A Double-Blind, Placebo-Controlled Assessment of the Tolerability and Efficacy of XT-150 for the Treatment of Moderate to Severe Pain Due to Osteoarthritis of the Knee
Phase: PHASE2
Conditions: Osteoarthritis, Knee
Sponsor: Xalud Therapeutics, Inc.



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PROTOCOL APPROVAL PAGE
A DOUBLE-BLIND, PLACBO-CONTROLLED ASSESSMENT OF THE 
TOLERABILITY AND EFFICACY OF XT-150 FOR THE TREATMENT OF 
MODERATE TO SEVERE PAIN DUE TO OSTEOARTHRITIS OF THE KNEE
Protocol XT-150-2-0204
Version 1: 1 October 2019
Amendment 1: 6 January 2020
Amendment 2: 25 March 2020
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1.0
PROTOCOL SYNOPSIS 
Sponsor: Xalud Therapeutics, Inc./Xalud Therapeutics Australia Pty LTD
Study Number: Protocol XT-150-2-0204
Product Name: XT-150
Protocol Title: A Double-Blind, Placebo-Controlled Assessment of the Tolerability and Efficacy of
XT-150 for the Treatment of Moderate to Severe Pain Due to Osteoarthritis of the Knee
Planned Study Centers: 5 (US and Australia)
Phase of Development: 2
Objectives 
Primary: 
To confirm the safety and tolerability of intra-articularly-injected XT-150
Secondary: To establish analgesic efficacy of intra-articularly-injected XT-150
Study Design
This is a Phase 2 safety and efficacy study of XT-150 in adult participants experiencing moderate to 
severe pain due to osteoarthritis of the knee.
Participants will provide informed consent and meet all study eligibility criteria before any study 
procedures are initiated. Baseline confirmation of study eligibility will be completed the day before 
or day of study drug administration. The Index Knee for study drug injection will be the OA-
affected joint identified by Kellgren-Lawrence grade of 2 or 3; and :20$& 3DLQ 6XEVFDOH   RQ D
scale of 20. 
Study drug will be administered by intra-articular (IA) injection into the joint space of the Index 
Knee.
About 270 participants will be randomly enrolled into 1 of 3 treatment groups (approximately 90
participants/ group). Treatment Groups:
A. Placebo (1 mL)
B. 150 μg XT-150 (1 mL)
C. 450 μg XT-150 (1 mL)
Participants will undergo the study in 2 stages, A and B:
D. Placebo-controlled for 6 months
E. Continued follow up for 6 months with the option of UDQGRPO\ UHFHLYLQJ D VLQJOH  ȝJ RU
 ȝJ injection as the second injection to the Index Knee (knee dosed in Stage A).
Safety parameters and efficacy endpoints for each participant will be evaluated monthly for about 1 
year from the first XT-150 dose (Stage A, Day 0)
The Schedule of Assessments and Procedures is presented in Table 1 (Stage A) and Table 2 (Stage B).
Day 0 is defined as the day of study drug administration. Subsequent study days are defined by the 
number of consecutive calendar days after drug administration.
Number of Participants and Treatment Groups: 
About 270 participants will be enrolled in one of 3 treatment groups (90 participants/group) and 
evaluated. 
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Inclusion Criteria
Participants are required to meet ALL of the following inclusion criteria:
1. Symptomatic disease due to osteoarthritis, defined as a WOMAC Pain VFRUH  8 (worst possible 
= 20)
2. Focused Analgesia Selection Test (Analgesic Solutions, Wayland, MA) will be used to 
determine whether patients can report pain with sufficient consistency to enter the clinical trial
(See Appendix 4)
3. Males and females between 45 and 85 years of age, inclusive  
4. Kellgren-Lawrence grading of 2 or 3 within the last 6 months 
5. Stable analgesic regimen during the 4 weeks prior to enrollment 
6. In the judgment of the Investigator, acceptable general medical condition 
7. Life expectancy >6 months
8. Male and female participants who are heterosexually active and not surgically sterile must agree 
to use effective contraception, including abstinence, for the duration of the study
9. Have suitable knee joint anatomy for intra-articular injection
10. Willing and able to return for the follow-up (FU) visits 
11. Able to read and understand study instructions, and willing and able to comply with all study 
procedures 
Exclusion Criteria
Participants must NOT meet any of the following exclusion criteria:
1. Hypersensitivity, allergy, or significant reaction to any ingredient of the study drug, including 
double-stranded DNA, 
2. Previously received XT-150 injection(s)
3. Scheduled partial or complete knee replacement within 6 months; participant agrees not to 
schedule a knee replacement during Stage A of the study
4. History of knee arthroplasty on the Index Knee, i.e., selected for study injection(s)
5. History of rheumatoid arthritis or other inflammatory disease
6. History of immunosuppressive therapy; systemic steroids in the last 3 months
7. Received knee injection with hyaluronic acid or stem-cells in the last 6 months
8. Knee injection of glucocorticoid in the last 3 months 
9. Current treatment with systemic immunosuppressive (systemic corticosteroid therapy or other 
strong immunosuppressant)
10. Currently receiving systemic chemotherapy or radiation therapy for malignancy
11. CliniFDOO\ VLJQLILFDQW KHSDWLF GLVHDVH DV LQGLFDWHG E\ FOLQLFDO ODERUDWRU\ UHVXOWV  WLPHV WKH
upper limit of normal for any liver function test (e.g., aspartate aminotransferase, alanine 
aminotransferase)
12. Severe anemia (Grade 3; hemoglobin <8.0 g/dL, <4.9 mmol/L, <80 g/L; transfusion indicated), 
Grade 1 white cell counts (lymphocytes <LLN - 800/mm3; <LLN - 0.8 x 109 /L, neutrophils 
<LLN - 1500/mm3; <LLN - 1.5 x 109 /L)
13. Positive serology for human immunodeficiency virus, hepatitis B virus, or hepatitis C virus 
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Table 2.
Schedule of Assessments and Procedures – Stage B
Scheduled Event
Follow up Visit Dayd 
210
(±7)
240
(±7)
270
(±7)
300
(±7)
330
(±7)
360
(±7)
KOOS/WOMAC
X
X
X
X
X
X
BPI
X
X
X
X
X
X
Patient response to OA question
X
X
X
X
X
X
X
X
X
X
X
X
X
Brief physical examination
X
X
X
X
X
X
Record height and weight, 
calculate BMI
X
Vital signs
X
X
X
X
X
X
Clinical exam of the treated joints
X
X
X
X
X
X
Record AEs
X
X
X
X
X
X
Record SAEs
X
X
X
X
X
X
X
X
X
X
X
X
Record concomitant medications
X
X
X
X
X
X
Serum for anti-IL-10 antibody
assessments
X
Serum pregnancy testb
X
Administer studydrugc
x
x
x
x
x
Footnotes to Table 2
b.
Women of child-bearing potential
c.
Participants may elect for one (1) XT-150 IA injection into the Index Knee at any point during Stage B up to 
Day 330, inclusive. The XT-150 dose (150 μg or 450 μg) will be randomly assigned. 
d.
A telephone call documenting safety and efficacy assessments may be used for participants unable to 
physically attend follow up visits due to COVID19 infection or corona virus exposure concerns 
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2.0
TABLE OF CONTENTS
1.0 
PROTOCOL SYNOPSIS................................................................................3 
2.0 
TABLE OF CONTENTS..............................................................................10 
3.0 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITIONS OF 
TERMS...........................................................................................................14 
4.0 
BACKGROUND AND RATIONALE.........................................................16 
4.1 
XT-150.................................................................................................16 
4.2 
Nonclinical Pharmacology and Toxicology.........................................16 
4.3 
Clinical Experience..............................................................................17 
4.4 
Summary of Known Benefits and Potential Risks...............................18 
4.4.1 
Potential Benefits................................................................18 
4.4.2 
Known Risks.......................................................................19 
4.4.3 
Potential Risks.....................................................................19 
4.4.4 
Safety of Interleukin-10 ......................................................19 
4.4.5 
Possible Anticipated Adverse Events and Clinical 
Monitoring...........................................................................21 
4.4.6 
Risk-Benefit Summary........................................................21 
4.5 
Justification for Dosing Regimen ........................................................22 
4.6 
Population to be Studied......................................................................22 
4.7 
Statement of Compliance.....................................................................22 
5.0 
STUDY PURPOSE AND OBJECTIVES....................................................22 
6.0 
STUDY DESIGN............................................................................................22 
6.1 
Description of the Study......................................................................22 
6.2 
Follow up Assessments........................................................................23 
6.3 
Number of Participants ........................................................................24 
6.4 
Expected Duration of Subject Participation.........................................24 
6.5 
Method of Treatment Assignment and Blinding .................................24 
7.0 
SELECTION, DISCONTINUATION, AND WITHDRAWAL OF 
