Conditions: Osteoarthritis, Knee
Keywords: osteoarthritis knee topical therapy pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 210
Healthy volunteers: no

Brief summary:
Phase 2 multicenter, double-blind, randomized, parallel-group, vehicle-controlled study to evaluate the efficacy, safety, and local tolerability of G001 topical gel compared to matching Vehicle topical gel in patients with symptomatic OA of the knee.

Each patient's participation is approximately 7 weeks (\~1 week screening, 4 weeks of treatment, and 2 weeks of post-treatment follow-up). Eligible patients with adequate OA pain in the index knee are randomized (1:1 allocation ratio) at the Baseline/Flare Visit 1.

Following screening, prior NSAID and/or acetaminophen use is discontinued to allow for washout and symptom flare. Patients are instructed to rate their worst daily and nightly pain in their daily diary, as well as to document all study drug applications and any rescue medication (acetaminophen) use for breakthrough pain. Acetaminophen may be used as rescue medication only, except within 12 hours prior to the Baseline Visit and within 12 hours prior to any post-baseline efficacy assessments (Weeks 2, 4, and 5). Patients are instructed to return to the clinic 3 to 7 days after the last study drug application for Flare Visit 2, and within approximately 2 weeks after the last study drug application for end-of-study evaluations.

Detailed description:

Arms:
arm 1: G001 Topical Gel, 4 grams applied to the index knee four times a day over 4 weeks. arm 2: Vehicle Topical Gel, 4 grams applied to the index knee four times a day over 4 weeks.

Interventions: intervention 1: G001 Topical Gel intervention 2: Vehicle
Intervention descriptions: intervention 1: Non-steroidal anti-inflammatory drug for topical administration intervention 2: Vehicle Gel for topical administration

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
1 
Title Page 
Protocol Title: 
Protocol Number: 
Protocol Version: 
Compound:   
Brief Title:  
Study Phase:  
Sponsor Name:  
Address:  
Medical Monitor: 
Phase 2 Multicenter, Double-blind, Randomized, Parallel-
Group, Vehicle-Controlled Study to Evaluate the Efficacy, 
Safety, and Local Tolerability of G001 in Patients with 
Osteoarthritis (OA) of the Knee 
2020-G001-P2  (ClinicalTrials.gov ID: NCT05007808)
4.0 (December 7, 2022) 
G001 (Celecoxib Gel 4% for Topical Administration) 
Efficacy and Safety of G001 in Patients with Osteoarthritis 
(OA) of the Knee 
Phase 2  
Buzzz Pharmaceuticals Limited 
15 Main Street, Raheny, Dublin 5, Ireland 
Atalah Haun 
Veristat, LLC 
Telephone: 647-745-8762  
Email: Atalah.Haun@veristat.com 
This study will be carried out in accordance with Good Clinical Practice (GCP) as set out by the 
International Council for Harmonisation (ICH). 
Confidential Information 
The information in this study protocol is legally privileged and confidential. Any disclosure, 
copying or distribution of the information contained within is strictly prohibited without written 
consent from the Sponsor. 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
2 
 
Protocol Approval Page 
 
Phase 2 Multicenter, Double-blind, Randomized, Parallel-Group, Vehicle-
Controlled Study to Evaluate the Efficacy, Safety, and Local Tolerability of 
G001 in Patients with Osteoarthritis (OA) of the Knee 
Protocol Number: 2020-G001-P2  
Version: 4.0 (December 7, 2022)  
Replaces Version: 3.0 (April 29, 2021) 
 
 
Buzzz Pharmaceuticals Limited 
15 Main Street 
Raheny, Dublin 5 
Ireland 
 
 
 
 
Sponsor Representatives: 
 
 
 
 
Dr. Anna Power, CEO 
Buzzz Pharmaceuticals Limited 
 
Date 
(MMM-DD-YYYY) 
 
 
 
 
Dr. Deirdre O’Keeffe, Head of IP and Portfolio Management 
Buzzz Pharmaceuticals Limited 
 
Date 
(MMM-DD-YYYY) 
 
 
 
 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
3 
Investigator Signature Page 
 
Phase 2 Multicenter, Double-blind, Randomized, Parallel-Group, Vehicle-
Controlled Study to Evaluate the Efficacy, Safety, and Local Tolerability of 
G001 in Patients with Osteoarthritis (OA) of the Knee 
Protocol Number: 2020-G001-P2  
Version: 4.0 (December 7, 2022)  
Replaces Version: 3.0 (April 29, 2021) 
 
 
Buzzz Pharmaceuticals Limited 
15 Main Street 
Raheny, Dublin 5 
Ireland 
 
 
I have read the protocol and agree to comply with all of the procedures contained herein. 
 
 
 
 
 
[Name] 
Principal Investigator 
 
Date 
(MMM-DD-YYYY) 
 
 
 
 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
4 
Table of Contents 
List of Abbreviations .....................................................................................................................8 
Administrative Structure ............................................................................................................11 
1. 
Protocol Summary ........................................................................................................12 
1.1. 
Synopsis ..........................................................................................................................12 
1.2. 
Study Design Schema .....................................................................................................20 
1.3. 
Schedule of Assessments (SoA) .....................................................................................22 
2. 
Introduction ...................................................................................................................25 
2.1. 
Background on the Condition: Osteoarthritis .................................................................25 
2.1.1. 
Epidemiology and Disease Burden .................................................................................25 
2.1.2. 
Pathophysiology ..............................................................................................................25 
2.1.3. 
Management ....................................................................................................................26 
2.2. 
Background on Oral Celecoxib.......................................................................................26 
2.2.1. 
Clinical Experience with Oral Celecoxib .......................................................................27 
2.3. 
Background on G001 (Celecoxib Gel 4% for Topical 
Administration) ...............................................................................................................28 
2.3.1. 
Nonclinical Experience with G001 .................................................................................28 
2.3.2. 
Clinical Experience with G001 .......................................................................................28 
2.4. 
Study Rationale ...............................................................................................................35 
2.5. 
Benefit/Risk Assessment ................................................................................................35 
2.5.1. 
Risk Assessment .............................................................................................................36 
2.5.2. 
Benefit Assessment .........................................................................................................39 
2.5.3. 
Overall Benefit: Risk Conclusion ...................................................................................39 
3. 
Objectives and Endpoints ............................................................................................40 
4. 
Study Design ..................................................................................................................42 
4.1. 
Overall Design ................................................................................................................42 
4.2. 
Scientific Rationale for Study Design ............................................................................43 
4.3. 
Justification for the Primary Efficacy Measure ..............................................................44 
4.4. 
Justification for Dose ......................................................................................................45 
4.5. 
Justification for the Reference Product / Control Group ................................................46 
4.6. 
End of Study Definition ..................................................................................................46 
5. 
Study Population ...........................................................................................................47 
5.1. 
Inclusion Criteria ............................................................................................................47 
5.2. 
Exclusion Criteria ...........................................................................................................48 
5.3. 
Lifestyle Considerations .................................................................................................50 
5.4. 
Screen Failures ................................................................................................................50 
6. 
Study Treatment and Concomitant Therapy .............................................................51 
6.1. 
Overview of the Study Interventions ..............................................................................51 
6.2. 
Study Drug Storage, Handling, Administration, and 
Accountability .................................................................................................................52 
6.2.1. 
Study Drug Storage and Handling ..................................................................................52 
6.2.2. 
Study Drug Dosage and Administration .........................................................................52 
6.2.3. 
Study Drug Accountability .............................................................................................54 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
5 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................54 
6.3.1. 
Randomization ................................................................................................................54 
6.3.2. 
Blinding...........................................................................................................................54 
6.3.3. 
Emergency Unblinding ...................................................................................................55 
6.4. 
Study Drug Compliance..................................................................................................56 
6.5. 
Dose Modifications, Interruptions, and Delays ..............................................................56 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................56 
6.7. 
Treatment of Overdose ...................................................................................................56 
6.8. 
Concomitant Therapy .....................................................................................................57 
6.8.1. 
Prohibited Medication and Interventions ........................................................................57 
6.8.2. 
Exceptions to Prohibited Medication and Interventions .................................................59 
6.8.3. 
Rescue/Breakthrough Pain Medicine ..............................................................................59 
7. 
Discontinuation of Study Drug and Patient Withdrawal ..........................................60 
7.1. 
Discontinuation of Study Drug .......................................................................................60 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................60 
7.2. 
Patient Withdrawal from the Study ................................................................................60 
7.3. 
Lost to Follow up ............................................................................................................61 
8. 
Study Assessments and Procedures.............................................................................62 
8.1. 
Screening Assessments and Activities ............................................................................62 
8.1.1. 
Informed Consent Form and Screening Logs .................................................................62 
8.1.2. 
Demographic Data, General Medical and Disease History and 
Prior/Concomitant Medications ......................................................................................62 
8.1.3. 
Weight and Height Measurements ..................................................................................63 
8.1.4. 
Screening Serology .........................................................................................................63 
8.1.5. 
Radiological Examination ...............................................................................................63 
8.1.6. 
Worst Daily Pain Assessment (11-point Pain NRS) .......................................................63 
8.1.7. 
Screening Diary ..............................................................................................................63 
8.1.8. 
Other Screening Assessments .........................................................................................64 
8.2. 
Efficacy Assessments .....................................................................................................64 
8.2.1. 
WOMAC OA Index ........................................................................................................64 
8.2.2. 
Global Assessments of Disease Activity ........................................................................65 
8.2.3. 
Global Assessments of Treatment Benefit ......................................................................65 
8.2.4. 
Treatment Diary ..............................................................................................................65 
8.3. 
Safety Assessments .........................................................................................................66 
8.3.1. 
Physical Examinations ....................................................................................................66 
8.3.2. 
Vital Signs Measurements ..............................................................................................66 
8.3.3. 
Electrocardiograms .........................................................................................................66 
8.3.4. 
Clinical Safety Laboratory Assessments ........................................................................67 
8.3.5. 
Pregnancy Testing ...........................................................................................................67 
8.3.6. 
Urine Drug Screen ..........................................................................................................67 
8.3.7. 
Skin Irritation Test ..........................................................................................................67 
8.4. 
Adverse Events, Serious Adverse Event, and Other Safety 
Reporting ........................................................................................................................68 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
6 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................68 
8.4.2. 
Method of Detecting AEs and SAEs ..............................................................................68 
8.4.3. 
Follow-up of AEs and SAEs ...........................................................................................68 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...............................................................69 
8.4.5. 
Pregnancy ........................................................................................................................69 
8.4.6. 
Disease-Related Events Not Qualifying as AEs .............................................................69 
8.4.7. 
Adverse Events of Special Interest .................................................................................69 
9. 
Statistical Considerations .............................................................................................70 
9.1. 
Sample Size Determination ............................................................................................70 
9.2. 
Analysis Sets ...................................................................................................................70 
9.3. 
Statistical Analyses .........................................................................................................71 
9.3.1. 
General Considerations ...................................................................................................71 
9.3.2. 
Primary Endpoint ............................................................................................................71 
9.3.3. 
Secondary Endpoints ......................................................................................................72 
9.3.4. 
Subgroup Analyses of Efficacy Endpoints .....................................................................73 
9.3.5. 
Safety Analyses ...............................................................................................................73 
9.3.6. 
Analysis of Skin Irritation ...............................................................................................74 
9.4. 
Interim Analysis ..............................................................................................................74 
10. 
Supporting Documentation and Operational Considerations ..................................75 
10.1. 
Regulatory and Ethical Considerations...........................................................................75 
10.1.1. Financial Disclosure........................................................................................................75 
10.1.2. Informed Consent Process ..............................................................................................76 
10.1.3. Data Protection................................................................................................................76 
10.1.4. Dissemination of Clinical Study Data.............................................................................76 
10.2. 
Data Collection and Management...................................................................................76 
10.2.1. Data Quality Assurance ..................................................................................................76 
10.2.2. Electronic Case Report Forms ........................................................................................77 
10.2.3. Patient and Clinician-Reported Outcome Data ...............................................................77 
10.2.4. Source Documents ..........................................................................................................77 
10.2.5. Record Retention ............................................................................................................78 
10.3. 
Study Documentation and Monitoring ...........................................................................78 
10.3.1. Study Documentation......................................................................................................78 
10.3.2. Site Inspections and Monitoring .....................................................................................78 
10.3.3. Protocol Amendments .....................................................................................................79 
10.3.4. Protocol Deviations .........................................................................................................79 
10.4. 
Other Operational Considerations ..................................................................................79 
10.4.1. Study and Site Start and Closure ....................................................................................79 
11. 
Appendices .....................................................................................................................81 
11.1. 
Appendix 1: ACR Criteria for the Diagnosis of Osteoarthritis ......................................81 
11.2. 
Appendix 2: Kellgren & Lawrence Grading for Knee 
Osteoarthritis ...................................................................................................................82 
11.3. 
Appendix 3: WOMAC for Knee Osteoarthritis (Sample) ..............................................83 
11.4. 
Appendix 4: Skin Irritation Scale ...................................................................................84 
11.5. 
Appendix 5: Clinical Laboratory Tests ...........................................................................86 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
7 
11.6. 
Appendix 6: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................87 
11.6.1. Definition of AE .............................................................................................................87 
11.6.2. Definition of SAE ...........................................................................................................88 
11.6.3. Recording of AEs and SAEs and Reporting Period........................................................89 
11.6.4. Assessment of AE/SAE Intensity ...................................................................................90 
11.6.5. Assessment of AE/SAE Causality ..................................................................................91 
11.6.6. Reporting of SAEs ..........................................................................................................92 
11.6.7. AE and SAE Follow-up and Outcomes ..........................................................................93 
11.7. 
Appendix 7: Estimated Glomerular Filtration Rate ........................................................94 
12. 
References ......................................................................................................................95 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
8 
List of Abbreviations 
 
