. 
AEs will be followed until the subject’s last visit or resolution, whichever comes first. For 
subjects who discontinue from the study within 30 days of their last study injection, AEs that are 
ongoing at the subject’s last visit will be followed for 30 days after administration of the last 
dose or until resolution, whichever comes first. Resolution is defined as the return to baseline 
status or stabilization of the condition. SAEs and selected AEs identified by the Investigator or 
the Sponsor to warrant further follow-up that are ongoing at a subject’s last visit will be followed 
until resolution. 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
39 
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 study medication that are both serious and unexpected 
to the FDA according to 21 CFR 312.32. All Investigators participating in ongoing studies with 
the study medication 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 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  
• The date of the report 
Follow-up information must be detailed in a follow-up SAE report and reported to the 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 (DSPV) 
Famina Hemani, Executive Director, DSPV 
Email: sherry.beckman@biosplice.com 
Email: famina.hemani@biosplice.com 
DSPV Phone: (858) 371-4144 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
40 
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  
• An explanation 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 the subject or partner of the 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 pregnancy will be collected on a Sponsor Pregnancy Report Form. Information will be 
collected for any pregnancy in a female subject which occurs during the study, including 
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 
Monitor(s) per the Medical Monitoring Plan. In addition, on-site review will be conducted by 
Clinical Research Associates. 
9. 
CLINICAL MONITORING 
All aspects of the study will be monitored by the Sponsor or designees with respect to current 
GCP and Standard Operating Procedures (SOPs) for compliance with applicable government 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
41 
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 that 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 
The statistical hypotheses being tested in this study are: the least squares estimate of 
improvement from parent-study baseline in clinical and radiographic outcomes at Visit 3E (i.e., 
after 24 months of treatment) is greater for subjects who received LOR compared to those who 
received placebo. Details of the statistical hypothesis tests will be outlined in the SAP. 
10.3 
ANALYSIS DATASETS 
Full Analysis Set (FAS): All subjects who receive a study injection in the current study, 
analyzed as randomized in the parent study. 
Per-Protocol Analysis Set (PPAS): FAS subjects who complete the study and do not have any 
major protocol deviations in the current or parent study that might impact efficacy. 
Safety Analysis Set (SAS): All subjects who receive a study injection in the current study, 
analyzed as treated in the current study.  
10.4 
DESCRIPTION OF STATISTICAL METHODS 
10.4.1 GENERAL APPROACH 
For continuous variables, the number of subjects in the analysis, mean, standard deviation, 
median, minimum, and maximum will be reported. All categorical endpoints will be summarized 
using frequencies and percentages. 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
42 
10.4.2 ANALYSIS OF SAFETY ENDPOINT(S) 
Safety analyses will be performed on subjects who receive a study injection. Safety assessments 
include physical examinations, vital signs, clinical laboratory tests, solicitation of AEs and 
concomitant medications, and general medical evaluations. No formal statistical analyses are 
planned. Safety will be evaluated based on the incidence, seriousness, severity, and relationship 
of AEs and by changes in clinical laboratory parameters and vital signs, relative to parent-study 
baseline. For subjects who cross over from placebo to LOR, subsequent changes in laboratory 
parameters and vital signs will be relative to Visit 3E. 
10.4.3 ANALYSIS OF EFFICACY ENDPOINT(S) 
Change over time through Visit 3E in mJSW, pain NRS, WOMAC Pain, WOMAC Function, 
and WOMAC Total will be characterized using mixed-effects models for repeated measures 
(MMRM). The models will estimate change from parent-study baseline with treatment, visit, 