PARTICIPANTS............................................................................................24 
7.1 
Participant Inclusion Criteria ...............................................................24 
7.2 
Participant Exclusion Criteria ..............................................................25 
7.3 
Requalification for Entry .....................................................................26 
7.4 
Participant Withdrawal Criteria ...........................................................26 
7.4.1 
Withdrawal from Study Protocol........................................26 
7.4.2 
Early Discontinuation from Study Drug Administration....27 
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7.5 
Replacement of Participants.................................................................27 
7.6 
Study Termination by Sponsor and Termination Criteria....................27 
8.0 
STUDY DRUGS.............................................................................................27 
8.1 
Formulation and Preparation of Study Drug........................................27 
8.1.1 
Directions for Use ...............................................................28 
8.1.2 
Instructions for Storage and Handling ................................28 
8.2 
XT-150 administration.........................................................................28 
8.3 
Placebo administration.........................................................................28 
8.4 
XT-150 Blinding..................................................................................28 
8.5 
Comparator...........................................................................................29 
8.6 
Compliance ..........................................................................................29 
8.7 
Previous and Concomitant Medications and Substances.....................29 
8.7.1 
Prohibited medications........................................................29 
8.7.2 
Rescue Medications.............................................................29 
8.7.3 
....................................29 
8.8 
Accountability Procedures...................................................................30 
8.9 
Study Drug Handling and Disposal .....................................................30 
9.0 
STUDY PROCEDURES...............................................................................30 
9.1 
Screening..............................................................................................30 
9.2 
Baseline................................................................................................31 
9.3 
Day 0....................................................................................................32 
9.4 
Between clinic visits: ...........................................................................33 
9.5 
Follow up Visits – Stage A ..................................................................33 
9.6 
Follow up Visit – Stage A, Day 180 [±7 days)....................................34 
9.7 
Follow up Visits – Stage B ..................................................................34 
10.0 
ASSESSMENT OF SAFETY........................................................................35 
10.1 
Safety Parameters.................................................................................35 
10.2 
Adverse Events of Noted Interest in IL-10 Protein Trials ...................35 
10.3 
Adverse Events....................................................................................36 
10.4 
Adverse Event Reporting.....................................................................36 
10.5 
Definitions............................................................................................37 
10.5.1 
Adverse Event.....................................................................37 
10.5.2 
Suspected Adverse Drug Reaction......................................38 
10.5.3 
Life-Threatening AE or Life-Threatening Suspected 
Adverse Drug Reaction.......................................................38 
10.5.4 
Serious AE or Serious Suspected Adverse Reaction ..........38 
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10.5.5 
Unexpected AE or Unexpected Suspected Adverse Drug 
Reaction...............................................................................39 
10.6 
Adverse Event Classification...............................................................39 
10.6.1 
Relationship to Investigational Drug...................................39 
10.6.2 
Severity................................................................................39 
10.6.3 
Serious Adverse Event ........................................................40 
10.7 
Adverse Event Follow-up....................................................................41 
10.8 
Adverse Events of Special Interest ......................................................41 
10.8.1 
Localized Signs of Infection or Inflammation at the 
Injection Site .......................................................................41 
10.9 
Toxicity Management ..........................................................................41 
10.10 Risks for Women of Child-Bearing Potential or During Pregnancy ...41 
11.0 
ASSESSMENT OF EFFICACY PARAMETERS......................................42 
12.0 
ASSESSMENT OF ANTI-IL-10 ANTIBODIES.........................................42 
13.0 
STATISTICAL METHODS.........................................................................43 
13.1 
Determination of Sample Size .............................................................43 
13.2 
Analysis Populations............................................................................43 
13.3 
Analysis of Study Population and Participant Characteristics.............44 
13.4 
Safety Analyses....................................................................................44 
13.5 
Analysis of Efficacy.............................................................................44 
13.5.1 
Multiplicity of endpoints.....................................................44 
13.5.2 
Statistical methods for the binary outcomes .......................45 
13.5.3 
Statistical methods for the continuous or graded endpoints
.............................................................................................45 
13.5.4 
Statistical methods for time-to-event endpoints..................45 
13.6 
Bioanalytical Analyses.........................................................................46 
13.7 
Handling of Dropouts and Missing, Unused, and Spurious Data........46 
13.8 
Termination Criteria.............................................................................46 
13.9 
Deviation Reporting.............................................................................46 
14.0 
INVESTIGATOR REQUIREMENTS.........................................................46 
14.1 
Protocol Adherence..............................................................................46 
14.1.1 
Investigator or Designee Experience...................................46 
14.2 
Case Report Forms...............................................................................46 
14.3 
Source Document Maintenance ...........................................................47 
14.4 
Study Monitoring Requirements..........................................................47 
14.5 
Study Completion ................................................................................47 
15.0 
QUALITY CONTROL AND QUALITY ASSURANCE...........................48 
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16.0 
PROTECTION OF HUMAN PARTICIPANTS.........................................48 
16.1 
Informed Consent.................................................................................49 
16.2 
IRB/HREC Approval...........................................................................49 
17.0 
DATA HANDLING AND RECORD KEEPING........................................49 
17.1 
Direct Access to Source Data/Documentation.....................................49 
17.2 
Study Drug Accountability ..................................................................50 
17.3 
Retention of Records............................................................................50 
18.0 
FINANCING AND INSURANCE................................................................50 
19.0 
PUBLICATION POLICY.............................................................................50 
20.0 
REFERENCES...............................................................................................50 
21.0 
APPENDICES................................................................................................52 
Appendix 1: Clinical Laboratory Tests............................................................52 
Appendix 2: 
BPI.......................................................................................53 
Appendix 3: 
KOOS..................................................................................54 
Appendix 4:  Focused Analgesia Selection Test (FAST) ................................55 
Appendix 5: Kellgren-Lawrence Grading........................................................56 
Appendix 6: Investigator Signature.................................................................57 
 