ACR 
American College of Rheumatology 
AE 
adverse event 
Ae24 
urinary excretion over 24 hours 
Ae48 
urinary excretion over 48 hours 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ASA 
acetyl salicylic acid  
AST 
aspartate aminotransferase 
AUC24 
area under the (analyte concentration versus time) curve from time zero to 24 hours  
AUCinf 
area under the (analyte concentration versus time) curve from time zero to infinity 
AUCt 
area under the (analyte concentration versus time) curve calculated for the interval from 
time zero to the last measurable time point 
BARL 
Bay Area Research Logistics  
BMI 
Body Mass Index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CABG 
coronary artery bypass surgery 
CBC 
complete blood count 
CDASH 
Clinical Data Acquisition Standards Harmonization 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
Cav 
average plasma concentration (AUC24/24) 
CIOMS 
Council for International Organizations of Medical Sciences  
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL 
apparent total body clearance of drug after topical application (CL=Dose/AUCinf) 
CLSA 
Canadian Longitudinal Study on Aging 
Cmax 
maximum measured plasma analyte concentration over the sampling period 
Cmin 
minimum/last measured plasma analyte concentration over the sampling period 
CONSORT 
Consolidated Standards of Reporting Trials 
COX 
cyclooxygenase 
COVID-19 
Coronavirus 2019 
CRO 
Contract Research Organization 
CS 
clinically significant 
CSR 
clinical study report 
CTA 
Clinical Trial Application 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DMC 
data monitoring committee  
e.g. 
exempli gratia (for example) 
ECG 
electrocardiogram 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
9 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture  
eGFR 
Estimated Glomerular Filtration Rate  
EOT 
End-of-Treatment (visit) 
EOS 
End-of-Study (visit) 
ES 
effect size  
ESR 
erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
FPFV 
first patient first visit  
FV1 
Flare Visit #1 (Baseline) 
FV2 
Flare Visit #2 (3-7 days after the last study drug application) 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GI 
gastrointestinal 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IGA 
Investigator Global Assessment 
IMP 
investigational medicinal product 
INR 
(prothrombin) International Normalized Ratio 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
JRA 
Juvenile Rheumatoid Arthritis  
JSN 
joint space narrowing 
Kel 
apparent first-order elimination rate constant 
KLRG 
Kellgren and Lawrence Radiographic Grading 
LDH 
lactate dehydrogenase 
LOCF 
last observation carried forward  
LPLV 
last patient last visit  
MCID 
minimally clinically important difference 
MD 
mean difference 
mg 
milligram 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIS 
mean irritation score 
mITT 
modified Intent-to-Treat (Population) 
mL 
milliliter  
MOST 
Multicenter Osteoarthritis Study  
NHIS 
National Health Interview Survey  
NIMP 
non-investigational medicinal product 
NRS 
Numerical Rating Scale 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
10 
NSAID 
non-steroidal anti-inflammatory drug 
OA 
osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
OMERACT 
Outcome Measures in Rheumatology  
PGA 
Patient Global Assessment 
PK 
pharmacokinetic 
PP 
Per Protocol (Population) 
QTL 
quality tolerance limits  
RA 
rheumatoid arthritis  
RBC 
red blood cell 
RCT 
randomized controlled trial 
RF 
rheumatoid factor 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
SD 
standard deviation 
SF 
synovial fluid 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SMD 
standardized mean difference 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reactions  
T1/2 
apparent elimination half-life 
TEAE 
treatment-emergent adverse events  
Tmax 
time of the maximum measured plasma analyte concentration over the sampling period 
ULN 
upper limit of normal 
U.S./USA 
United States of America 
VAS 
Visual Analogue Scale 
WBC 
white blood cell 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
YLD 
years lived with disability  
 
 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
11 
Administrative Structure 
STUDY FUNCTION 
RESPONSIBLE PARTY 
Study Sponsor 
 
 
 
 
Buzzz Pharmaceuticals Limited 
15 Main Street, Raheny, Dublin 5, Ireland 
Tel: +44-773-310-4786 
Contact: Dr. Deirdre O’Keeffe 
Head of IP and Portfolio Management 
E-mail: deirdre@hotmail.co.uk 
Investigational Medicinal Product (IMP) 
Manufacturing  
 
Egis Pharmaceuticals PLC  
1106 Budapest, Keresztúri street 30-38, Hungary 
Tel: +36-1-803-5555 
Fax: +36-1-803-5529, +36-1-803-5511 
IMP Labeling & Distribution to Sites 
 
Bay Area Research Logistics (a division of Bay Area 
Health Trustee Corp.)  
293 Wellington St. N Unit 123 
Hamilton, Ontario, L8L 8E7 Canada 
Tel: +1-905-527-1938 
Tel: +1-844-892-BARL(2275) 
Medical Monitor  
 
Dr. Atalah Haun 
Veristat, LLC 
Tel: +1-647-745-8762  
Email: Atalah.Haun@veristat.com 
Safety Reporting 
PV and Safety Manager 
Veristat, LLC 
Tel: 1-888-662-0657 
Fax: 1-888-662-0647  
Email: pharmacovigilance@veristat.com  
Clinical Monitoring & Site Management 
Data Management &  
Statistical Support 
 
Veristat, LLC  
134 Turnpike Road, Suite 200 
Southborough, MA 01772, USA 
Tel: +1 508-826-9015 
1 Eva Road, Suite 111 
Etobicoke, Ontario, M9C 4Z5, Canada 
Contact: Heather Karabaich, Senior Project Manager  
E-mail: Heather.Karabaich@veristat.com 
Central Laboratory: 
Safety laboratory testing 
 
DYNACARE  
115 Midair Court, Brampton Ontario, L6T 5M3, Canada 
Tel: + 1-800-668-2714 
E-mail: coopera@dynacare.ca 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
12 
1. 
Protocol Summary 
1.1. 
Synopsis 
Study Title 
Phase 2 Multicenter, Double-blind, Randomized, Parallel-Group, Vehicle-
Controlled Study to Evaluate the Efficacy, Safety, and Local Tolerability of 
G001 in Patients with Osteoarthritis (OA) of the Knee 
Study Design 
Double-blind, randomized, parallel-group, vehicle-controlled clinical trial  
No. of sites 
The study will be completed at approximately 10 centres located in Canada 
(Quebec and Ontario)  
Objectives: 
The objectives of this study are to explore the efficacy, safety, and local 
tolerability of G001 compared to vehicle in patients with symptomatic 
osteoarthritis (OA) of the knee 
Number of Patients 
A total of 210 patients are planned to be enrolled to provide 174 evaluable 
patients (i.e. the modified intent-to-treat [mITT] population for the primary 
efficacy analysis) 
Study Population 
Adult patients with primary OA of the knee and moderate OA pain at the time of 
enrolment 
Inclusion Criteria 
 
Patients must meet all of the following criteria to qualify for the study: 
1. Male or female age ≥40 years  
2. Documented diagnosis of OA of the knee, meeting American College of 
Rheumatology (ACR) criteria for classification of idiopathic (primary) OA 
(see Appendix 1) for at least 6 months prior to Screening  
3. Radiologic evidence of OA of the knee of grade 2 (mild) or grade 3 
(moderate) according to Kellgren and Lawrence Radiographic Grading (see 
Appendix 2) 
4. Worst daily pain (within 24 hours prior to Screening and Baseline) in the 
index knee between 4 and 8 on the 11-point pain Numerical Rating Scale 
(NRS)  
5. On stable analgesic therapy (i.e. at least 3 days per week for at least 30 days 
prior to Screening) with an oral or topical non-steroidal anti-inflammatory 
drug (NSAID) and/or acetaminophen  
6. In reasonably good general health (apart from OA), as assessed by the 
Investigator 
7. Females of childbearing potential: adequate birth control and negative 
pregnancy test at Screening and Baseline.  
A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state (≥ 24 continuous 
months of amenorrhea with no identified cause other than menopause), and 
is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian 
tubes, and/or uterus) or another cause as determined by the Investigator (e.g., 
Müllerian agenesis). 
Adequate birth control is defined as: stable dose of an oral contraceptive for 
at least 2 months prior to the first study drug administration, intrauterine 
device, bilateral tubal ligation, barrier method of contraception in conjunction 
with spermicidal jelly, or abstinence. 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
13 
8. Negative urine drug screen (including for cannabinoids) at Screening and 
Baseline 
9. Subject is willing to participate in the study, comply with the study 
requirements 
and 
voluntarily 
provide 
written 
informed 
consent.  
 