treatment × visit interaction, and parent-study baseline value as covariates. Unadjusted 95% 
confidence intervals and P values will be reported. The potential confounding effect of change in 
NSAID/acetaminophen usage on the treatment effect will be considered for sensitivity analysis. 
ANCOVA will be used to analyze the change in SF-36 domain scores and summary component 
scores through Visit 3E. Change will be assessed from parent-study baseline between the active 
and placebo treatment groups. The models will be adjusted for parent-study baseline. Unadjusted 
95% confidence intervals and P values will be reported.  
PASS will be analyzed using logistic regression. Logistic regression will also be used to compare 
the proportion of Outcome Measures in Rheumatology Clinical Trials (OMERACT)-
Osteoarthritis Research Society International (OARSI) responders and “strict” responders (Pham 
et al. 2003) between treatment groups through Visit 3E, as well as proportion of subjects 
achieving a 20%, 50%, and 70% improvement. 
Maintenance of LOR’s effects on pain and function of the target knee will be characterized by 
summarizing likelihood of response in pain NRS, WOMAC Pain, and WOMAC Function in the 
current study for those subjects that had a response in the parent study. Response will be 
characterized as a 20%, 50%, and 70% improvement. 
After all subjects have received LOR at Visit 3E, all further efficacy analyses will be descriptive 
in nature.  
10.4.4 BASELINE DESCRIPTIVE STATISTICS 
Baseline is defined as the last value recorded before a study injection of the parent study (i.e., 
parent-study baseline). Baseline descriptive statistics from parent study will include age, sex, 
race, height, weight, body mass index (BMI), mJSW, Kellgren-Lawrence (KL) grade, and the 
presence of symptomatic and radiographic OA. 
For subjects who cross over from placebo to LOR, Visit 3E (i.e., first exposure to LOR) will 
serve as an additional reference point for analysis. 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
43 
10.4.5 PLANNED INTERIM ANALYSES  
Not applicable to this study. 
10.4.5.1 
SAFETY REVIEW 
Medical monitoring of study safety assessment data will be performed during periodic safety 
reviews detailed in the Medical Monitoring Plan. 
10.4.5.2 
EFFICACY REVIEW 
Not applicable to this study.  
10.4.6 EXPLORATORY ANALYSES 
Not applicable to this study.  
10.4.7 SUB-GROUP ANALYSES 
Not applicable to this study. 
10.5 
SAMPLE SIZE 
The sample size of up to approximately 500 subjects was estimated based on practical 
considerations, such as the number of subjects anticipated to complete study SM04690-OA-11, 
but there is no set cap on enrollment.  
10.6 
MEASURES TO MINIMIZE BIAS 
10.6.1 BLINDING PROCEDURES 
Subjects consented in this study will have been previously treated with an IA injection of either 
LOR or placebo in their target knee in a parent study that was double-blinded. The blind for the 
subject’s previous treatment with either LOR or placebo will be maintained in this study for 
Investigators, site personnel, and subjects only, although the Sponsor will remain blinded to 
treatment assignment until the database from the parent study has been locked. At Visit 1E, 
preparation of LOR or placebo for injection and the injections are to be performed by an 
Unblinded Investigator who has minimal contact with the subject for other aspects of the study, 
as described in Section 6.1.5. At Visit 3E and for any subsequent injections, the LOR injections 
do not need to be performed by a designated Unblinded Investigator due to the open-label nature 
of the remaining portion of the study. 
10.6.2 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
The blind may be broken by a qualified physician who is an Investigator in this study in the 
event of a medical emergency in which knowledge of the identity of the study medication is 
critical to the management of the subject’s immediate course of treatment. Before breaking the 
blind, the Investigator should determine that the information is necessary (i.e., that it will alter 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
44 
the subject’s immediate course of treatment).  
If deemed necessary to break the blind for a study subject, the Medical Monitor(s) is to be 
contacted to obtain concurrence. If it is not possible to contact the Medical Monitor(s) 
beforehand, he or she should be contacted as soon as possible after breaking the blind for a 