List of Tables 
Table 1. 
Schedule of Assessments and Procedures – Stage A...................................7 
Table 2. 
Schedule of Assessments and Procedures – Stage B...................................9 
Table 3.  Human Clinical Trials with XT-150 ..........................................................17 
Table 4. 
Final Drug Product Quantitative Composition Per Vial ............................27 
Table 5.  Guidelines for Assessing Relationship of Event to Study Drug................39 
Table 6.  Guidelines for Severity Assessments.........................................................40 
Table 7.  Treatment Effect That Can Be Detected....................................................43 
 
 
 
 
 
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3.0
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITIONS OF 
TERMS
Abbreviation
Definition
AE
Adverse event
ANCOVA
Analysis of covariance
Anti-interleukin-10
antibody
Antibody that binds IL-10
aPTT
Activated partial thromboplastin time
BPI
Brief Pain Inventory of Intensity and Interference
BMI
Body mass index
CBC
Complete blood count
CTCAE
Common Terminology Criteria for Adverse Events (V5.0)
CCI
Chronic Constriction Injury-induced pain model
CNS
Central nervous system
CRF
Case report form
ds DNA
Double stranded DNA
FDA
Food and Drug Administration
FU
Follow-up
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HREC
Human Research Ethics Committee
IA
Intra-articular
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IL
Interleukin
IL-10
Interleukin-10
Index Knee
The knee receiving injection of study drug
INR
International normalized ratio
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Abbreviation
Definition
IRB
Institutional Review Board
IT
Intrathecal
ITT
Intent-to-Treat
IV
Intravenous
KOOS
Knee injury and Osteoarthritis Outcome Score
MedDRA
Medical Dictionary for Regulatory Activities
NP
Neuropathic
OA
Osteoarthritis
OTC
Over the counter
pDNA
Plasmid DNA
PI
Principal Investigator
PT
Prothrombin time
PTT
Partial thromboplastin time
QST
Quantitative Sensory Testing
SAE
Serious adverse event
SAER
Serious adverse event report
SAP
Statistical Analysis Plan
SOP
Standard operating procedure
TEAE
Treatment-emergent adverse event
TGA
Therapeutics Goods Administration
VASPI or VAS
Visual Analog Scale of Pain Intensity
VNRS
Verbal Numerical Rating Scale
WOMAC
Western Ontario and McMaster Universities Osteoarthritis Index
XT-150
Plasmid DNA, 
, expressing a 
proprietary variant of human IL-10 protein, formulated in a 
 solution for injection.
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Stage B continues for an additional six months of safety and efficacy monitoring during 
which participants can elect for a second injection to the Index Knee.  Active 150 Ɋ or 
450 Ɋ XT-150 will be randomly chosen for the second injection.  
Participants will provide informed consent and meet all study eligibility criteria before 
any study procedures are initiated. FAST (Appendix 4:  Focused Analgesia Selection 
Test) will be used to select patients who reliably report the magnitude of thermal
stimulations.
Baseline confirmation of study eligibility will be completed within one day preceding 
study drug administration. Study drug will be administered by intra-articular (IA) 
injection into the joint space of the knee.
About 270 participants will be randomly enrolled into 1 of 3 treatment groups 
(approximately 90 participants/group). Treatment Groups:
1. Placebo (1 mL)
2. 150 μg XT-150 (1 mL)
3. 450 μg XT-150 (1 mL)
The study will be conducted in 2 stages, A and B:
A. Placebo controlled for 6 months
B. Continued follow up for 6 months with the option of randomly receiving a single 
 ȝJ RU  ȝJ injection as the second injection to the Index Knee (knee dosed 
in Stage A).
Safety parameters and efficacy endpoints for each participant will be evaluated monthly 
for about 1 year from the first XT-150 dose (Stage A, Day 0)
The Schedules of Assessments and Procedures are presented in Table 1 and Table 2. Day 
0 is defined as the day of study drug administration. Subsequent study days are defined 
by the number of consecutive calendar days after drug administration. 
6.2
Follow up Assessments
All participants will be assessed for physical examination findings and vital signs
following signing of the informed consent form (ICF) and for AEs and SAEs, throughout 
the study for each treatment group.
Serum samples will be collected from all participants to test for the presence of anti-IL-
10 antibodies. Samples will be analyzed using a validated assay by an independent, 
central bioanalytical laboratory. Procedures for collection, storage, and shipping of 
immunogenicity samples are described in the study Lab Manual.
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Efficacy assessments will be performed at the screening visit (WOMAC Pain Score for
eligibility), then all measures at Baseline, on Day 7, Day 30, and approximately monthly 
thereafter for up to 1 year. Efficacy endpoints will be evaluated at each study visit and 
overall.
A telephone call documenting safety and efficacy assessments may be used for participants unable 
to physically attend follow up visits due to COVID-19 infection or corona virus exposure concerns.  
Home services may be employed for blood collections. 
6.3
Number of Participants
About 270 participants will be treated and evaluated. 
6.4
Expected Duration of Subject Participation
Subject participation will require a commitment of approximately 1 year of safety, 
tolerability, and efficacy evaluation. In addition, a screening visit will occur up to 30 days 
before enrollment.
Baseline assessments for study eligibility will be completed within one day before study 
drug administration. Day 0 is defined as the day of study drug administration.
Subsequent study days are defined by the number of consecutive calendar days thereafter.
Follow-up visits will occur on Study Day 7, Study Day 30, and approximately monthly 
thereafter.
6.5
Method of Treatment Assignment and Blinding
After informed consent has been obtained, participants will be screened for study 
eligibility before enrollment.
In Stage A, participants will be randomly enrolled into one of 3 groups, two XT-150
treatment groups  ȝJ RU  ȝJ or placebo.
At any time in Stage B up to Day 330, inclusive, participants can elect for a single 
injection to the knee dosed in Stage A (Index Knee).  The second injection dose will be 
randomized to be HLWKHU  ȝJ RU  ȝJ ;7-150.  There will be no placebo comparator 
in Stage B.  
Instructions for study drug preparation and dosing are given in Section 8.0.
7.0
SELECTION, DISCONTINUATION, AND WITHDRAWAL OF 
PARTICIPANTS
To be enrolled in this study, all participants must meet all of the following inclusion 
criteria and none of the exclusion criteria. 
7.1
Participant Inclusion Criteria
Participants are required to meet ALL of the following inclusion criteria:
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1. Symptomatic disease due to osteoarthritis, defined as a :20$& 3DLQ VFRUH  
(worst possible = 20)
2. Focused Analgesia Selection Test (Analgesic Solutions, Wayland, MA) will be 
used to determine whether patients can report pain with sufficient consistency to 
enter the clinical trial (See Appendix 4)
3. Males and females between 45 and 85 years of age, inclusive.  
4. Kellgren-Lawrence grading of 2 or 3 within the last 6 months (See Appendix 5)
5. Stable analgesic regimen during the 4 weeks prior to enrollment. 
6. In the judgment of the Investigator, acceptable general medical condition 
7. Life expectancy >6 months
8. Male and female participants who are heterosexually active and not surgically 
sterile must agree to use effective contraception, including abstinence, for the 
duration of the study.
9. Have suitable knee joint anatomy for intra-articular injection
10. Willing and able to return for the follow-up (FU) visits 
11. Able to read and understand study instructions, and willing and able to comply 
with all study procedures 
7.2
Participant Exclusion Criteria
Participants must NOT meet any of the following exclusion criteria:
1. Hypersensitivity, allergy, or significant reaction to any ingredient of the study 
drug, including double-stranded DNA, 
2. Previously received XT-150 injection(s)
3. Scheduled partial or complete knee replacement within 6 months; participant 
agrees not to schedule a knee replacement during Stage A of the study
4. History of knee arthroplasty on the Index Knee selected for study injection(s)
5. History of rheumatoid arthritis or other inflammatory disease
6. History of immunosuppressive therapy; systemic steroids in the last 3 months
7. Received knee injection with hyaluronic acid or stem-cells in the last 6 months
8. Knee injection of glucocorticoid in the last 3 months 
9. Current treatment with systemic immunosuppressive (systemic corticosteroid 
therapy or other strong immunosuppressant)
10. Currently receiving systemic chemotherapy or radiation therapy for malignancy
11. &OLQLFDOO\ VLJQLILFDQW KHSDWLF GLVHDVH DV LQGLFDWHG E\ FOLQLFDO ODERUDWRU\ UHVXOWV 
times the upper limit of normal for any liver function test (e.g., aspartate 
aminotransferase, alanine aminotransferase)
12. Severe anemia (Grade 3; hemoglobin <8.0 g/dL, <4.9 mmol/L, <80 g/L; 
transfusion indicated), Grade 1 white cell counts (lymphocytes <LLN - 800/mm3;
<LLN - 0.8 x 109 /L, neutrophils <LLN - 1500/mm3; <LLN - 1.5 x 109 /L)
13. Positive serology for human immunodeficiency virus, hepatitis B virus, or 
hepatitis C virus 
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14. Significant neuropsychiatric conditions; dementia, major depression, or altered 
mental state that in the opinion of the Investigator will interfere with study 
participation
15. Current treatment with systemic antibiotics or antivirals (EXCEPTION: topical 
treatments) 
16. Current anticoagulant or anti-platelet treatment (e.g., warfarin, heparins, factor X 
inhibitors, clopidogrel, prasugrel, ticagrelor, or dipyridamole).  Low-GRVH  325
mg/day) aspirin is permitted.
17. Known or suspected history of active alcohol or intravenous/oral drug abuse 
within 1 year before the screening visit
18. Use of any investigational drug or device within 3 months before enrollment or 
current participation in a trial that included intervention with a drug or device; or 
currently participating in an investigational drug or device study
19. Any condition that, in the opinion of the Investigator, could compromise the 
safety of the participant, the participant’s ability to communicate with the study 
staff, or the quality of the data
7.3
Requalification for Entry
Participants not fulfilling the entry criteria and not treated may be rescreened for 
participation if their eligibility characteristics have changed. 
7.4
Participant Withdrawal Criteria
7.4.1
Withdrawal from Study Protocol
Participants on study drug who wish to withdraw completely from this clinical study 
should be encouraged to complete the assessments for Day 360/Termination. However, 
participants may withdraw consent to participate in this study at any time without penalty 
or loss of benefits to which the participant is otherwise entitled. Every reasonable effort 
should be made to determine the reason a participant withdraws prematurely, and this
information should be recorded on the appropriate page(s) of the case report form (CRF). 
Participants may be withdrawn from the study for any of the following reasons and will 
be captured in CRFs:
x
Participant unable or unwilling to continue
x
Participant’s perceived lack of benefit
x
Participant elects to withdraw informed consent
x
Due to an adverse event
x
Protocol non-compliance
x
Participant is lost to follow up
x
The PI considers that it is in the participant’s best interest not to continue 
participation in the study
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8.8
Accountability Procedures
The pharmacy or study personnel are responsible for ensuring that all XT-150 study drug 
shipments, inventory, and use are recorded and accountability is maintained. 
The Sponsor’s site monitors will be responsible for checking drug accountability at the 
site. Inventory records must be readily available for inspection by regulatory authorities 
at any time. Each shipment of study drug will contain an acknowledgment of receipt 
section for site signature. Upon receipt of study drug, the pharmacy or study personnel 
will visually inspect the shipment and verify the number and condition of vials or 
capsules received. Refer to the Pharmacy Manual for additional information. 
8.9
Study Drug Handling and Disposal
Upon completion of the study, termination of the study, or upon written authorization 
from the Sponsor, all unused and partially used study drug will be centrally destroyed. 
All records of disposal by a centralized destruction site will be maintained by the 
Sponsor.
9.0
STUDY PROCEDURES
Study procedures should be completed within the windows provided in the Schedule of 
Assessments and Procedures located in Table 1 (Stage A) and Table 2 (Stage B).
However, if a participant is unable to attend a visit within the specified windows, the PI 
(or qualified designee) should discuss appropriate scheduling with the Medical Monitor 
(or appropriate designee).
A telephone call documenting safety and efficacy assessments may be used for participants unable 
to physically attend follow up visits due to COVID-19 infection or corona virus exposure concerns.  
Home services may be employed for blood collections. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
9.1
Screening
Unless otherwise indicated, screening assessments should be performed within 30 days of 
enrollment.
x
Obtain signed informed consent prior to initiating any study-related assessments or 
procedures
x
Obtain a complete medical history and risk factors (e.g., active malignancy, diabetes 
mellitus, immunosuppression, transplant recipient, trauma, dialysis) and Intensive 
Care Unit admission and discharge (if applicable)
x
Kellgren-Lawrence grading (obtain a new radiograph if not done in 6 months prior to 
Screening (See Appendix 5: Kellgren-Lawrence Grading)
x
Choice of Index Knee
o
Meets radiographic criteria:  Kellgren-Lawrence grade 2 or 3
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o
:20$& 3DLQ 6XEVFRUH  
o
If bilateral OA and both knees meet the first 2 criteria, the participant and 
investigator will jointly identify which knee will receive study drug
o
Record Left or Right knee as the Index Knee
x
Obtain history of all pain medications and all other medications (prescription and
over-the-counter [OTC]) and supplements)
x
Conduct FAST assessment
x
Participant training on accurate pain reporting
x
Clinical assessments
o
Conduct complete physical examination, including height and weight (calculate 
body mass index [BMI])
o
Measure vital signs (temperature and the site collected [oral, rectal, temporal, or 
tympanic], heart rate, blood pressure, and respiratory rate)
o
Verify WOMAC Pain SubsFRUH  8 attributable to the Index Knee.
x
Laboratory assessments
ż
Obtain blood samples for:

Hematology tests (complete blood count [CBC] with differential and platelets 
count),

coagulation laboratory tests (prothrombin time [PT] / international normalized 
ratio [INR] and either partial thromboplastin time [PTT] or activated partial 
thromboplastin time [aPTT]), 

HIV, Hepatitis B and C

Serum pregnancy test for women of child-bearing potential

Serum chemistry tests (Appendix 1)
x
Confirm participant qualification by inclusion/exclusion criteria
9.2
Baseline
Baseline assessments may be completed the day before or day of study drug 
administration, before the XT-150 injection.
 
x
Training for accurate pain reporting
x
Brief physical exam, including examination of Index Knee
x
Obtain any changes from the complete medical history. 
x
Record any changes or updates in medications, including pain medications and 
therapies administered since Screening visit.
x
Efficacy assessments
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o
Record Baseline BPI scores (Appendix 2)
o
Record Baseline KOOS (Appendix 3) 
o
Record participant’s response to the OA question: “Considering all the ways the 
OA in your knee affects you, how are you doing today?” on a scale of 1 to 5, 1
being very good (asymptomatic and no limitation of normal activities) to 5, very 
poor (very severe, intolerable symptoms and inability to carry out normal 
activities) 
o
Record baseline non-prescription pain therapies or practices
o
x
Clinical assessments
o
Measure vital signs (temperature and the site collected [oral, rectal, temporal, or 
tympanic], heart rate, blood pressure, and respiratory rate) 
x
Laboratory assessments
ż
Obtain serum for analysis of anti-IL-10 antibodies
x
Confirm participant qualification by inclusion/exclusion criteria. Enroll participant
prior to dosing 
9.3
Day 0
x
Before administering study drug:
ż
Confirm that all study criteria are met (inclusion and exclusion)
ż
Brief physical exam
ż
Injection site examination of the Index Knee
ż
Record any ongoing medical observations that occurred since Screening visit
ż
Record any new AEs since Screening
ż
Record any concomitant medications since Screening including prescription, 
OTC, and herbal medications. Ensure no excluded medications.
x
Administer study drug (Section 8.0 for details on preparation)
ż
Aseptic techniques will be used in the preparation and administration of XT-150.
ż
Injections to the knee space will be guided by ultrasound, fluoroscopy or 
equivalent visualization
ż
All injections of study drug must be performed by a specialist who is qualified, 
trained, and experienced to perform intra-articular injections
ż
Examine injection site for infections or reactions
x
Clinical assessments
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x
Grade 1 (unexplained) fever – 38.6°C to 39°C
x
Grade 2 allergic, cytokine release, or infusion-related reactions - Therapy or infusion 
interruption indicated but responds promptly to symptomatic treatment (e.g.,
antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications indicated for 
 KRXUV
x
Grade 2 injection site reaction - Pain; lipodystrophy; edema; phlebitis
x
Grade 2 neutropenia - <1500 to 1000/mm3; <1.5 to 1.0 x109/L
10.3
Adverse Events
Medical history will be collected for all participants at the time of informed consent. 
After consent, all AE’s will be collected.  The Investigator will assess all AEs and SAEs 
and will record the following information on the appropriate CRF page:
x
Date of onset 
x
Date of resolution or stabilization
x
Severity
x
Relationship to study drug 
x
Action taken with study medication
Medically indicated laboratory tests (emergency or unscheduled tests) should be 
conducted at the local laboratory. The Investigator should employ best medical judgment 
in determining how to manage AEs and SAEs. Any questions regarding AE or SAE 
management should be directed to the Medical Monitor.
10.4
Adverse Event Reporting
The Sponsor has obligations for expedited reporting of SAEs meeting specific criteria to 
worldwide regulatory authorities. Therefore, the Sponsor must be notified immediately 
regarding any SAE that occurs after informed consent.
All SAEs must be reported to the Medical Monitor by phone or email within 24 hours of 
the investigational site’s knowledge of the event.
All SAEs and discontinuations due to AEs will be reported to the IRB/HREC.
The study site will also transmit a Serious Adverse Event Report (SAER) to the site study 
monitor and sponsor by facsimile or email within 24 hours. Contact details will be 
provided to all sites. An optional initial report can be made via telephone, but a 
completed SAER must still be faxed or emailed within 24 hours of the site’s knowledge 
of the event. The study sites will be provided with SAER forms wherein the following 
information is requested. 
x
Participant identification, Investigator name, and site number
x
SAE information: event term, onset date, severity, and causal relationship
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x
The outcomes attributable to the event (i.e., death, a life-threatening AE, inpatient 
hospitalization, prolongation of existing hospitalization, a persistent or significant 
disability or incapacity, or other important medical event[s])
x
A summary of relevant test results, pertinent laboratory data, and any other relevant 
medical history
x
The first and last dates of study drug administration. NOTE: as this is a double-blind 
study, SAERs should not indicate specific study drug assignments
x
Indicate if the study drug was discontinued or the study drug administration schedule 
modified
x
Supplemental information may include the following hospital records: laboratory 
results, radiology reports, progress notes, admission and emergency room notes, 
holding and observation notes, discharge summaries, autopsy reports, and death 
certificates
In addition, relevant CRF pages should be appended to communicate relevant study drug 
and participant outcome information. The SAER should be faxed or emailed within 24 
hours with as much of the above information as available at the time. The following 
minimum information is required for reporting an SAE: participant identification, 
reporting source, and an event or outcome. Supplemental information may be transmitted 
using a follow-up report and should not delay the initial report. The Sponsor may contact 
the investigational site to solicit additional information or follow up on the event. 
The Investigator must take all therapeutic measures necessary for resolution of the SAE. 
Any medications or procedures necessary for treatment of the SAE must be recorded on 
the appropriate pages of the participant’s CRF.
10.5
Definitions
10.5.1
Adverse Event
An AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a drug, and does not imply any judgment about causality. An AE can arise with any use 
of the drug and with any route of administration, formulation, or dose, including an 
overdose.
Osteoarthritis-related events should not be considered or recorded as AEs unless the 
event fits the definition for an SAE (Section 10.5.4), in which case the SAE form must be 
submitted for safety reporting in the appropriate timeframe and entered as an AE into the 
CRF.
Laboratory abnormalities should not be recorded as AEs or SAEs unless they are 
associated with clinical signs or symptoms, or require medical intervention. However, 
each laboratory abnormality (e.g., clinically significant changes detected on hematology, 
or lab chemistries) independent from any underlying medical condition that requires 
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medical or surgical intervention, or that leads to interruption of study drug infusion or 
discontinuation, must be recorded as an AE, or SAE if applicable. If the laboratory 
abnormality is part of a clinical condition or syndrome, it should be recorded as the 
syndrome or diagnosis rather than as the individual laboratory abnormality. In addition, 
laboratory abnormalities or other abnormal test assessments that are associated with signs 
or symptoms must be recorded as AEs or SAEs if they meet the definition of an AE (or 
SAE) as described above or in Section 10.5.4. 
10.5.2
Suspected Adverse Drug Reaction
A suspected adverse drug reaction is any AE for which there is a reasonable possibility 
that the drug caused the AE. For the purposes of Investigational New Drug safety 
reporting, ‘‘reasonable possibility’’ means there is evidence to suggest a causal 
relationship between the drug and the AE. Suspected adverse drug reaction implies a 
lesser degree of certainty about causality than adverse reaction, which means any AE 
caused by a drug.
10.5.3
Life-Threatening AE or Life-Threatening Suspected Adverse Drug 
Reaction
An AE or suspected adverse drug reaction is considered ‘‘life threatening’’ if, in the view 
of either the Investigator or Sponsor, its occurrence places the patient or participant at 
immediate risk of death. It does not include an AE or suspected adverse reaction that, had 
it occurred in a more severe form, might have caused death.
10.5.4
Serious AE or Serious Suspected Adverse Reaction
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:
x
Death
x
A life-threatening AE – see definition above 
x
Inpatient hospitalization or prolongation of existing hospitalization
x
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions
x
Congenital anomaly/birth defect in the offspring of a participant who received 
study drug
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.
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10.5.5
Unexpected AE or Unexpected Suspected Adverse Drug Reaction
An AE or suspected adverse drug reaction is considered “unexpected” if:
x
It is not listed in the Investigator’s Brochure or is not listed at the specificity or 
severity that has been observed 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if an Investigator’s Brochure referred only to elevated hepatic enzymes 
or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be
unexpected (by virtue of greater specificity) if an Investigator’s Brochure listed only 
cerebral vascular accidents. 
‘‘Unexpected,’’ as used in this definition, also refers to AEs or suspected adverse 
reactions that are mentioned in the Investigator’s Brochure as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.
10.6
Adverse Event Classification
10.6.1
Relationship to Investigational Drug
The Investigator’s assessment of causality must be provided for all AEs (serious and non-
serious) (Table 5). An Investigator’s causality assessment is the determination of whether 
there exists a reasonable possibility that the study drug caused or contributed to an AE.
Clinical failure that qualifies as an AE without evidence of study drug toxicity should be 
considered unrelated to study drug.
Table 5.
Guidelines for Assessing Relationship of Event to Study Drug
Unrelated
There is little or no chance that the Investigational Product 
caused the AE; other conditions, including concurrent illnesses, 
progression or expression of the disease state, or a reaction to a 
concomitant medication best explain the event
Related
The association of the AE with the Investigational Product is 
unknown, however, the AE is not clearly due to another 
condition, or a reasonable temporal association exists between 
the AE and treatment administration and, based on the 
Investigator's clinical experience, the association of the AE with 
the Investigational Product seems likely
AE = adverse event
10.6.2
Severity 
All AEs will be graded for severity to describe the maximum intensity of the AE based 
on Common Terminology Criteria for Adverse Events (CTCAE) criteria (version 5.0).
For purposes of consistency, these intensity grades are defined in Table 6.
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Table 6.
Guidelines for Severity Assessments
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated
Grade 2
Moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (e.g., preparing 
meals, shopping for groceries or clothes, using the telephone, managing 
money)
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living (bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden)
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to adverse event
These criteria, in addition to good clinical judgment, should be used as a guide for 
determining the causal assessment. If the event is believed to be unrelated to study drug 
administration, then an alternative explanation should be provided.
10.6.3
Serious Adverse Event