Additional Inclusion Criteria Assessed at Baseline/Flare Visit #1 (FV1): 
Following Screening, prior NSAID and acetaminophen use will be discontinued 
to allow for washout (3 to 7 days) and symptom flare. Acetaminophen may be 
used as rescue medication only, with the following exception: no rescue 
medication is allowed within 12 hours prior to the Baseline/FV1 visit. 
10. Development of a flare of pain following washout of stable analgesic 
(NSAID and/or acetaminophen) therapy, defined as follows: 
• 
An increase of ≥2 points (out of possible 20) from the Screening 
assessment in the Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) Pain Subscale score for the index knee; 
and 
• 
A score of ≥2 points (out of possible 4) on at least one of the 5 items in 
the WOMAC Pain Subscale (for the index knee). 
Exclusion Criteria 
 
Patients who meet any of the following criteria will be excluded from the study: 
Exclusions Related to OA: 
1. Radiologic evidence of severe OA of the knee (Kellgren and Lawrence grade 
4) (see Appendix 2)  
2. Secondary OA of the index knee (such as septic arthritis, inflammatory joint 
disease, gout, articular fracture, major dysplasia, congenital abnormality, 
hemochromatosis) 
3. Any other arthritis, included but not limited to rheumatoid arthritis (RA), 
psoriatic arthritis, etc. 
4. History of pseudo-gout or inflammatory flare-ups 
5. History of severe neurological conditions (such as multiple sclerosis, sciatica, 
fibromyalgia, etc.) 
6. Any other chronic pain conditions (e.g., back pain) or disabling conditions 
affecting the joints 
7. Non-ambulatory or requires the use of crutches or a walker 
8. Started using a cane within 30 days prior to Screening 
9. Worst daily pain (within 24 hours prior to Baseline/FV1) in the contralateral 
knee assessed as >2 on the 11-point pain NRS scale. 
Study Drug-Related Exclusions & Other Medical Conditions 
10. Skin disorder present at the study drug application site 
11. Presence of contraindications, warnings, or precautions (listed in the 
Canadian Product Monograph for oral celecoxib), that may put the subject at 
risk, as assessed by the Investigator 
12. Known sensitivity to celecoxib, any NSAID, or menthol 
13. History of aspirin-sensitive asthma 
14. History of any of the following: 
a. Known coronary artery disease or cerebral artery disease 


CONFIDENTIAL 
Buzzz Pharmaceuticals Limited 
 
Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
14 
b. Coronary artery bypass surgery (CABG) within 1 year prior to 
Screening 
c. Any other severe or uncontrolled cardiovascular disease, as assessed 
by the Investigator 
d. Systolic blood pressure (SBP) >149 mmHg and/or diastolic blood 
pressure (DBP) >94 mmHg at Screening 
15. Severe, uncontrolled hepatic, renal, or other systemic disease, as assessed by 
the Investigator 
16. Any malignancy within the previous 5 years, except for superficial skin 
cancer not on the index knee, cured with local therapy  
17. Documented gastroduodenal ulcer or gastrointestinal (GI) bleeding within 
the last 6 months or presence of other GI disorder that could put the patient 
at increased risk or interfere with the interpretation of the safety results of the 
study 
18. Uncontrolled diabetes or diabetic neuropathy 
19. Psychiatric or psychological conditions that in the opinion of the Investigator 
may affect the subject’s pain assessments (such as depression, anxiety, pain 
catastrophizing, poor sleep quality) 
20. Any of the following abnormal Screening laboratory test results:  
a. serum creatinine ≥ 1.5 times the upper limit of normal (ULN) or 
Estimated Glomerular Filtration Rate (eGFR) < 60 mL/min/1.73 m2 
(Appendix 7); 
b. aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
or gamma-glutamyl transferase (GGT) ≥ 2 times the ULN;  
c. hemoglobin < 10 g/dL 
21. Positive serology for human immunodeficiency virus (HIV) antibody, 
hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody at 
Screening 
22. Documented alcohol or other substance abuse within 1 year 
23. Body Mass Index (BMI) above 40 kg/m2 
24. Patients who are currently pregnant or planning to be become pregnant or are 
breast-feeding. 
Prohibited Prior, Current, or Planned Treatments: 
25. Any history of major surgery to the index knee, or minor knee surgery or 
injury to the index knee within 1 year prior to Screening 
26. Knee arthroscopy (index knee) within 3 months prior to Screening 
27. Planned or candidate for knee replacement or knee reconstruction surgery 
28. Treatment with or need for any of the following: (1) oral or intramuscular 
corticosteroids within the past 90 days; (2) intra-articular corticosteroid 
injection into the index knee within the past 90 days, or into any other joint 
within the past 30 days; (3) current use of topical corticosteroids on the index 
knee 
29. Received intra-articular viscosupplementation/hyaluronate, joint lavage, or 
other invasive therapies to the index knee in the past 90 days 


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Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
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30. Prior stable therapy (defined as >3 days per week prior to the Screening) with 
an opioid analgesic, or anticipated need for opioid analgesic use during the 
study  
31. Use of sedative hypnotic medication, antidepressants with known analgesic 
effect, antipsychotics, antiepileptics, and anti-Parkinson drugs within the past 
14 days 
Note: "Known analgesic effect" is defined as any documented evidence of a 
significant effect on pain outcomes, and is not equivalent to an approved 
indication or proven efficacy. 
32. Regular use of medication for headaches (≥10 days within 30 days prior to 
Screening) 
33. Use of another investigational drug within the previous 30 days or five half-
lives of the investigational product, whichever is longer 
34. Use of any oral or topical NSAID (apart from the investigational medicinal 
product [IMP]) is prohibited during the study 
35. Receipt of a coronavirus 2019 (COVID-19) vaccine within 7 days prior to 
Screening, or anticipated during the study (between Screening and Week 5).  
Patients who received their first dose of the vaccine may be enrolled as long 
as their second dose is scheduled later than the planned Week 5 study visit. 
The dates of the first and second COVID-19 vaccine dose (actual or planned) 
should be documented in the patient’s study file. 
Additional Exclusion Criterion Assessed at Baseline/FV1: 
36. Non-compliance with the daily diary requirement during the 7-day Screening 
period (defined as <3 days of daily or nightly pain assessments or <3 days of 
rescue medication entries). 
Study duration 
Each patient’s participation will be approximately 7 weeks (~1 week Screening, 
4 weeks of treatment, and 2 weeks of post-treatment follow-up). Additional pre-
screening time (after informed consent was obtained) may be required for 
washout periods and radiological examination. 
Study Assessments 
Following Screening, prior NSAID and/or acetaminophen use will be 
discontinued to allow for washout (3 to 7 days) and symptom flare. 
Acetaminophen may be used as rescue medication only, with the following 
exception: no rescue medication is allowed within the 12 hours prior to the 
Screening Visit and the Baseline/FV1 visit.  
Patients will be given a study diary and instructed to enter the following on a 
daily basis during the 7-day screening period: 
• 
Between 6 a.m. and 7 a.m., patients should rate their night-time pain in the 
index knee (i.e., knee selected for study treatment) on the 11-point pain NRS 
• 
Between 10 p.m. and 11 p.m., patients should rate their worse pain in the 
index knee during the day and enter any breakthrough pain medication 
(acetaminophen) use during the day. 
Diary entries will be reviewed at the Baseline/FV1 visit.  
Eligible patients with adequate OA pain in the index knee at the Baseline/FV1 
visit will be randomly assigned in a 1:1 allocation ratio to receive G001 or 
Vehicle Gel.  
Patients will have a demonstration of the study drug application at the clinic and 
receive their first dose before being sent home. Rescue medication use is 


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Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
16 
discouraged, but acetaminophen may be used, as needed, at a dose not exceeding 
500 mg per dose and 2,000 mg/day to manage breakthrough pain. No rescue 
medication use is permitted within 2 hours after each IMP application, and within 
12 hours prior to each efficacy assessment (i.e., at the Week 2, Week 4/End-of-
Treatment [EOT] visits, and Week 5/Flare Visit #2 [FV2]).  
Patients will be given a study diary and instructed to enter the following on a 
daily basis: 
• 
Between 6 a.m. and 7 a.m. (before the first daily study drug application), 
patients should rate their night-time pain in the index (i.e., treated) knee  
• 
During the day: patients should enter the time of each study drug application 
• 
Between 10 p.m. and 11 p.m. (before the last daily study drug application), 
patients should rate their worse pain in the index knee during the day and 
enter any adverse event (AE) experienced,  and breakthrough pain medication 
use during the day. 
Patients will return to the clinic twice during the treatment period for efficacy and 
safety assessments: at Week 2 (after 14 ± 1 day of study treatment), and at Week 
4/EOT (after 28 ± 2 days of study treatment). During these visits, patients will 
undergo the following efficacy assessments: WOMAC Index, Patient Global 
Assessment (PGA), Investigator Global Assessment (IGA), review of patient 
diary. In addition, the Investigator (or qualified designee) will contact the patient 
by phone after one week of treatment (Week 1, study Day 8 ± 1), and after three 
weeks of treatment (Week 3, study Day 22 ± 1), to verify compliance with the 
study drug application and daily diary completion requirements, and to follow up 
on how the IMP is tolerated. 
Patients will return to the clinic 3 to 7 days after the last IMP application for a 
second Flare Visit (Week 5/FV2), and within approximately 2 weeks after the 
last IMP application (Week 6; Day 43 ± 3) for an End-of-Study (EOS) evaluation. 
Daily diary completion will continue (as described above) until the Week 5/FV2 
visit.  
Patients who discontinue study treatment prematurely will be asked to return to 
the clinic for the EOT visit assessments at the time of withdrawal, and the EOS 
visit 14 ± 2 days after the last IMP application, unless the patient withdraws 
consent from any further study participation. 
Safety will be assessed throughout the study through recording of AEs and 
concomitant medications, complete physical examination, safety laboratory tests 
(complete blood count [CBC], blood chemistry, coagulation tests, and urinalysis), 
12-lead electrocardiogram (ECG), vital signs, and skin irritation assessments at 
the following visits:   
• 
AEs and concomitant medications: self-reported or solicited by non-directive 
questioning of the patient at each visit. AEs ongoing at the EOS visit will be 
followed until resolution or an acceptable outcome has been reached, as 
assessed by the Medical Monitor. 
• 
Safety laboratory tests (including a urine pregnancy test for females of 
childbearing potential) at Screening, Baseline/FV1, Week 2, Week 4/EOT, 
and Week 6/EOS. A repeat serum pregnancy test is required in case the urine 
test is positive. 
• 
Standard 12-lead ECGs (in a supine position, after resting for at least 5 
minutes) at the Screening, and Week 4/EOT visits.  


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Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
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• 
Complete physical examination at Screening and Week 4/EOT, and a 
symptom-driven examination at Week 6/EOS. 
• 
Vital signs: sitting (after 3 minutes of rest) at Screening, Baseline/FV1, Week 
2, Week 4/EOT, and Week 6/EOS. 
• 
Skin irritation will be tested on a scale of 0 to 7 (from 0=no evidence of 
irritation to 7=strong reaction spreading beyond test site) at Week 2, Week 
4/EOT, and Week 6/EOS. 
Primary 
outcome 
measure(s) 
• 
Change from Baseline in WOMAC Pain Subscale Score, at Week 4/EOT 
The WOMAC Pain Subscale score is derived by summing the five pain scores on 
the WOMAC OA Index (pain during walking, using stairs, in bed, sitting or lying, 
and standing), each measured on a 5-point Likert scale (0=none, 1=mild,  
2=moderate, 3=severe, and 4=extreme). The maximum WOMAC Pain Subscale 
rating is 20 and higher scores indicate worse pain. 
Secondary 
outcome 
measures 
 
• 
Mean worst daytime and mean worst nighttime pain severity scores (11-point 
pain NRS, from patient diary) at Week 4/EOT and Week 5/FV2, including 
mean changes from Baseline 
• 
Percentages of patients achieving ≥20%, ≥30%, and ≥50% reduction from 
Baseline in worst daytime pain severity scores (11-point pain NRS, from 
patient diary) at Week 4/EOT 
• 
Percentages of patients achieving ≥20%, ≥30%, and ≥50% reduction from 
Baseline in worst nighttime pain severity scores (11-point pain NRS, from 
patient diary) at Week 4/EOT 
• 
Change from Baseline to Week 4/EOT in WOMAC Physical Function 
Subscale score  
• 
Change from Baseline to Week 4/EOT in WOMAC Total score  
• 
Change from Baseline to Week 4/EOT in WOMAC Stiffness Subscale score 
• 
Change from Baseline to Week 2 in WOMAC Total and Subscale scores 
• 
Change from Week 4/EOT to Week 5/FV2 in WOMAC Total and Subscale 
scores 
• 
Change from Baseline in PGA of disease activity over time 
• 
Change from Baseline in IGA of disease activity over time 
• 
PGA and IGA of overall treatment benefit at Week 2 and Week 4/EOT 
• 
Incidence of rescue medication use, number of doses, and percentage of days 
with any rescue medication use during the last week of study treatment, and 
overall during the study treatment period (between the first and last study 
drug dose dates).  
The WOMAC OA Index consists of 24 items divided into 3 subscales: Pain (5 
items), Stiffness (2 items), and Physical Function (17 items). Each item is 
measured on a 5-point Likert scale. Scoring instructions are provided in the in the 
WOMAC 3.1 User Guide XI. 
The pain NRS is an ordinal 11-point Likert scale, with scores ranging from 0 (no 
pain) to 10 (worst possible pain). 
PGA and IGA of disease activity are the patient’s and assessor’s evaluation of 
OA, respectively, in the in the index knee over the last 48 hours on a 5-point 
Likert scale, where 0=very good; 1=good; 2=fair; 3=poor; and 4=very poor. PGA 