subject. Details regarding the emergency unblinding will be documented in Medidata Rave 
Randomization and Trial Supply Management (RTSM) and medical records. Instructions on how 
to unblind treatment assignment will be provided to each Investigator and kept within a guidance 
document at each site. No other blinded site users will have access roles to Medidata Rave 
RTSM that will allow treatment assignment unblinding. 
Any subject whose blind has been broken (to parent-study treatment assignment) will continue 
their follow-up visits per protocol.   
In circumstances when the blind is unintentionally broken at the investigational center, the 
breaking of the blind should be reported to the designated Sponsor Clinical Research Associate 
as soon as possible after breaking the blind for a subject. 
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: 
• The oral and written communication with the subject regarding the study (including 
the risks and benefits of the study), 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 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
45 
will be trained at the Investigator Meeting and/or individual, on-site 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 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 
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 before 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 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
46 
before being asked to sign and date the ICF. Written informed consent must be provided (signed 
and dated) by the potential study participant before 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, regulatory authorities, 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 
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. 
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, OR DATA 
Not applicable to this study. 
13.5 
FUTURE USE OF STORED SPECIMENS  
Not applicable to this study. 
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. 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
47 
Data required by the protocol will either be collected within eCRFs of the study-specific 
Medidata Rave database or provided directly to the Sponsor by 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 11, 312, and 812. Data to 
be transferred external to Rave may include central laboratory data and imaging results. 
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 before destroying any records associated with the study. 
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 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 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, 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
48 
transferred to a different facility, or 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 
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. Names of all Investigators and Sponsor representatives 
responsible for designing the study and analyzing the results will be included in the 
publication(s). 
 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
49 
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 
ismail.simsek@biosplice.com  
(858) 926-2999 
Central radiology reader 
Medical Metrics, Inc. (MMI) 
2121 Sage Road, Suite 300 
Houston, Texas 77056 
(713) 850-7500 
Central laboratory 
Medpace Central Laboratories 
5365 Medpace Way 
Cincinnati, Ohio 45227 
(800) 749-1737 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
50 
16. 
LITERATURE REFERENCES  
Dougados, M. and M. C. Hochberg (2011). Management of osteoarthritis. Rheumatology. M. C. 
Hochberg, A. J. Silman, J. S. Smolen, M. E. Weinblatt and M. H. Weisman. PA, USA, Elsevier: 
1793-1799. 
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. 
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. 
Nevitt, M. C., D. T. Felson and G. Lester (2006). " A Knee Health Study." "The Osteoarthritis 
Initiative.". 
Pham, T., D. Van Der Heijde, M. Lassere, R. D. Altman, J. J. Anderson, N. Bellamy, M. 
Hochberg, L. Simon, V. Strand, T. Woodworth, M. Dougados and O. Omeract (2003). "Outcome 
variables for osteoarthritis clinical trials: The OMERACT-OARSI set of responder criteria." J 
Rheumatol 30(7): 1648-1654. 
Wu, L., X. Huang, L. Li, H. Huang, R. Xu and W. Luyten (2012). "Insights on biology and 
pathology of HIF-1alpha/-2alpha, TGFbeta/BMP, Wnt/beta-catenin, and NF-kappaB pathways in 
osteoarthritis." Curr Pharm Des 18(22): 3293-3312. 
 