Any adverse experience occurring at any dose of study medication that occurs between 
the time of informed consent and the clinic visit on Day 360 that results in any of the 
following outcomes:
x
Death 
x
Life-threatening situation (participant is at immediate risk of death)
x
Inpatient hospitalization or prolongation of existing hospitalization
x
Persistent or significant disability/incapacity
x
Congenital anomaly/birth defect in the offspring of a participant who received study 
drug
x
Events that jeopardize the participant sufficiently that medical or surgical intervention 
may be required to prevent one of the above outcomes. Examples may include, but 
are not limited, to:
ż
Intensive treatment in an emergency room or at home for allergic 
bronchospasm
ż
Blood dyscrasias that do not result in hospitalization
ż
Seizures that do not result in hospitalization
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10.6.3.1
Serious Adverse Event Definition Clarifications
x
Death is an outcome of an AE, and not an AE in itself
x
All deaths during study drug administration or up to the FU visit on Day 90,
regardless of cause or relationship, must be reported
x
“Occurring at any dose” does not imply that the participant is actively receiving study 
drug at the time of the event
x
“Life-threatening” means that the participant was at immediate risk of death from the 
event as it occurred. This does not include an event that might have led to death, had 
it occurred with greater severity.
x
Complications that occur during hospitalizations are AEs. If an AE prolongs 
hospitalization, it is an SAE.
x
“Inpatient hospitalization” means the participant has been formally admitted to a 
hospital for medical reasons, for any length of time. This may or may not be 
overnight. It does not include presentation and care within an emergency department 
(although an emergency department visit may define a medically important event, 
which is also considered an SAE).
x
The Investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and other clinical information. In such cases, the diagnosis should be 
documented as the AE or SAE, rather than as the individual signs or symptoms.
10.7
Adverse Event Follow-up
All unresolved SAEs (“ongoing” at discharge) will be followed by the study staff until 
resolution or deemed stable.
10.8
Adverse Events of Special Interest 
10.8.1
Localized Signs of Infection or Inflammation at the Injection Site
Events that, in the opinion of the Investigator, may represent localized signs of infection 
or inflammation at the XT-150 injection site (e.g., pain, erythema, swelling, pruritus, 
warmth, hematoma, induration) must be recorded as AEs on the CRF. In general, these 
events will be temporally related to the injection.
10.9
Toxicity Management 
The Investigator should employ best medical judgment in determining how to manage 
AEs. Any questions regarding AE management should be directed to the Medical 
Monitor.
10.10 Risks for Women of Child-Bearing Potential or During Pregnancy
The risks of XT-150 administration during pregnancy have not been evaluated. Male and 
female participants who are heterosexually active and not surgically sterile must agree to 
use effective contraception, including abstinence, for the duration of the study.
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13.0
STATISTICAL METHODS
Efficacy will be assessed at baseline (before XT-150 injection) and at each study visit, 
starting at Day 7 [±1 day]. 
All participants will be included in the safety analysis. 
A comprehensive Statistical Analysis Plan (SAP) will be prepared and finalized before 
database lock. Descriptive statistics (mean, standard deviation, median, minimum, and 
maximum for continuous variables and count and percentages for categorical variables) 
for demographics and other baseline characteristics will be provided by treatment group 
for all participants in the Intent-to-Treat (ITT) and Safety Populations.
13.1
Determination of Sample Size
A total of 270 subjects will be randomized to the 3 treatment groups in a 1:1:1 ratio. The 
sample size of 90 subjects per group provides more than 90% power to detect a greater 
responder rate in at least one XT-150 group compared to placebo and 85% power to 
detect both arms superior to placebo, assuming the responder rate is 30% in each XT-150
group and 10% in the placebo group. As a sensitivity analysis of different assumptions on 
the response rates in the placebo and XT-150 groups, Table 7 shows the statistical power 
to detect that at least one treatment group provides greater response than placebo and to 
detect that both treatment groups provide greater responses.
Table 7.
Treatment Effect That Can Be Detected
Placebo response 
rate (%)
XT-150 response 
rate (%) in both 
treatment arms
Statistical Power (%)
To detect at least one 
treatment arm 
superior to placebo
To detect both 
treatment arms 
superior to placebo
10
25
78
57
30
95
85
35
99
97
15
25
38
18
30
70
46
35
91
77
13.2
Analysis Populations
The Intent-to-Treat (ITT) Population will comprise all enrolled participants who received 
the treatment injection, analyzed according to randomized treatment.  The ITT Population 
will be the primary analysis population for efficacy.
The Safety Population will comprise all participants who receive any amount of study 
drug, analyzed according to treatment actually received.
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13.3
Analysis of Study Population and Participant Characteristics
Demographics (including age, race, and gender), medical history including history of 
pain medication use, Baseline assessments (including height, weight, BMI, WOMAC
Pain Score, BPI, and KOOS), clinical signs and symptoms, and administration of study 
drug will be summarized in the ITT and Safety Populations.
13.4
Safety Analyses
All participants who receive any amount of study drug (Safety Population) will be 
included in the safety analyses.
Safety will be evaluated by presenting summaries of AEs and vital signs. Safety variables 
will be tabulated by treatment group. 
Adverse events will be graded using the CTCAE v5.0 and will be coded using the 
Medical Dictionary of Regulatory Affairs (MedDRA®), Version 18 or higher. AEs will 
be collected for each participant from the signing of the informed consent through the last 
study visit on Day 360.
A treatment-emergent adverse event (TEAE) is defined as an AE that occurs during or 
after study drug administration. The incidence of TEAEs will be presented by system 
organ class (SOC) and preferred term (PT), by SOC, PT, and relationship to the study 
drug administration, and by SOC, PT, and severity. In addition, the incidence of serious 
TEAEs and TEAEs leading to discontinuation of study drug will be presented by SOC 
and PT. 
Descriptive statistics for clinical laboratory test results, and vital signs, and for changes 
from Baseline, will be presented by time point. Baseline is defined as the measurement 
closest to, but prior to, the administration of study drug. Incidences of potentially 
clinically significant clinical laboratory results, and vital signs, as defined in the SAP, 
will also be summarized by time point. A summary of abnormal physical examination 
findings will also be presented.
13.5
Analysis of Efficacy
All inferential analyses of efficacy will be based on the first 180 days after dose 
administration (Stage A) and on the analysis of time from Day 0 until patient request for 
a second injection (see Section 13.5.4). Other analyses of data from Stage B and 
comparisons between Stage A and B will be descriptive; such analyses will be specified 
in the SAP.
13.5.1
Multiplicity of endpoints
The statistical analysis of the primary endpoint will preserve a familywise error rate of 
0.025 (one-sided), accounting for statistical tests of each of the two XT-150 doses to 
placebo with respect to the primary endpoint.
P-values from analyses of other endpoints may be interpreted as descriptive statistics.
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13.6
Bioanalytical Analyses 
Whole blood samples from participants who received the XT-150 will be analyzed for 
anti-IL10 antibodies using a validated assay. Any detection of anti-IL-10 antibodies will 
be described by treatment and timepoint.
13.7
Handling of Dropouts and Missing, Unused, and Spurious Data
Every effort will be made to collect all data at specified times. All participants who 
received any dose of XT-150 study drug but with missing outcome data will nonetheless 
be included in the Safety Population. Treatment of missing or spurious data will be 
specified in the SAP.
13.8
Termination Criteria
Withdrawals from the study and from study drug will be summarized in a listing.
13.9
Deviation Reporting
Protocol deviations will be summarized by treatment group. Protocol deviations are 
defined as any variation from the protocol, including enrollment of a participant who did 
not meet all inclusion and exclusion criteria and failure to perform the assessments and 
procedures within the required time frame.
14.0
INVESTIGATOR REQUIREMENTS
14.1
Protocol Adherence
The Investigator must adhere to the protocol as detailed in this document and agree that 
the Sponsor must approve any change to the protocol before seeking approval from the 
IRB/HREC. The Investigator will be responsible for enrolling only those participants
who have met the protocol inclusion and exclusion criteria.
14.1.1
Investigator or Designee Experience
The Investigator or Investigator’s designee is required to be qualified, trained, and 
experienced in the administration of study drug by intra-articular injection.
14.2
Case Report Forms
The CRF will be supplied by the Sponsor or designee for the recording of all information 
and study data as specified by this protocol. All CRFs must be completed by trained 
study personnel. The Investigator is responsible for ensuring that the CRF data are 
entered and completed in a timely manner.
Once all data queries and issues have been resolved for each participant, the Investigator 
will electronically sign each participant’s CRF to attest to the accuracy of the data.
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Amendment 2, 25 March 2020
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14.3
Source Document Maintenance
Source documents are defined as documentation related to original observations and 
activities of a clinical investigation. Source documents may include, but are not limited 
to, study progress notes, study- or participant-specific e-mail correspondence, computer 
printouts, laboratory data, and recorded data from automated instruments. All source 
documents produced in this study will be maintained by the Investigator and made 
available for inspections by the Sponsor and by regulatory authorities. The original 
signed ICF (and any updates, if appropriate) for each participating participant shall be 
filed with records kept by the Investigator, and a copy shall be given to the participant.
A telephone call documenting safety and efficacy assessments may be used for participants unable 
to physically attend follow up visits due to COVID-19 infection or corona virus exposure concerns.  
Participant responses will be captured in source documents, including circumstances for use of 
telephone follow up.
14.4
Study Monitoring Requirements
An authorized Sponsor representative will conduct site visits to inspect study data, 
participants’ medical records, and CRFs in accordance with International Council for
Harmonisation (ICH) guidelines, GCPs, and the foreign regulations and guidelines, as 
applicable. A study monitor will be utilized for monitoring ongoing drug accountability 
and adherence to protocol procedures.
The Investigator will allow representatives of the Sponsor and regulatory authorities to 
inspect facilities and records relevant to this study.
14.5
Study Completion
The Sponsor requires the following data and materials before a study can be considered 
complete or terminated:
x
Laboratory findings, clinical data, and study test results from Screening throughout 
the study until Day 360
x
CRFs (including data queries) properly completed by appropriate study personnel and 
signed and dated by the Investigator
x
Copies of complete drug accountability records (drug inventory log and an inventory 
of returned or destroyed clinical material)
x
Copies of protocol amendments and IRB/HREC approval and notification, if 
appropriate
x
A summary of the study prepared by the Investigator (an IRB/IEC summary letter is 
acceptable)
 