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Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
18 
and IGA of treatment benefit use the same scale and time frame, evaluating the 
impact of the treatment. 
Safety outcome measures 
 
• 
Frequency and severity of AEs, study drug-related AEs, serious adverse 
events (SAEs), and AEs leading to study drug discontinuation 
• 
Changes in safety laboratory test results, vital signs measurements, 12-lead 
ECG, and physical examination findings.  
• 
Frequency and severity of application site AEs 
• 
Skin irritation test scores at Week 2, Week 4/EOT, and Week 6/EOS. 
Test Product Route and  
Doses  
G001 (Celecoxib Gel 4%) for topical administration, containing celecoxib 40 
mg/g as active ingredient. 
The formulation also includes menthol 1.5% (15 mg/g), added as solubilizer. 
Reference Products Route 
and  Doses  
Vehicle formulation, containing all excipients of G001 (including menthol 1.5%), 
but without celecoxib.  
Investigational Medicinal 
Product Application 
Method,  Frequency and 
Duration of Treatment 
4 grams of the IMP (test or reference product) will be applied to the target knee 
four times daily for 4 weeks as follows:  
• 
1st dose between 6 a.m. and 7 a.m.  
• 
2nd dose: between 11 a.m. and  12 p.m. (~5 hours after the first dose) 
• 
3rd dose: between 4 p.m. and 5 p.m. (~5 hours after the second dose) 
• 
4th dose: between 10 p.m. and 11 p.m. (~6 hours after the third dose and 
shortly after the daily pain assessment). 
Note: the first study drug application (Day 1) may occur between 6 a.m. and 8 
a.m. Subsequent application times on Day 1 may be modified accordingly, to 
maintain the ∼5-hour interval between consecutive applications. 
Accurate dosing will be ensured by using a dosing card. The patient will be 
instructed to measure 4 grams of the gel using the dosing card, then apply the 
measured amount to the index knee, and massage it in over at least 1 minute to 
ensure adequate application over the affected joint. 
The first dose will be applied at the clinic, in the presence of the designated 
unblinded administrator; subsequent applications will be made by the patient (at 
the clinic or their home, as applicable). 
Study treatment will continue for 4 weeks (28 ± 2 days). 
Duration of follow-up 
Patients will have a safety follow-up assessment 2 weeks (14 ± 3 days) after their 
last IMP application. 
Follow-up of SAEs and AE related to the IMP will continue until resolution of 
the event or until a stable condition is reached. 
Statistical Considerations 
Analysis Populations: 
• 
Modified Intent-to-Treat Population (mITT): The mITT will include all 
randomized patients who received at least one dose of study drug and 
provided both Baseline/FV1 and Week 4/EOT efficacy assessments. The 
mITT population will be the primary analysis population for the assessment 
of efficacy, with patients assessed according to the treatment they were 
randomized to. 
• 
Per Protocol (PP) Population: The PP population will include all patients in 
the mITT population who completed the study without major protocol 
violations that could impact the assessment of efficacy. The primary and 


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Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
19 
secondary efficacy analyses will also be completed on the PP population as 
supportive. 
• 
Safety Population: The Safety population will include all patients who 
received any amount of study drug. Patients will be assessed according to the 
treatment they received. The Safety Population will be used for all safety 
analyses. 
 
Sample Size Estimation: 
A total sample size of 174 evaluable patients (87 per group) achieves 80% power 
to detect a difference among treatment groups analysed using a t-test with a 
significance level (alpha) of 0.05. The assumed difference in group means from 
vehicle control under the alternative hypothesis is 1.5 points in the WOMAC 
Likert pain subscale (0-20 scale). The common standard deviation (SD) is 
assumed to be 3.5.  
Based on available literature, it is estimated that up to 20% of patients may 
withdraw from the study prior to the Week 4 efficacy assessment. Therefore, to 
control for possible dropouts, the sample size is increased to 210, or 105 per 
treatment arm. 
 
Analysis Methods: 
A detailed Statistical Analysis Plan (SAP) will be developed. All data collected 
will be documented using summary tables, figures, and/or patient data listings 
presented by treatment group. For continuous variables, descriptive statistics 
(number [n], mean, median, standard deviation, minimum and maximum) will be 
presented. For categorical variables, frequencies and percentages will be 
presented. 
The primary endpoint, change from Baseline in the WOMAC Pain Subscale 
rating at the Week 4/EOT visit, will be analyzed via an analysis of covariance 
(ANCOVA) model to compute the t-test for the difference between group means 
adjusted for Baseline WOMAC pain score. The analysis will be performed on the 
mITT population with no imputation for missing data. Statistical significance will 
be assessed using a significance level of 0.05. 
Changes from baseline in average worst daytime and in average worst nighttime 
pain severity scores at Week 4/EOT in the two treatment groups will be compared 
using a t-test. Percentages of patients achieving ≥20%, ≥30% and ≥50% reduction 
from baseline in worst daytime pain and in worst nighttime pain severity scores 
(11-point pain NRS) at Week 4/EOT will be compared between treatment groups 
using Fisher’s exact test. 
The analysis of secondary efficacy endpoints of WOMAC Physical Function 
Subscale, WOMAC Stiffness Subscale and WOMAC Total Score will be 
consistent with that described for the primary endpoint.  
For PGA and IGA, patients will be classified according to the following three 
categories: (1) "improved" (defined as a reduction of 2 grades or more from 
Baseline for grades 2 through 4 or a change in grade from 1 to 0); (2) "worsened" 
(defined as an increase of 2 or more grades from Baseline for grades 0 through 2 
or a change in grade from 3 to 4); or (3) “no change” (remaining patients). The 
categorical responses will be presented by treatment and visit. 


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Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
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Rescue medication (acetaminophen) use will be assessed in terms of number of 
rescue doses, total daily dose, and the percentage of days with any rescue 
medication use during the last week of study treatment, and overall during the 
study treatment period (between the first and last study drug dose dates). 
Subgroup analyses of primary and select secondary endpoints may be performed 
on prior OA treatment (pre-study NSAID or acetaminophen use only) depending 
on the number of patients in each category.  
Safety: 
Adverse events (AEs) will be coded using the most recent version of Medical 
Dictionary for Regulatory Activities (MedDRA) and presented by System Organ 
Class (SOC) and Preferred Term for each treatment group.  Additional displays 
will highlight the Investigator-rated severity and relationship to study treatment 
as well as SAEs, withdrawals due to AEs, and application site AEs. 
Laboratory parameters (and changes from Baseline in these parameters) will be 
summarized. In additional, shift changes in categories (normal, low, high, 
missing) will be presented by treatment group across the visits.  Clinically 
relevant laboratory abnormalities will be recorded as AEs. 
Vital signs measurements (and changes from Baseline in these measurements) 
will be summarized. Clinically relevant changes in vital signs will be recorded as 
AEs. 
Clinically relevant abnormal physical examination findings will be recorded as 
medical history at Baseline (prior to the first dose of study treatment), and as AEs 
if detected after the first dose of study treatment.  
Local tolerability (skin irritation) assessments will be summarized by treatment 
group and study visits. 
 
1.2. 
Study Design Schema 
A study design schema is provided in Figure 1. 


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Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
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Figure 1 Study Design Schema 
 
 
 
 
 
 
 
 
Abbreviations: ACR=American College of Rheumatology; BL=Baseline; EOS=end-of-study; EOT=end-of-treatment; FV1=Flare 
Visit #1; IMP=Investigational Medicinal Product; KLRG=Kellgren and Lawrence Radiographic Grading; NSAID=nonsteroidal 
anti-inflammatory drugs; OA=osteoarthritis; QID=quarter in die (four times daily); WOMAC=Western Ontario and McMaster 
Universities Osteoarthritis Index 
[1] Flare state is confirmed at the Baseline/FV1 visit (3-7 days after the Screening visit) as follows: 
• 
An increase of ≥2 points (out of possible 20) from the screening assessment in the WOMAC Pain Subscale score for the 
index knee; and 
• 
A score of ≥2 points (out of possible 4) on at least one of the 5 items in the WOMAC Pain Subscale for the index knee. 
 
 
 
Male and female 
patients aged ≥40 
years with a 6-
month documented 
history of OA of the 
knee, meeting 
ACR criteria, and 
radiologic evidence 
of grade 2 or 3 
disease according 
to KLRG 
… 
Prior NSAID and/or 
acetaminophen 
discontinued 
 
 
Confir-
mation 
of 
Flare 
State 
at BL/ 
FV1 
[1] 
 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N 
 
1:1 
N=210 
G001 (Celecoxib Gel 4%)  
Treatment Regimen (both groups): 
4 g of the IMP applied to the Index 
knee QID for 28 ± 2 days: 
Vehicle Gel  
 
 
Primary 
Endpoint 
Assessm
ent at 
Week 4 
(EOT) 
 
 
 
 
 
EOS 


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Protocol 2020-G001-P2 V43.0 (December 7, 2022) 
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1.3. 
Schedule of Assessments (SoA) 
 
Study Visit 
Screening  
Visit 
BL/FV1  
Visit 
Week 1 
Phone call 
Week 2 
Visit 
Week 3 
Phone call 
Week 4/EOT 
Visit 
Week 5/FV2 
Visit 
Week 6/EOS 
Visit 
Study Day 
Day -7 to -3
Day 1 
Day 8±1 
Day 15±1 
Day 22±1 
Day 29±2 
3-7 Days  
After EOT  
Day 43±3 
Written informed consent [a] 
X 
 
 
 
 
 
 
 
Demographic data [b] 
X 
 
 
 
 
 
 
 
Medical and medication history [c]  
X 
 
 
 
 
 
 
 
OA diagnosis (ACR criteria) [d] 
X 
 
 
 
 
 
 
 
Radiological examination [e] 
X 
 
 
 
 
 
 
 
WOMAC Index [f] 
X 
X 
 
X 
 
X 
X 
 
PGA of disease activity [g]  
X 
X 
 
X 
 
X 
X 
 
IGA of disease activity [g]  
X 
X 
 
X 
 
X 
X 
 
PGA of overall treatment benefit [g] 
 
 
 
X 
 
X 
 
 
IGA of overall treatment benefit [g] 
 
 
 
X 
 
X 
 
 
Worst daily pain 11-point NRS (24-hour recall), 
index knee [h] 
X 
X 
 
 
 
 
 
 
Worst daily pain 11-point NRS (24-hour recall), 
contralateral knee [i] 
X 
X 
 
 
 
 
 
 
Physical examination [j] 
X 
 
 
 
 
X 
 
X 
Height, weight, and BMI 
X 
 
 
 
 
 
 
 
Vital signs measurements [k]  
X 
X 
 
X 
 
X 
 
X 
Standard 12-lead ECG [l] 
X 
 
 
 
 
X 
 
 
Safety Laboratory Testing [m] 
X 
X 
 
X 
 
X 
 
X 
Urine pregnancy test [n] 
X 
X 
 
 
 