 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
51 
APPENDIX 
Appendix 1. 
Prohibited Concomitant Medications and Procedures (Supplement)  
1) Excluded and prohibited centrally acting analgesics include, but are not limited to, the 
following: 
• Gabapentin (Neurontin, Horizant, Gaberone, Gralise, Fusepaq Fanatrex) 
• Pregabalin (Lyrica) 
• Carbamazepine (Tegretol, Carbatrol, Epitol, Equetrol) 
• Duloxetine (Cymbalta, Irenka) 
• Milnacipran (Savella) 
• Orphenadrine Citrate (Norflex, Orfro, Orphenate, Mio-Rel, Antiflex) 
• Amitriptyline (Elavil, Vanatrip) 
• Clomipramine (Anafranil) 
• Nortriptyline (Aventyl, Pamelor) 
• Desipramine (Norpramin) 
• Imipramine (Tofranil) 
• Doxepin (Prudoxin, Sinequan, Zonalon, Silenor) 
• Ketamine (Ketalar) 
• Sodium Oxybate (Xyrem, GHB) 
 
2) Other non-listed anticonvulsants are also prohibited. 
 
3) Excluded and prohibited electrotherapy treatments include, but are not limited to, the 
following: 
• Diathermy 
• TENS 
• NMES 
• Interferential therapy 
• Shortwave therapy 
• Iontophoresis 
• LASER 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
52 
Appendix 2. 
Amendments 
AMENDMENT 02 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A Long-Term Extension Study Evaluating the Safety and Efficacy of 
Lorecivivint in Subjects with Osteoarthritis of the Knee 
Purpose: 
The purpose of this amendment is to refine the study design into a 
long-term extension study in which subjects will receive study 
injections annually and placebo subjects will cross over to LOR after 
the first study injection. 
Summary of Changes: The table below provides a list of changes and their rationale. 
Change 
Sections Affected 
Rationale 
Protocol Amendment 02 Version 00 has been 
added on the title page. 
Title Page 
Change was made to capture the dates 
of previous and current protocol 
versions 
Protocol date and version have been updated as 
applicable 
All 
Change was made to reflect current 
protocol amendment 
Study title was changed (replaced “48-Week, 
Placebo-Controlled, Single-Blind” with “Long-
Term”) 
Throughout 
Changes were made to align with 
revised study design. 
“Samumed, LLC” was replaced with “Biosplice 
Therapeutics, Inc.” or deleted. 
Throughout 
Change was made for administrative 
reasons. 
Titles of signatories were updated. 
Sponsor Signature 
Page 
Change was made for administrative 
reasons. 
Primary and secondary objectives were edited. 
Sections 1.1 and 3.1 
Edits were made to align with new 
long-term study design.  
Efficacy endpoints were updated to be “over the 
course of the study” where applicable.  
Sections 1.1 and 3.2 
Edits were made to align with new 
long-term study design. 
Study design was revised, including: 
• 
Limiting single-blind and placebo-control 
to the first 48 weeks; remainder of the 
study is open-label and uncontrolled. 
• 
Study visits were added (phone visit at 
Week 52 and clinic visits approximately 
every 26 weeks). 
• 
Subjects will receive LOR injections 
approximately every 52 weeks after Visit 
3E. 
• 
Study and participant duration were 
updated accordingly. 
• 
EOS and ET visits were replaced with a 
single Termination Visit. 
Sections 1.1, 2.3.1, 
4.1, 4.2, 4.4, 5.6, 6.1.4, 
6.1.5, 6.1.9, 7.5, and 
7.8 
 