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Amendment 2, 25 March 2020
Confidential 
Page 48
15.0
QUALITY CONTROL AND QUALITY ASSURANCE
Written standard operating procedures (SOPs) will be followed to ensure that the study is 
conducted and data are generated, documented (recorded), and reported in compliance 
with the protocol, GCP, and the applicable regulatory requirements. Quality control will 
be applied to each stage of data handling. Regular monitoring, as defined in ICH GCP, 
Section 1.8, “The act of overseeing the progress of a clinical trial, and of ensuring that it 
is conducted, recorded, and reported in accordance with the protocol, SOPs, GCP, and the 
applicable regulatory requirement(s)”, will be conducted throughout the conduct of the 
study.
The purpose of monitoring is to verify that:
x
Rights and well-being of the human participants are protected
x
The reported study data are accurate, complete, and verifiable from source documents
x
The conduct of the study is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with the applicable regulatory requirements
x
Monitoring is an integral role in the quality control of a clinical trial and is designed 
to ensure and verify the quality of the study
To fulfill the Quality Assurance requirements of GCP, audits will be conducted to assess 
and assure the reliability and integrity of a study’s quality control systems and recognized 
standards.
The purpose of an audit is to:
x
Ensure participant safety
x
Assure compliance to study protocol procedures, regulatory requirements, and SOPs
x
Assure data quality
16.0
PROTECTION OF HUMAN PARTICIPANTS
This study will be conducted in compliance with the ICH Technical Requirements for 
Registration of Pharmaceuticals for Human Use E6 GCP: Consolidated Guidelines, the 
ethical principles of the Declaration of Helsinki, FDA GCP guidelines, and any additional 
national or IRB/IEC-required procedures, particularly those related to the Corona Virus
Disease 2019 (COVID-19) pandemic.
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Protocol XT-150-2-0204
 