X 
 
X 
Urine drug screen 
X 
X 
 
X 
 
X 
 
X 
Review of Inclusion / Exclusion criteria 
X 
X 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
Study drug dispensing/reconciliation 
 
X 
 
X 
 
X 
 
 
Study drug application (4 times per day) [o]  
 
X 
X 
X 
X 
X 
 
 
Adverse event recording  
X 
X 
X [p] 
X 
X [p] 
X 
X 
X 
Concomitant medications & therapies  
X 
X 
X [p] 
X 
X [p] 
X 
X 
X 
Skin irritation assessment [q] 
 
 
 
X 
 
X 
 
X 


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Protocol 2020-G001-P2 V43.0 (December 7, 2022) 
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Study Visit 
Screening  
Visit 
BL/FV1  
Visit 
Week 1 
Phone call 
Week 2 
Visit 
Week 3 
Phone call 
Week 4/EOT 
Visit 
Week 5/FV2 
Visit 
Week 6/EOS 
Visit 
Study Day 
Day -7 to -3
Day 1 
Day 8±1 
Day 15±1 
Day 22±1 
Day 29±2 
3-7 Days  
After EOT  
Day 43±3 
Patient diary completion [r] 
Completed by the patient on a daily basis 
 
Review of the Patient Diary [s] 
 
X 
X [p] 
X 
X [p] 
X 
X 
 
Abbreviations: ACR=American College of Rheumatology; BL=Baseline; BMI=body mass index; BP=blood pressure; ECG=electrocardiogram; EOS=End-of-
Study; EOT=End-of-Treatment; FV1=Flare Visit #1; FV2=Flare Visit #2; IGA=Investigator Global Assessment; NRS=Numerical Rating Scale; PGA=Patient 
Global Assessment; WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index 
[a] Written informed consent is required before performing any study-specific tests or procedures. 
[b] Demographics include age, gender, and self-reported race/ethnicity.   
[c] Medical history OA history (date of diagnosis, prior treatment), general medical history, surgical history, and reproductive status. Medication history includes 
pharmacological treatment (oral,  parenteral, intra-articular, or topical) used in the past 90 days, with focus on medications used for the management of OA, and 
prohibited medications; see Section 6.8.1.   
[d] Documented diagnosis of OA of the knee, meeting ACR criteria for classification of idiopathic (primary) OA (see Appendix 1) for at least 6 months prior to 
Screening is required for enrolment. 
[e] Patients will undergo conventional radiological (X-ray) examination of the index knee during Screening. Exemptions include patients who: (1) had an X-ray of 
the index knee completed within 3 months prior to the Screening visit, and (2) received no treatment since that may have altered the radiological findings, including 
OA grade. Radiologic evidence of OA of the knee of grade 2 (mild) or grade 3 (moderate) according to Kellgren and Lawrence Radiographic Grading (see Appendix 
2) is required for enrolment. 
[f] Patients will complete the 5-point Likert format of the WOMAC 3.1 Index; see Appendix 3. To qualify for randomization, all participants need to develop a 
flare of pain following washout (3-7 days) of stable analgesic (NSAID and/or acetaminophen) therapy, defined as (1) an increase of ≥2 points from Screening in 
the WOMAC Pain Subscale score for the index knee; and (2) a score of ≥2 points on at least one of the 5 items in the WOMAC Pain Subscale (for the index knee). 
[g] PGA/IGA of disease activity (or PGA/IGA of treatment benefit) evaluates OA in the in the index knee over the last 48 hours on a 5-point Likert scale, where 
0=very good; 1=good; 2=fair; 3=poor; and 4=very poor. 
[h] Worst daily pain (within 24 hours prior to Screening and Baseline/FV1) in the index knee needs to be between 4 and 8 on the 11-point pain NRS for enrolment. 
[i] Worst daily pain (within 24 hours prior to Baseline/FV1) in the contralateral knee needs to be ≤2 on the 11-point pain NRS scale for enrolment. 
[j] Complete physical examination at Screening and Week 4/EOT, and symptom-driven examination at Week 6/EOS. A complete physical examination will be 
performed with special attention to the cardiovascular, gastrointestinal, and musculoskeletal systems, as well as skin and subcutaneous tissues. Investigators may 
use medical judgment to determine the need for evaluating the breast, genital, and anorectal areas at each applicable study visit. 
[k] Vital signs measurements will include sitting (after 3 minutes of rest) blood pressure (BP), heart rate (HR),  respiratory rate (RR), and body temperature. Two 
consecutive BP readings (at least 1 minute apart) will be recorded, and the average of the two readings will be entered in the eCRF. 


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Protocol 2020-G001-P2 V43.0 (December 7, 2022) 
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[l] Standard 12-lead ECG, taken in a supine position, after resting for at least 5 minutes. 
[m] Includes: Haematology, Biochemistry, Coagulation tests, Urinalysis; see Appendix 5. 
[n] A confirmatory serum pregnancy test must be completed in case the urine test is positive. Patients with a positive pregnancy test during Screening will be 
excluded from the study. Patients with a positive pregnancy test during the treatment or post-treatment follow-up period will be withdrawn from the study. 
[o] The first dose will be applied at the clinic, in the presence of a qualified unblinded treatment administrator; subsequent applications will be completed by the 
patient at the clinic (on Day 15/Week 2 Visit) or at their home (all other applications). Accurate dosing will be ensured by using a dosing card (to be used for all 
study drug applications). Patients will be dispensed a two-week supply of study drug (three tubes of 100 grams) on Day 1 (Baseline/FV1) and on Day 15 (Week 2 
Visit), and will be asked to return all unused study drug supplies at the next study visit. 
[p] The Investigator (or qualified designee) will contact the patient by phone after one week of treatment (Week 1, study Day 8 ± 1), and after three weeks of 
treatment (Week 3, study Day 22 ± 1), to verify compliance with the study drug application and daily diary completion requirements, and to follow up on how the 
IMP is tolerated. 
[q] Skin irritation will be assessed by the Investigator using the Berger/Bowman Scoring Scale; see Appendix 4. To the extent feasible, the same scorer should 
complete all three skin irritation assessments (Week 2, Week 4/EOT, and Week 6/EOS) for a patient. 
[r] Patients will be given a study diary and instructed to enter the following on a daily basis, from the Screening visit through the Week 5/FV2 visit: (1) Each 
morning between 6 a.m. and 7 a.m. (before the first daily study drug application on treatment days), patients should rate their worst night-time pain in the index 
knee on the 11-point pain NRS; (2) Between 10 p.m. and 11 p.m. (before the last daily study drug application on each treatment day), patients should rate their 
worse daytime pain in the index knee on the 11-point pain NRS and enter any adverse event experienced, and breakthrough pain medication use during the day; 
(3) In addition, on treatment days, patients should enter the time of each study drug application.  
[s] Non-compliance with the daily diary requirement during the Screening period (defined as <3 days of daytime or nighttime pain assessments or <3 days of rescue 
medication entries) will result in exclusion from the study.  
 
 
 


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2. 
Introduction 
2.1. 
Background on the Condition: Osteoarthritis 
2.1.1. 
Epidemiology and Disease Burden 
Osteoarthritis (OA) is a degenerative joint disease that is highly prevalent, and a leading cause of 
disability around the globe (Cross et al. 2014; GBD 2017). The global incidence and prevalence 
of OA have been estimated at 14.7 million and 301.6 million, respectively, and the years lived 
with disability (YLD) associated with OA at 16.3 million (ranking 12th among 328 diseases), with 
a 31.5% increase in the number of cases, and a 2.4% increase in the age-standardized rates between 
2006 and 2016 (GBD 2017; Kolasinski et al. 2020). In Canada (as in Western Europe overall), OA 
is the 10th leading cause of disabilities (GBD 2017). 
The estimated national prevalence and incidence rates for OA vary depending on the definition of 
OA, the specific joint(s) being evaluated, and the population being studied (Vina and Kwoh 2018).  
Based on data from the National Health Interview Survey (NHIS) collected during 2013–2015, an 
estimated 54.4 million (22.7%) adults had physician-diagnosed arthritis in the United States (U.S.), 
and 23.7 million (43.5% of those with arthritis) had arthritis-attributable activity limitations  
(Barbour et al. 2017; CDC 2020). Of all arthritis cases, over 32.5 million U.S. adults have OA 
(CDC 2020). In Canada, the overall prevalence of diagnosed OA in primary care is estimated at 
14% (Birtwhistle et al. 2015). However, a recent report from the Canadian Longitudinal Study on 
Aging (CLSA) involving 23,186 respondents aged 45 to 85 years indicates that ~21% of this age 
group has a diagnosis of OA in Canada, and ~25% reported symptoms typical of OA, but without 
an OA diagnosis (of the ~25%, symptoms were present in one joint in 21%, and in more than one 
joint in 4.5% of cases). Factors associated with significantly higher likelihood of a diagnosed OA 
or possible OA included older age, female sex, being overweight or obese, having a greater number 
of co-occurring conditions, and lower household income (Yip et al. 2020). Other recognized 
person-level risk factors include African-American race, genetic predispositions, diet-related 
factors, and high bone density/mass, whereas joint-level risk factors include specific bone/joint 
shapes, thigh flexor muscle weakness, joint malalignment, participation in certain 
occupational/sports activities, and joint injury (Vina and Kwoh 2018). 
Clinically, the knee is the most common site of OA (accounting for approximately 85% of the OA 
burden worldwide), followed by the hand and hip (Hunter and Bierma-Zeinstra, 2019).  
2.1.2. 
Pathophysiology 
Osteoarthritis is a heterogeneous disease with a very complex pathology that involves  mechanical, 
inflammatory, and metabolic factors, which ultimately lead to structural destruction and failure of 
the synovial joint. Each of the common OA risk factors might instigate a different mechanistic 
pathway leading to OA. The disease affects the whole joint, and involves cartilage degradation, 
bone remodeling, osteophyte formation, and synovial inflammation, leading to pain, stiffness, 
swelling, and loss of normal joint function. Overall, the disease is an active dynamic alteration 
arising from an imbalance between the repair and destruction of joint tissues (Vina and Kwoh 
2018; Hunter and Bierma-Zeinstra, 2019; Kolasinski et al. 2020). 