Study design was refined to allow for 
long-term evaluation of safety and 
efficacy.  
Exclusion #3 was revised to include, “Any known 
reason identified by the Investigator or Sponsor 
that the subject may not be compliant…” 
Sections 1.1 and 5.2 
Change was made to refine exclusion 
criteria. 
Exclusion criterion #8 (regarding men who are 
sexually active and of reproductive potential) was 
deleted. 
Sections 1.1 and 5.2 
Male contraception requirements were 
removed to align with PK studies 
demonstrating no detectable systemic 
exposure following IA injection of 
LOR. 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
53 
Change 
Sections Affected 
Rationale 
Estimated subject number and number of sites 
were edited. 
Sections 1.1, 4.1, and 
10.5  
Change was made for accuracy 
Contraception guidelines were revised for 
WOCBP and removed for men.  
Section 5.3.1 
Male contraception requirements were 
removed to align with PK studies 
demonstrating no detectable systemic 
exposure following IA injection of 
LOR. 
Instructions for a Total or Partial Knee 
Replacement Follow-Up were added to the 
protocol. 
Section 5.6.2 
Follow-up was added to allow for 
assessment of TKR/PKR surgery 
outcomes. 
Guidance on study drug injection was updated, 
including adding a recommendation for aspiration 
of moderate to large effusions in the target knee 
prior to injection.  
Section 6.1.5 
Changes were made to provide further 
guidance on IA injections. 
Accountability procedures were revised. 
Section 6.2 
Accountability procedures for blinded 
versus open-label IP were clarified.  
Timing of study specific procedures was revised 
where applicable.  
Sections 7.1 and 7.2 
Changes were made to align with 
revised study design.  
Fasting requirements for labs was removed (except 
for Visit 3E).  
Section 7.2.1 
Change was made as fasting was more 
relevant to biomarker sample 
collection. 
Study visits and Schedule of Events were revised. 
Section 7.3 
Changes were made to align with 
revised study design. 
Prohibited procedures were modified. 
Section 7.6 
Changes were made to refine 
prohibited procedures. 
SAE reporting information and sponsor contact 
information was updated. 
Section 8.4.2 
Changes were made to clarify initial 
SAE reporting and for administrative 
reasons. 
Reporting of pregnancy was limited to pregnant 
subjects (not pregnant partners of a male subject). 
Section 8.4.5 
Changes were made to align with 
removal of male contraception 
requirements. 
Descriptions of statistical methods were updated. 
Sections 1.1 and 10.4 
Changes were made to align with 
revised study design. 
Medical monitor roles were updated. 
Section 15.2 
Change was made for administrative 
reasons. 
General editorial/grammatical edits. 
Throughout 
Changes were made for clarity and 
accuracy. 
 
 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Protocol SM04690-OA-07 
Biosplice Therapeutics, Inc.  
AM02V00 
04 May 2021 
 
Confidential
 
 
54 
AMENDMENT 01 VERSION 00 SUMMARY OF CHANGES 
Study Title: 
A 48-Week, Placebo-Controlled, Single Blind Extension Study 
Evaluating the Safety and Efficacy of Lorecivivint in Subjects with 
Osteoarthritis of the Knee 
Purpose: 
The purpose of this amendment is to refine the study design. 
Summary of Changes: The table below provides a list of changes and their rationale. 
Change 
Sections Affected 
Rationale 
Protocol Amendment 01 Version 00 has been 
added on the title page. 
Title Page 
Change was made to capture the dates 
of previous and current protocol 
versions 
Protocol date and version have been updated as 
applicable 
All 
Change was made to reflect current 
protocol amendment 
“Estimated date first subject consented” was 
changed from July to August 2020. “Estimated 
date last subject completed” was changed from 
December to September 2022. 
Section 1.1 
Change was made for accuracy 
The window between the parent-study EOS visit 
and Visit 1E was extended from 2 to 6 weeks. 
Sections 1.1, 4.1, 
7.3.1, and 7.3.4 
Change was made to allow Visit 1E to 
occur up to 6 weeks after the parent-
study EOS visit.  
Made the following correction: “…recorded on 
specific pages of the eCRF or electronic diary.” 
Sections 7.1.1 and 
8.1.1 
An electronic diary is not being used 
in this study 
The following addition was made: “Per-Protocol 
Analysis Set (PPAS): FAS subjects who complete 
the study and do not have any major protocol 
deviations in the current or parent study that might 
impact efficacy.” 
Section 10.3 
Change was made to provide further 
clarification to the analysis datasets. 
 
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved

Signature Page for VV-TMF-172218 v1.0
Signature Page for VV-TMF-172218 v1.0
Reason for signing: Approved
Name: Ismail Simsek
Role: Medical Director
Date of signature: 05-May-2021 03:09:28 GMT+0000
Reason for signing: Approved
Name: Christopher Swearingen
Role: Vice President, Clinical Outcomes and
Analytics
Date of signature: 05-May-2021 03:29:30 GMT+0000
Reason for signing: Approved
Name: Mark Fineman
Role: Vice President, Clinical Development
Date of signature: 05-May-2021 03:40:05 GMT+0000
SM04690-OA-07-protocol-amend-02-v0-0-04may2021_VV-TMF-172218_1.0_Approved