 
 
Amendment 2, 25 March 2020
Confidential 
Page 49
16.1
Informed Consent
This study will be conducted in compliance with ICH E6 GCP: Consolidated Guidelines 
pertaining to informed consent. Participants will give written consent to participate in the 
study at the first visit, prior to initiation of any study-related procedures, after having 
been informed about the nature and purpose of the study, participation and termination 
conditions, risks, and benefits. If a participant is unable to provide written informed 
consent, the participant’s legally acceptable representative may provide written consent, 
as approved according to institution-specific guidelines. The ICF must be signed and 
dated by the participant, or the participant’s legally authorized representative, prior to 
study participation. A copy of the ICF must be provided to the participant or the 
participant’s legally authorized representative. If applicable, it will be provided in 
certified translation for non-English-speaking participants. Signed consent forms must 
remain in the participant’s study file and be available for verification by Sponsor at any 
time.
16.2
IRB/HREC Approval
This protocol, the ICF, and all relevant supporting data must be submitted to the 
IRB/HREC for approval. The protocol, ICF, and any advertisement used to recruit study 
participants must be approved by the IRB/HREC. Approval by the IRB/HREC of the 
protocol and ICF must be obtained before the study may be initiated.
The Investigator is responsible for informing the IRB/HREC of any changes made to the 
protocol, and to advise them, at least once a year, about the progress of the study. The 
Investigator is also responsible for notifying the IRB/HREC of any significant AEs that 
occur during the study.
17.0
DATA HANDLING AND RECORD KEEPING
Training sessions, regular monitoring of Investigators by Sponsor-designated personnel, 
instruction manuals, data verification, crosschecking, and data audits will be performed to 
ensure the quality of all study data. Investigator meetings will be performed to train 
Investigators and other study personnel in the appropriate collection of study data. The 
Sponsor or designee will review and validate study data according to standard 
procedures.
It will be the responsibility of the Investigator to ensure that the essential documents are 
available at the Investigator or institutional site. Any or all of these documents may be 
participant to, and should be available for, monitoring by the Sponsor or inspection by the 
regulatory authorities as defined in the monitoring plan.
17.1
Direct Access to Source Data/Documentation
The Investigator agrees by his/her participation that the results of this study may be used 
for submission to national or international registration. If required, these authorities will 
be provided with the name of the Investigator and his or her address, qualifications, and 
extent of involvement. It is understood that the Investigator is required to provide 
Sponsor with all study data, complete reports, and access to all study records.
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Amendment 2, 25 March 2020
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Page 50
Data generated by this study must be available for inspection by any regulatory 
authorities, by Sponsor, and by the IRB/IEC as appropriate. At a participant’s request, 
medical information may be given to his or her personal physician or other appropriate 
medical personnel responsible for his or her welfare. Medical information obtained from 
participants during the course of this study is confidential and disclosure to third parties 
other than those noted above is prohibited.
17.2
Study Drug Accountability
All supplies of XT-150 study drug required for completion of this study will be provided 
by the Sponsor. It is the responsibility of the Investigator and study staff to ensure that a 
current record of drug inventory and drug accountability is maintained. Inventory and 
accountability records must be readily available for inspection and are open to inspection 
at any time by applicable regulatory authorities.
17.3
Retention of Records
Essential clinical documents should be retained until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product 
and shipment and delivery of the drug for investigational use is discontinued. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements of specific ICH- and non-ICH countries, or by an agreement with 
the Sponsor. The Sponsor will inform the Investigator/institution as to when these 
documents no longer need to be retained.
18.0
FINANCING AND INSURANCE
The financing and insurance for this study are outlined in the Clinical Trial Agreement.
19.0
PUBLICATION POLICY
The data generated in this clinical study are the exclusive property of the Sponsor and are 
confidential. Authorship on any publication of the results from this study will be based on 
contributions to study design, enrollment, data analysis, and interpretation of results.
20.0
REFERENCES
Busner J, Targum SD. The clinical global impressions scale: applying a research tool in 
clinical practice. Psychiatry (Edgmont). 2007 Jul;4(7):28-37.
Chernoff AE, Granowitz EV, L Shapiro, E Vannier, G Lonnemann, JB Angel, JS 
Kennedy, AR Rabson, SM Wolff and CA Dinarello. A randomized, controlled trial of IL-
10 in humans. Inhibition of inflammatory cytokine production and immune responses. J
Immunol. 1995 154:5492-5499.
Common Terminology Criteria for Adverse Events (CTCAE) criteria (version 4.03,
2010).
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FDA, Guidance for Industry: Considerations for Plasmid DNA Vaccines for Infectious 
Disease Indications. 2005. Available at 
http://www.fda.gov/OHRMS/DOCKETS/98fr/05d-0047-gdl0001.pdf. Accessed 
01DEC2016.
Ferraro B, Morrow, M, Hutnick NA, Shin TH, Lucke CE, Weiner DB. Clinical 
Applications of DNA Vaccines: Current Progress. Clinical Infectious Diseases. 2011 
53(3):296–302.
Gôrecki DC. "Dressed-up" naked plasmids: emerging vectors for non-viral gene therapy. 
Discov Med. 2006 Oct;6(35):191-7.
Huhn RD, Radwanski E, Gallo J, Affrime MB, Sabo R, Gonyo G, Monge A, Cutler DL.
Pharmacodynamics of subcutaneous recombinant human interleukin-10 in healthy 
volunteers. Clin Pharmacol Ther. 1997 62(2):171-80.
Huhn RD, Radwanski E, O'Connell SM, Sturgill MG, Clarke L, Cody RP, Affrime MB, 
Cutler DL. Pharmacokinetics and immunomodulatory properties of intravenously 
administered recombinant human interleukin-10 in healthy volunteers. Blood. 1996
87(2):699-705.
Kellgren JH, Lawrence JS.  Radiological Assessment of Osteo-arthrosis.  Ann. Rheum 
Dis. 1957, 16:494-502.
Kohn MD, Sassoon, AA, Fernando ND.  Classifications in Brief:  Kellgren-Lawrence 
Classification of Osteoarthritis.  Clin Orthop Relat Res.  2016, 474:1886-1893.
Milligan, ED, Sloane EM, Langer SJ, Cruz PE, et al. Controlling neuropathic pain by 
adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-
10. Molecular Pain. 2005 1:9.
Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the 
interleukin-10 receptor. Annu Rev Immunol. 2001 19:683–765.
Prazeres DM, Monteiro GA. Plasmid Biopharmaceuticals. Microbiol Spectr. 2014 
Dec;2(6). doi: 10.1128/microbiolspec.PLAS-0022-2014.
Sawada, M, Suzumura, A, Hosoya, H, Marunouchi, T & Nagatsu, T. Interleukin-10
Inhibits Both Production of Cytokines and Expression of Cytokine Receptors in 
Microglia. J Neurochem 2001 72, 1466–1471.
van Deventer SJ, Elson CO, Fedorak RN. Multiple doses of intravenous interleukin 10 in 
steroid-refractory Crohn's disease. Crohn's Disease Study Group. Gastroenterology. 1997
113(2):383-9.
Xu L, Anchordoquy T. Drug delivery trends in clinical trials and translational medicine: 
challenges and opportunities in the delivery of nucleic acid-based therapeutics. J Pharm 
Sci. 2011 100(1):38-52.
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Protocol XT-150-2-0204
 