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Pain is the most disabling symptom in OA, and a major driver of clinical decision making and 
health service use. The pain in knee OA is typically an intermittent and mainly weight-bearing 
(mechanical) pain. Pain mechanisms involved in OA include peripheral nociceptive pain 
mechanisms, as well as pain sensitization by means of neuropathic pain mechanisms or central 
pain mechanisms. The concept and understanding of ‘flare-ups’ in knee OA are evolving; however, 
they are now considered broader than just an exacerbation of pain (Hunter and Bierma-Zeinstra, 
2019). 
Clinical diagnosis is made based on symptoms (pain, brief morning stiffness, and  functional 
limitations) and a brief physical examination (crepitus, restricted or painful movement, joint 
tenderness, and bony enlargement), according to appropriate diagnostic criteria, such as the those 
from the American College of Rheumatology (ACR) (Altman et al. 1986; Kolasinski et al. 2020). 
2.1.3. 
Management 
The main objectives in the management of knee OA are to alleviate pain, restore function, slow 
down the progression of disease and maintain a patients’ health-related quality of life (Huang et 
al. 2020). According to current treatment guidelines (Bannuru et al. 2019; Bruyère et al. 2019; 
Kolasinski et al. 2020), a comprehensive plan for the management of OA in an individual patient 
may include pharmacological treatment (topical, oral, intra-articular), as well as educational, 
behavioral, psychosocial, and physical interventions. Of the pharmacological interventions, 
medications with the least systemic exposure (i.e., local therapy) are preferred. Strongly 
recommended medications for the treatment of knee OA include topical nonsteroidal anti-
inflammatory drugs (NSAIDs) as  first choice (to be considered prior to use of oral NSAIDs, 
particularly in patients with more limited disease), oral NSAIDs, and IA glucocorticoid injections, 
whereas topical capsaicin, acetaminophen, duloxetine, and tramadol are conditionally 
recommended (Bannuru et al. 2019; Kolasinski et al. 2020). For oral NSAIDs (the mainstay of the 
pharmacologic management of OA), doses should be as low as possible, and treatment should be 
continued for as short a time as possible (Kolasinski et al. 2020).  
Topical NSAIDs have a moderate effect on pain, with efficacy similar to that of oral NSAIDs; 
however, due to the low systemic absorption, they have a much better safety profile (Rannou et al. 
2016). A meta-analysis of 215 randomized controlled trials (RCTs) (41,392 participants) found 
that the overall treatment effect for pain was the largest with topical NSAIDs (effect size [ES]=1.37, 
95% CI 1.19 to 1.55), of which 0.85 (95% CI 0.77 to 0.93) was attributable to contextual effect 
(i.e., ES of the placebo group) (Zou et al. 2016). The most common adverse events (AEs) 
associated with topical NSAIDs are local skin reactions, which are minor, and transient (Bannuru 
et al. 2019). 
2.2. 
Background on Oral Celecoxib 
Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide), a 
cyclooxygenase (COX)-2 selective inhibitor, belongs to the pharmacological class of NSAIDs. 
Celecoxib has established analgesic, anti-inflammatory, and antipyretic properties. 
Celecoxib capsules for oral use are indicated (in the U.S. and Canada) for relief of symptoms 
associated with OA, adult rheumatoid arthritis (RA), and ankylosing spondylitis (Celebrex CPM 
2022; Celebrex USPI 2021). Additional approved indications include the short-term (≤7 days) 


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management of moderate to severe acute pain in adults (in conditions such as musculoskeletal 
and/or soft tissue trauma including sprains, postoperative orthopedic, and pain following dental 
extraction) in Canada (Celebrex CPM 2022), and Juvenile Rheumatoid Arthritis (JRA) in patients 
2 years and older, and primary dysmenorrhea in the U.S. (Celebrex USPI 2021). The recommended 
(and maximum) daily oral dose is 200 mg administered as a single dose or as two divided doses 
(100 mg twice per day) (Celebrex CPM 2022; Celebrex USPI 2021). 
2.2.1. 
Clinical Experience with Oral Celecoxib 
The clinical efficacy of oral celecoxib in the treatment of the signs and symptoms of OA have been 
demonstrated in placebo- and active-controlled clinical trials of up to 12 weeks duration (Celebrex 
CPM 2022; Celebrex USPI 2021). Approval for the OA indication was granted based on five 
pivotal RCTs, including three 12-week placebo- and active (naproxen)-controlled studies (Study 
C-020, N=1092, Study C-021, N=1214, and Study C-054, N=1060), and two 6-week placebo-
controlled studies (Study C-060, N=684, and Study C-087, N=715), as well as five supportive 
RCTs (FDA Statistical Review 1998; Moore et al. 2005).  In patients with OA, treatment with 
celecoxib 100 mg twice daily or 200 mg once daily resulted in improvement in Western Ontario 
and McMaster Universities (WOMAC) OA index, a composite of pain, stiffness, and functional 
measures in OA. In three 12-week studies of pain accompanying OA flare, celecoxib doses of 100 
mg twice daily and 200 mg twice daily provided significant reduction of pain within 24 to 48 hours 
of initiation of dosing.  Doses of 200 mg twice daily provided no additional benefit above that seen 
with 100 mg twice daily (Celebrex CPM 2022; Celebrex USPI 2021). A total daily dose of 200 
mg has been shown to be equally effective whether administered as 100 mg twice daily or 200 mg 
once daily (Williams et al. 2000; Williams et al. 2001; Celebrex CPM 2022; Celebrex USPI 2021). 
Response to oral celecoxib was independent of age, gender, severity, or duration of OA (Celebrex 
CPM 2022). 
Significant pain reductions as measured on the Likert version of WOMAC Pain Subscale were 
also demonstrated in short-term (6-week) randomized, placebo-controlled trials, with mean 
treatment differences (oral celecoxib compared vs placebo) generally around -1.5 to -1.6 (Williams 
et al. 2000; McKenna et al. 2001; Rother et al. 2007), and occasionally higher (Gibovsky et al. 
2003; Essex et al. 2014). 
A systematic review and meta-analysis of 36 published RCTs involving 17,206 adult patients with 
OA of the knee(s) or hip(s) (9402 exposed to celecoxib 200 mg/day) found that oral celecoxib was 
statistically significantly superior to placebo in reducing pain, as assessed by the WOMAC visual 
analogue scale (VAS) Pain Subscale score at 6 weeks (mean difference [MD] -3.28, 95% CI -4.51 
to -2.06, P < 0.001; 12 studies, 4178 participants); 12 weeks (standardized mean difference [SMD] 
-0.32; 95%CI -0.40 to -0.23, P < 0.001; 9 studies, 3328 participants); 13 weeks (MD -1.06, 95% 
CI -1.31 to -0.80, P < 0.001; 5 studies, 3853 participants); and 24 weeks (MD -13.1, 95%CI -24.69 
to -1.51, P = 0.03; 1 study, 631 participants) (Puljak et al. 2017).   
A detailed description of the chemistry, pharmacology, efficacy, and safety of oral celecoxib is 
provided in the Celebrex Product Monograph (Celebrex CPM 2022). 


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2.3. 
Background on G001 (Celecoxib Gel 4% for Topical Administration) 
G001 is a novel gel formulation of celecoxib for topical administration being developed by Buzzz 
Pharmaceuticals Ltd., Ireland (hereunder referred to as Buzzz or Sponsor) for the treatment of 
signs and symptoms of OA of the knee and hand.  
The following sections provide a brief overview of the nonclinical and clinical experience with 
G001. Further details, including a description of the chemistry and pharmacology of the product, 
is provided in the G001 Investigator’s Brochure (G001 IB, 2022). 
2.3.1. 
Nonclinical Experience with G001 
Data generated in nonclinical models suggest topical application of celecoxib in a gel formulation 
is effective and well tolerated. In a 5-day study in a rat model of RA, described in the literature, 
topically administered celecoxib (1%) in two different gel formulations reduced signs of arthritis 
(arthritis index, dermatological sum score, histopathology) compared to control (Nirbhavane et al. 
2018). In another study, topical administration of 8% celecoxib gel significantly reduced pain 
scores at 24.5 and 30.5 hours in a sodium urate model of joint inflammation in Beagle dogs, 
although there was no effect on edema by this route (Baranowski et al. 2018). The average 
concentrations of celecoxib were similar in the serum and synovial fluid (220.9±92.7 ng/mL and 
203.0±0.3 ng/mL, respectively) in a Beagle dog study following 7 days of topical administration.  
After a 7-day washout, concentrations decreased, but not significantly, suggesting slow clearance 
of celecoxib. 
The Sponsor conducted additional nonclinical toxicology studies to support the clinical study for 
the celecoxib gel formulation. In in vitro local tolerance studies, G001 at concentrations of 3% and 
4% showed no evidence of eye hazard in isolated bovine corneas.  In in vivo local tolerance studies, 
G001 4% topical gel showed no sensitization effects following repeat administration in albino 
guinea pigs. Additionally, there were no adverse clinical signs, changes in body weight or food 
consumption, or signs of skin irritation following 10- or 28-day administration (4 doses per day) 
in Göttingen minipigs. 
2.3.2. 
Clinical Experience with G001 
One double-blind, randomized, parallel-group, single- and multiple-dose study (Study 2019-4679) 
evaluated the clinical safety, tolerability, and pharmacokinetics (PK) of Celecoxib Gel 1.5% and 
4% under single- and multiple dose conditions in healthy volunteers. The study was completed in 
two consecutive parts.  
2.3.2.1. 
Study 2019-4679 Design and Assessments 
In Part I, 18 adult male and female subjects were randomized to receive a single application of the 
investigational medicinal product (IMP; Celecoxib Gel 1.5% [Treatment A] or Celecoxib Gel 4% 
[Treatment B]); see Table 1. Concentrations of celecoxib were measured in plasma from PK blood 
samples collected over a 168-hour interval following IMP application and from urine samples 
collected over a 48-hour interval postdose. Using these data, maximum measured plasma analyte 
concentration (Cmax), area under the concentration versus time curve for the interval from time 
zero to the last measurable time point (AUCt), AUC from time zero to infinity (AUCinf), time of 
the maximum measured plasma analyte concentration (Tmax), apparent first-order elimination rate 


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constant (Kel), elimination half-life (T1/2), urinary excretion over 48 hours (Ae48), and percent drug 
recovered were estimated using a noncompartmental approach.  
Upon conclusion of Part I, an interim review of the PK and safety data was completed by the study 
data monitoring committee (DMC).  
Part II was conducted in two cohorts, each consisting of 24 male and female subjects. The 
treatment schedule for the two cohorts is detailed in Table 1. For both cohorts, PK blood samples 
were collected over a 24-hour interval on days 1 and 7, and one sample was taken on each of the 
following study days: 5, 6, 10, 14, 21, 28, and 35. Last measured plasma analyte concentration 
(Cmin), Cmax, AUC from time zero to 24 hours (AUC24), average plasma concentration (Cav), Tmax, 
fluctuation, urinary excretion over 24 hours (Ae24), and percent drug recovered were estimated 
using a noncompartmental approach for day 1 and day 7. Ae24 was determined based on urine 
samples collected up to 24 hours following the first drug application on days 1 and 7. 
Table 1 G001 Treatment Regimens in Phase 1 Study 2019-4679  
Study Part  Cohort 
Treatment 
Group 
Dosing Regimen 
Part I 
Single-dose 
N/A 
Treatment A 
Single application of 4 ± 0.10 g of Celecoxib Gel 1.5% to each knee 
(total of ~8 g containing 120 mg of celecoxib) 
Treatment B 
Single application of 4 ± 0.10 g of Celecoxib Gel 4% to each knee (total 
of ~8 g containing 320 mg of celecoxib) 
Part II 
Multiple-
dose 
Cohort 1 
Treatment C 
4 daily applications of 4 ± 0.10 g of Celecoxib Gel 1.5% to the left knee 
(total of ~16 g containing 240 mg of celecoxib daily) for 7 days 
Treatment D 
4 daily applications of 4 ± 0.10 g of Celecoxib Gel 4% to the left knee 
(total of ~16 g containing 640 mg of celecoxib daily) for 7 days 
Cohort 2 
Treatment E 
4 daily applications of 4 ± 0.10 g of Celecoxib Gel 1.5% to each knee, 
and 2 ± 0.10 g to each hand (total of ~48 g containing 720 mg of 
celecoxib daily) for 7 days 
Treatment F 
4 daily applications of 4 ± 0.10 g of Celecoxib Gel 4% to each knee, and 
2 ± 0.10 g to each hand (total of ~48 g containing 1920 mg of celecoxib 
daily) for 7 days 
In both parts, safety was assessed throughout the study; parameters included the frequency of 
treatment-emergent adverse events (TEAEs) and their severity and relationship to the IMP, clinical 
laboratory abnormalities, vital signs abnormalities, and electrocardiogram (ECG) abnormalities. 
In addition, subjects underwent skin irritation assessments (comprised of a dermal response 
scoring system and other effects scoring system) at 24 hours after the IMP application in Part I, 
and approximately 24 hours after the first IMP application of day 1 and approximately 12 hours 
after the last IMP application of day 7 in Part II. 
2.3.2.2. 
Study 2019-4679 Summary of Results 
A total of 66 healthy adult subjects received IMP during the study; 18 subjects received a single 
dose of IMP in Part I, and 48 subjects received multiple doses of IMP over 7 days in Part II. 
PK Summary 
A summary of celecoxib PK parameters following administration of single (Part I) and multiple 
doses of celecoxib (Part II) is provided in Table 2. The following overview focuses on the highest 


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dose of Celecoxib Gel (i.e., 4%) administered under single (Treatment B) and multiple dose 
conditions (Treatment D and Treatment F).  
Following single administration of Celecoxib Gel 4% (Treatment B), the average peak exposure, 
as measured by mean Cmax, was 0.747 ng/mL (Coefficient of Variation [CV], 92%). This value is 
approximately 940 times lower than the peak exposure measured following a single oral dose of 
celecoxib 200 mg (705 ng/mL) (Davies et al. 2000; Celebrex CPM 2022). In Treatment group D 
(i.e., a dose schedule most closely resembling that in the planned Phase 2 study), mean Cmax was 
1.212 ng/mL (CV 36%) on Day 1, and 2.477 ng/mL (CV 62%) on Day 7. At the highest dose 
intensity administered in Treatment F (~48 grams of Celecoxib Gel containing 1920 mg of 
celecoxib applied daily), mean Cmax was 3.210 ng/mL (CV 62%) on Day 1, and 7.375 ng/mL (CV 
59%) on Day 7 (data not shown in Table 2). Published PK data for oral celecoxib 200 mg 
administered under similar multiple-dose conditions are not available; however, the Cmax levels 
detected following administration of Celecoxib Gel 4% on Day 1 in Treatment groups D and F 
respectively, were approximately 582 and 220 times lower than the peak exposure measured 
following a single oral dose of celecoxib 200 mg.  
Following single administration of Celecoxib Gel 4% (Treatment B), the average systemic 
exposure of celecoxib, as measured by mean AUCt and AUCinf, was 48.165 ng·h/mL (CV 70%) 
and 52.880 ng·h/mL (CV 56%), respectively. In comparison, the reported mean AUC value 
measured following a single oral dose of celecoxib 200 mg was 7830 ng·h/mL (Davies et al. 2000), 
i.e., approximately 148 to 163 times higher. 
Mean Tmax and T1/2 were approximately 42 and 49 hours, respectively, after a single application of 
Celecoxib Gel 4% (Treatment B) compared to 2.8 and 11.2 hours, respectively, following a single 
oral dose of celecoxib 200 mg) (Davies et al. 2000; Celebrex CPM 2022).  
The percent of celecoxib recovered in the urine over 48 hours was negligible after a single 
application of Celecoxib Gel at either dose strengths.  
Table 2 Summary of Celecoxib PK Parameters Following Administration of G001, Study 
2019-4679  
 
Part I 
Part II, Cohort 1 
Part II, Cohort 2 
 
A 
 N = 9 
B 
 N = 9 
C 
 N = 12 
D 
N = 12 
E 
N = 12 
F 
N = 12 
Cmax (ng/mL) 
Arithm. Mean (CV%) 
0.276 (90) 
0.747 (92) 
1.144 (101) 1.817 (70) 4.075 (130) 5.293 (74) 
Geometric Mean 
0.198 
0.490 
0.758 
1.552 
2.495 
4.099 
AUCt (ng·h/mL) 
Arithm. Mean (CV%) 
15.052 (72) 48.165 (70) 
- 
- 
- 
- 
Geometric Mean 
12.059 
34.852 
- 
- 
- 
- 
AUCinf (ng·h/mL) Arithm. Mean (CV%) 
14.856 (73) 52.880 (56) 
- 
- 
- 
- 
Geometric Mean 
12.202 
44.597 
- 
- 
- 
- 
AUC24 (ng·h/mL) 
Arithm. Mean (CV%) 
2.231 (67) 
5.935 (76) 
15.912 
(111) 
25.276 
(88) 
49.897 
(110) 
79.574 
(70) 
Geometric Mean 
1.818 
3.805 
9.497 
19.087 
32.758 
61.183 
AUC24 Accumulation Ratio (Day 7 vs Day 
1) 
N/A 
N/A 
673.57 
335.51 
315.81 
302.12 
Tmax (hr), Mean (CV%) 
Day 1 
34.67 (39) 
41.93 (40) 
22.50 (10) 
24.01 (<1) 
19.01 (26) 
18.67 (25) 


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Part I 
Part II, Cohort 1 
Part II, Cohort 2 
 
A 
 N = 9 
B 
 N = 9 
C 
 N = 12 
D 
N = 12 
E 
N = 12 
F 
N = 12 
Day 7 
- 
- 
16.40 (52) 
13.45 (61) 
8.58 (89) 
10.17 (69) 
T1/2 (hr), Mean (CV%) 
Day 1 
38.60 (50) 
49.23 (40) 
- 
- 
- 
- 
CL (L/hr), Mean (CV%) 
11818.2 
(67) 
8761.2 (70) 
- 
- 
- 
- 
Ae48 (Part I) or 
Ae24 (Part II) 
(ng), Day 1 
Mean (SD) 
649.89 
(1438.69) 
751.18 
(778.69) 
444.78 
(550.89) 
4272.81 
(12691.16) 
7175.88 
(17225.88) 
7220.26 
(20487.98) 
Geometric Mean 
160.09 
337.89 
244.90 
699.91 
1002.29 
1291.72 
Ae48 (Part I) or 
Ae24 (Part II) 
(ng), Day 7 
Mean (SD) 
N/A 
N/A 
355.32 
(292.58) 
919.27 
(1440.18) 
2658.12 
(3894.88) 
11953.97 
(24260.89) 
Geometric Mean 
N/A 
N/A 
267.65 
365.26 
1256.65 
2509.50 
 
 
 
 
 
 
 
Abbreviations: Ae24 = urinary excretion over 24 hours; AUCinf = area under the concentration versus time curve for the interval 
from time zero hour to infinity; AUCt = area under the concentration versus time curve for the interval from zero hour to the last 
measurable time point; AUC24 = area under the concentration versus time curve for the interval from zero hour to 24 hours; CL=the 
apparent total body clearance of drug after topical application (CL=Dose/AUCinf); Cmax = maximum measured plasma analyte 
concentration; CV=coefficient of variation; SD=standard deviation; Tmax = time of the maximum measured plasma analyte 
concentration; T1/2 = elimination half-life 
Values are rounded to 3 decimal places. 
Safety Summary 
The administration of the IMP was generally well tolerated. No deaths or serious adverse events 
(SAEs) occurred during the study. The proportion of subjects who experienced at least one TEAE 
was 28% in Part I (Treatment A: 22%; Treatment B: 33%), 75% in Part II, Cohort 1 (Treatment C 
and D: 75% each), and 33% in Part II, Cohort 2 (Treatment E: 25%; Treatment F: 42%); refer to 
Table 3 for details. All TEAEs reported during the study were mild in severity. With the exception 
of 1 TEAE of urticaria for which the event outcome was unknown (subject was lost to follow-up), 
all TEAEs resolved prior to end-of-study (EOS). Four of 66 (6%) subjects (all in Part II, Cohort 
1) were taking concomitant medications during the study, for the treatment of AEs (most 
commonly fever). 
Table 3 Summary of Treatment-Emergent Adverse Events Reported in Study 2019-4679  
 
 Reported Incidence by Treatment Group 
n (%) of Subjects  
 
Part I 
Part II, Cohort 1 
Part II, Cohort 2 
 
A 
 N = 9 
B 
 N = 9 
C 
 N = 12 
D 
N = 12 
E 
N = 12 
F 
N = 12 
Any TEAEs 
2 (22.2%) 
3 (33.3%) 
9 (75.0%) 
9 (75.0%) 
3 (25.0%) 5 (41.7%) 
Drug-related AEs 
2 (22.2%) 
3 (33.3%) 
2 (16.7%) 
2 (16.7%) 
0 (0%) 
1 (8.3%) 
Application site adverse reactions 
0 (0%) 
2 (22.2%) 
2 (16.7%) 
2 (16.7%) 
0 (0%) 
1 (8.3%) 
SAEs 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
AEs leading to early discontinuation a 
0 (0%) 
0 (0%) 
2 (16.7%) 
1 (8.3%) 
0 (0%) 
0 (0%) 
Drug-related AEs leading to discount. 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
Severe TEAEs 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
 


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 Reported Incidence by Treatment Group 
n (%) of Subjects  
 
Part I 
Part II, Cohort 1 
Part II, Cohort 2 
 
A 
 N = 9 
B 
 N = 9 
C 
 N = 12 
D 
N = 12 
E 
N = 12 
F 
N = 12 
TEAEs Occurring at a Frequency of 
≥10% in any Treatment Group 
 
 
 
 
 
 
 
     Application site erythema 
0 (0%) 
1 (11.1%) 
2 (16.7%) 
2 (16.7%) 
0 (0%) 
1 (8.3%) 
     Application site rash 
0 (0%) 
1 (11.1%) 
0 (0%) 
0 (0%) 
0 (0%) 
0 (0%) 
     Headache 
1 (11.1%) 
1 (11.1%) 
1 (8.3%) 
0 (0%) 
0 (0%) 
0 (0%) 
     Heart rate increased 
0 (0%) 
0 (0%) 
4 (33.3%) 
3 (25.0%) 
0 (0%) 
0 (0%) 
     Influenza like illness 
0 (0%) 
0 (0%) 
2 (16.7%) 
0 (0%) 
0 (0%) 
0 (0%) 
     Nasal congestion 
0 (0%) 
1 (11.1%) 
1 (8.3%) 
0 (0%) 
0 (0%) 
0 (0%) 
     Neutrophil count decreased 
1 (11.1%) 
0 (0%) 
0 (0%) 
2 (16.7%) 
0 (0%) 
0 (0%) 
     Pyrexia 
1 (11.1%) 
0 (0%) 
3 (25.0%) 
1 (8.3%) 
0 (0%) 
0 (0%) 
     White blood cell count decreased 
1 (11.1%) 
0 (0%) 
0 (0%) 
2 (16.7%) 
0 (0%) 
0 (0%) 
Abbreviations: AE=adverse event; SAE=serious adverse event; TEAE=treatment-emergent adverse event 
 
Part I 
All 18 subjects randomized in Part I completed the study as per protocol. An overall summary of 
TEAEs is provided in Table 3.  
Drug-related AEs: Five subjects (28%) experienced 7 TEAEs that were deemed possibly related 
to the IMP. Two subjects (22%) in Treatment A experienced drug-related TEAEs of headache, 
pruritus, neutrophil count decreased, and white blood cell decreased, and 3 subjects (33%) in 
Treatment B experienced 3 drug-related TEAEs of application site erythema, application site rash, 
and headache. One subject who had neutrophil count decreased and white blood cell decreased 
after Treatment A presented with low leukocytes and neutrophils at Baseline.  
Other Safety Assessments: There were no consistent and clinically meaningful changes in mean 
laboratory values over time. Increases of >10% in mean serum bilirubin levels were detected in 
both Treatments A and B; however, all mean bilirubin levels remained within normal range. There 
were no consistent and clinically meaningful changes in mean vital signs or ECG parameters, 
including no indication of QT or QTcB prolongation, and no individual clinically significant (CS) 
vital signs or ECG abnormalities were reported as AEs. All physical examinations results were 
reported as normal in Part I.  
Skin Irritation: Skin irritation was evaluated approximately 24 hours after the IMP application and 
showed a Dermal Response Score of 0 (no evidence or irritation) and no “Other” effects, yielding 
mean ± SD Cumulative Irritation Scores of 0 ± 0  in both treatment groups. 
Part II,  Cohort 1 
Ten of 12 subjects (83.3%) randomized to Treatment C, and 11 of 12 subjects (91.7%) randomized 
to Treatment D completed treatment as per protocol. Three subjects (12.5%) discontinued due to 
TEAEs, including two subjects who received Treatment C (pyrexia and influenza like illness in 
one subject and pyrexia in the second subject), and one subject who received Treatment D (pyrexia 
and feeling hot). All five events were assessed by the Investigator as unrelated to the IMP.  
An overall summary of TEAEs is provided in Table 3. 