 
 
Amendment 2, 25 March 2020
Confidential 
21.0
APPENDICES
Appendix 1: Clinical Laboratory Tests
Hematology
Hemoglobin
hematocrit 
total and differential leukocyte count
red blood cell count
platelet count
Coagulation
Prothrombin time/ International Normalized Ratio
Partial thromboplastin time or activated partial thromboplastin time
Serum Chemistry
bilirubin (total and direct)
alkaline phosphatase
aspartate aminotransferase (AST)
alanine aminotransferase (ALT)
 
 
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Protocol XT-150-2-0204
 
 
 
Amendment 2, 25 March 2020
Confidential 
Appendix 2: BPI
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Protocol XT-150-2-0204
 
 
 
Amendment 2, 25 March 2020
Confidential 
Appendix 3: KOOS
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Knee injury and Osteoarthritis Outcome Score (KOOS), English version LK1.0 
 1 
KOOS KNEE SURVEY 
Today’s date: _____/______/______ Date of birth: _____/______/______
Name: ____________________________________________________
INSTRUCTIONS: This survey asks for your view about your knee. This 
information will help us keep track of how you feel about your knee and how 
well you are able to perform your usual activities. 
Answer every question by ticking the appropriate box, only one box for each 
question. If you are unsure about how to answer a question, please give the 
best answer you can. 
Symptoms 
These questions should be answered thinking of your knee symptoms during 
the last week.
 
S1. Do you have swelling in your knee? 
Never 
 
Rarely 
 
Sometimes 
 
Often 
 
Always 
 
S2. Do you feel grinding, hear clicking or any other type of noise when your knee 
       moves? 
Never 
 
Rarely 
 
Sometimes 
 
Often 
 
Always 
 
 
S3. Does your knee catch or hang up when moving? 
Never 
 
Rarely 
 
Sometimes 
 
Often 
 
Always 
 
S4. Can you straighten your knee fully? 
Always 
 
Often 
 
Sometimes 
 
Rarely 
 
Never 
 
S5. Can you bend your knee fully? 
Always 
 
Often 
 
Sometimes 
 
Rarely 
 
Never 
 
Stiffness
The following questions concern the amount of joint stiffness you have 
experienced during the last week in your knee. Stiffness is a sensation of 
restriction or slowness in the ease with which you move your knee joint. 
 
S6. How severe is your knee joint stiffness after first wakening in the morning? 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
S7. How severe is your knee stiffness after sitting, lying or resting later in the day? 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
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Knee injury and Osteoarthritis Outcome Score (KOOS), English version LK1.0 
 2 
Pain
P1. How often do you experience knee pain? 
Never 
 
Monthly 
 
Weekly 
 
Daily 
 
Always 
 
 
What amount of knee pain have you experienced the last week during the 
following activities? 
 
P2. Twisting/pivoting on your knee  
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
P3. Straightening knee fully 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
P4. Bending knee fully 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
P5. Walking on flat surface 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
P6. Going up or down stairs 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
P7. At night while in bed 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
P8. Sitting or lying 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
P9. Standing upright 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
Function, daily living 
The following questions concern your physical function. By this we mean your 
ability to move around and to look after yourself. For each of the following 
activities please indicate the degree of difficulty you have experienced in the 
last week due to your knee. 
 
A1. Descending stairs 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A2. Ascending stairs 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
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Knee injury and Osteoarthritis Outcome Score (KOOS), English version LK1.0 
 3 
For each of the following activities please indicate the degree of difficulty you 
have experienced in the last week due to your knee. 
 
A3. Rising from sitting 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A4. Standing 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A5. Bending to floor/pick up an object 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A6. Walking on flat surface 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A7. Getting in/out of car 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A8. Going shopping 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A9. Putting on socks/stockings 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A10. Rising from bed 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A11. Taking off socks/stockings 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A12. Lying in bed (turning over, maintaining knee position) 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A13. Getting in/out of bath 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
A14. Sitting 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A15. Getting on/off toilet 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
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Knee injury and Osteoarthritis Outcome Score (KOOS), English version LK1.0 
 4 
For each of the following activities please indicate the degree of difficulty you 
have experienced in the last week due to your knee. 
 
A16. Heavy domestic duties (moving heavy boxes, scrubbing floors, etc) 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
A17. Light domestic duties (cooking, dusting, etc) 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
Function, sports and recreational activities 
The following questions concern your physical function when being active on a 
higher level. The questions should be answered thinking of what degree of 
difficulty you have experienced during the last week due to your knee. 
SP1. Squatting 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
SP2. Running 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
SP3. Jumping 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
SP4. Twisting/pivoting on your injured knee 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
SP5. Kneeling 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
 
Quality of Life 
Q1. How often are you aware of your knee problem? 
Never 
 
Monthly 
 
Weekly 
 
Daily 
 
Constantly 
 
Q2. Have you modified your life style to avoid potentially damaging activities 
       to your knee? 
Not at all 
 
Mildly 
 
Moderately  
 
Severely 
 
Totally 
 
Q3. How much are you troubled with lack of confidence in your knee? 
Not at all 
 
Mildly 
 
Moderately  
 
Severely 
 
Extremely 
 
 
Q4. In general, how much difficulty do you have with your knee? 
None 
 
Mild 
 
Moderate 
 
Severe 
 
Extreme 
 
Thank you very much for completing all the questions in this questionnaire. 
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Protocol XT-150-2-0204
 
 
 
Amendment 2, 25 March 2020
Confidential 
Appendix 4:  Focused Analgesia Selection Test (FAST)
FAST is based on recording a subject’s pain reports in response to repeated 
administration of thermal noxious stimuli of various intensities to assess subject’s pain 
reporting skills.
Specifically, FAST utilizes the MEDOC TSA II device. The Thermal Sensory Analyzer 
II incorporates a Peltier element-based thermode (30×30 mm2). The thermode is applied 
to the ventral surface of the subject’s nondominant arm and the temperature is raised 
from a baseline of 32°C, peaked for 3 seconds at 1 of 7 designated temperatures (43°C, 
45°C, 47°C, 48°C, 49°C, 50°C, or 51°C), and then decreased down to the baseline. 
Stimulus duration is always 8 seconds, meaning that the rate of rise and fall varies from 
3.3 to 9°C/seconds depending on the destination temperature.
Subjects are asked to rate the peak pain intensity of each stimulus by using a 
computerized visual analog scale (CoVAS): a box attached to the computer with a (0–100
mm) slider that moves along a line from “no pain” to “worst pain imaginable”.
Each temperature is presented 7 times in a random block-ordered design (total of 49 
stimuli). Stimuli are triggered manually, allowing the subject sufficient time to rate the 
pain they perceived during each stimulus, resulting in interstimulus intervals of 10–20
seconds. The location of the thermode is adjusted every 14 stimuli to minimize 
sensitization and/or habituation effects. The duration of the FAST procedure is ~25 
minutes.
Data is sent electronically to Analgesic Solutions (AS) evaluators.  Within 48-72 hours, 
AS reports back to the clinical site the acceptability of results for enrollment into the 
clinical trial.
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Xalud Therapeutics, Inc.
Protocol XT-150-2-0204
Amendment 2, 25 March 2020
Confidential 
Appendix 6: Investigator Signature
I have read and understand the current version of protocol XT-150-2-0204 and the 
Investigator’s Brochure. I agree to the following:
1. To conduct the trial in compliance with GCP, with applicable regulatory
requirement(s), with the protocol agreed to by the Sponsor and given
approval/favorable opinion by the IRB/HREC.
2. To comply with procedures for data recording and reporting
3. To permit monitoring, auditing, and inspection by the Sponsor, its designated
representatives, and regulatory authorities
4. To retain the essential documents in the Investigator/institution files until the
Sponsor informs the Investigator or institution that these documents are no longer
needed
INVESTIGATOR SIGNATURE:
_____________________________________    ___________________________
[Investigator Signature]
Date
_____________________________________
[Investigator Name]
[Site Name]
[Site Address]
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