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Drug-related AEs: Eleven TEAEs occurred in 4 subjects (16.7%) and were assessed as drug-
related. All events were application site adverse reactions; 2 subjects in Treatment C experienced 
7 drug-related TEAEs (three events each of application site erythema and application site pain, 
and one event of application site hypersensitivity), and 2 subjects in Treatment D experienced 4 
drug-related TEAEs (two events of application site erythema, and one event each of application 
site hypersensitivity and application site irritation).  
Other Safety Assessments:    
Changes >10% in mean serum bilirubin (increase), leukocytes, and neutrophils (reduction) were 
detected with in both treatments treatment groups throughout the study; changes were also detected 
in mean transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), 
and triglycerides levels at some of the assessments timepoints for Treatment D. However, the 
clinical relevance of these changes is considered minimal, and none are indicative of a safety 
concern related to the IMP. Five subjects (21% of subjects dosed in Part II, Cohort 1) exhibited a 
total of 14 CS laboratory values that were reported as AEs. The frequency of these events was 
similar in the two groups (C and D). The most common CS laboratory abnormalities were white 
blood cell count decreased and neutrophil count decreased (2 subjects [8.3% of subjects in Part II, 
Cohort 1], 3 events each) following Treatment D. All laboratory AEs in Part II, Cohort 1 were 
assessed by the Investigator as mild and unrelated or unlikely related to the IMP. 
Increases in mean (and median) pulse rate were observed, including increases >20% at some 
assessment timepoints with both treatments (C and D). There were no other consistent or clinically 
meaningful changes in mean vital signs measurements. Clinically significant vital signs 
abnormalities (reported as AEs) occurred in 10 subjects (41.7%) treated in Part II, Cohort 1, and 
included heart rate increased (4 [33.3%] subjects in Treatment C and 3 [25.0%] subjects in 
Treatment D), pyrexia (3 subjects [25.0%] and 1 subject [8.3%], respectively), and blood pressure 
increased (0 and 1 subject [8.3%], respectively). All CS vital sign abnormalities were assessed by 
the Investigator as mild and unrelated to the IMP. 
There were no consistent or clinically meaningful changes over time in any of the ECG parameters, 
including no indication of QT or QTcB prolongation with either Treatment C or D. One CS ECG 
abnormality was detected in each group: electrocardiogram PR prolongation in one subject in 
Treatment C, and heart rate decreased in one subject in Treatment D. Both events started >6 days 
after IMP application, resolved within 7 days without intervention, and were assessed by the 
Investigator as mild and unrelated to the IMP. Clinically significant physical examination 
abnormalities (reported as AEs) occurred in two subjects in Treatment C (application site dryness 
and nasal congestion). 
Skin Irritation: Mean ± SD Cumulative Irritation Scores were 0.0 ± 0.0 in both groups (Treatment 
C and Treatment D) on Day 2 (approximately 24 hours after the first IMP application), and 0.1 ± 
0.32 in the Treatment C group and 0.0 ± 0.0 in the Treatment D group on Day 8 (approximately 
12 hours after the last IMP application). One subject (8.3%) in Treatment C had a Dermal Response 
Score of 1 (minimal erythema, barely perceptible), with an A(0) designation (defined as slightly 
glazed appearance) for “Other” Effects on Day 8. 
Part II, Cohort 2 
All 24 subjects randomized in Part II, Cohort 2 completed the study as per protocol. An overall 
summary of TEAEs is provided in Table 3. 


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Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
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Drug-related AEs: One subject (4.2%; Treatment F) experienced two TEAEs that were assessed 
as possibly related to the IMP; both were application site adverse reactions (application site 
erythema and application site dryness). 
Other Safety Assessments:    
At some of the assessments timepoints, increases >10% in mean serum bilirubin values were 
detected with both treatments (E and F) and reductions in mean neutrophil and leukocyte values 
were detected with Treatment F. However, apart from a borderline elevation in one subject, all 
bilirubin levels remained within normal range. Overall, these changes are of minimal clinical 
relevance and are not indicative of a safety concern related to the IMP. 
There were no consistent or clinically meaningful changes over time in any of the ECG parameters, 
including no indication of QT or QTcB prolongation with either treatment (E or F). Clinically 
significant ECG abnormality occurred in 1 subject (8.3%) in Treatment E (supraventricular 
extrasystoles 27 days after the last IMP application; assessed as mild and unrelated to the IMP). 
No clinically significant ECG abnormality occurred with Treatment F. All physical examination 
results were reported as normal in Part II, Cohort 2. 
Skin Irritation: Mean ± SD Cumulative Irritation Scores were 0.0 ± 0.0 in both groups (Treatment 
E and Treatment F) on Day 2 (approximately 24 hours after the first IMP application), and 0.0 ± 
0.0 in the Treatment E group, and 0.08 ± 0.29 in the Treatment F group on Day 8 (approximately 
12 hours after the last IMP application). One subject (8.3%) in Treatment F had a Dermal Response 
Score of 1 (minimal erythema, barely perceptible), with no “Other” effects on Day 8. 
The following is a complete list of application site reactions reported in Study 2019-4679: 
application site erythema, application site hypersensitivity, application site pain, application site 
irritation, application site dryness, application site rash, or application site bruise. 
2.3.2.3. 
Blinded Interim Safety Update from Study 2020-G001 
A total of 200 (of the planned 210) patients with primary symptomatic OA of the knee have been 
randomized (1:1) to G001 or vehicle gel up to the data cut-off date of 31 August 2022. Given that 
recruitment and blinded treatment and assessments are still ongoing, the current safety update for 
this study is limited to a blinded summary of TEAE data (G001 and vehicle groups combined) as 
of the data cut-off date. 
Based on blinded safety data collected to date, the study drug (administered four times per day 
over four weeks) is well tolerated. Four patients discontinued due to an AE, including hypertension 
(assessed as mild, and possibly related to blinded study treatment), ligament sprain (moderate, 
unrelated), muscle spasms (moderate, possibly related), and vision blurred (moderate, possibly 
related). No deaths and no study drug-related SAEs have occurred during the study to date. One 
SAE (atrial fibrillation) has been reported in a 77-year-old male with a history of hypertension and 
prior palpitations (self-reported); the event was assessed as mild, and not related to the blinded 
study treatment. Other cardiac events were limited to one non-serious event of extrasystoles in a 
66-year-old female, assessed as moderate and not related to the blinded study drug. Two events of 
(worsening) hypertension (both assessed as mild, and probably related to blinded study treatment) 
required dosing interruption or discontinuation.  
In the total population of 200 randomized OA patients at the time of the data cut-off, the overall 
frequency of TEAEs was 29.0%, with headache being the most common TEAE (6.5% of patients).  
Overall, the frequency of TEAEs assessed as at least possibly related to the blinded study treatment 


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has been low (9 patients, 4.5%). Of these, only headache and hypertension were reported for more 
than one patient (2 patients, 1.0%); the remaining related TEAEs occurred in one patient (0.5%) 
each, and included muscle spasms, administration site dryness, dermatitis contact, folliculitis, and 
vision blurred. A single application site reaction (application site dryness, assessed as mild, and 
certainly related to blinded study treatment) occurred in the study to date.  
For further details, refer to the Investigator’s Brochure (G001 IB, 2022). 
2.4. 
Study Rationale 
Non-steroidal anti-inflammatory drugs, including oral celecoxib are well established treatments 
for patients with OA. The similar efficacy of topical NSAIDs to that of oral NSAIDs in the 
management of OA pain, coupled with a much better safety profile due to the low systemic 
absorption (Rannou et al. 2016) make these treatment modalities a preferred first treatment option 
for patients with OA (Kolasinski et al. 2020). G001 is a novel gel formulation of celecoxib for 
topical administration, being developed for the treatment of the signs and symptoms of knee and 
hand OA.  
In a Phase 1 double-blind, randomized, parallel-group study (Study 2019-4679), G001 (dose 
strengths of 1.5% and 4%) was generally well tolerated when administered under single-dose 
(N=18) or multiple dose conditions (N=48) in adult healthy volunteers. All AEs reported in this 
study were mild in intensity, and the majority (75%) of the IMP-related AEs were mild and 
transient application-site adverse reactions. The systemic bioavailability of celecoxib was low after 
either single- or multiple-dose applications of G001, as compared to oral administrations of 
celecoxib at the recommended dose for OA treatment (200 mg/day); refer to Section 2.3.2.2 for 
details. 
The current Phase 2 study will provide the first evaluation of the efficacy, safety, and local 
tolerability of G001 in patients with OA. The study will enroll male or female patients aged 40 
years or above with a 6-month documented history of OA of the knee, meeting ACR criteria (see 
Appendix 1), and radiologic evidence of grade 2 (mild) or grade 3 (moderate) disease according 
to Kellgren and Lawrence Radiographic Grading (see Appendix 2). The dose strength to be 
evaluated in this study (4%) was previously assessed in healthy volunteers in Study 2019-4679, 
and the dosing regimen will closely resemble that in Treatment D in Study 2019-4679, with a 
longer treatment duration (4 weeks vs 1 week). A rationale for the dose selection is provided in 
Section 4.4. 
Based on the results of this study, the Sponsor plans to further evaluate G001 in Phase 3 clinical 
trials in patients with OA of the knee and hand. 
2.5. 
Benefit/Risk Assessment 
A summary of clinical experience, including AEs reported during administration of G001 in 
healthy adult subjects enrolled in the Phase 1 Study 2019-4679 is provided in Section 2.3.2.2. 
Consistent with clinical experience with other topical NSAIDs (Bannuru et al. 2019), the 
reasonably expected AEs of G001 are local, application site reactions. Based on experience from 
Study 2019-4679, these events may include application site erythema, application site 
hypersensitivity, application site pain, application site irritation, application site dryness, 
application site rash, or application site bruise. 


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More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of G001 may be found in the Investigator’s Brochure (IB) (G001 IB, 2022). 
2.5.1. 
Risk Assessment 
An overview of the known risks associated with oral celecoxib, along with an assessment of how 
these risks may be translated to administrations of G001, and a summary of strategies employed 
in the current Phase 2 study to mitigate these risks is provided in Table 4.  
Further details about the known risks associated with oral celecoxib can be found in the approved 
Celebrex label (Celebrex CPM 2022), and about the expected risks and reasonably expected AEs 
of G001 in the IB (G001 IB, 2022). 
Table 4 Risk Assessment: Oral vs Topical Celecoxib, Including Risk Mitigation Strategies 
Known Risks Associated with 
Oral Celecoxib (Celebrex CPM 
2022) 
Clinical Experience with G001 
(Phase 1 Study 2019-4679) 
Risk Mitigation Strategy in 
the Current Clinical Study 
Risk of serious (potentially fatal) 
CV thrombotic events (such as 
myocardial infarction and stroke/ 
cerebrovascular bleeding), higher 
with longer duration of treatment, 
and in patients with ischemic 
heart disease, cerebrovascular 
disease, CHF (NYHA II-IV)    
There 
were 
no 
SAEs 
or 
thrombotic 
events, 
and 
no 
findings indicative of increased 
risk of thrombosis in Study 
2019-4679. 
[1] Patients with any condition 
that is listed as contraindication 
or warning/precaution in the 
approved 
prescribing 
information for celecoxib are 
excluded from the study; see 
Section 5.2. 
Patients 
with 
uncontrolled, 
severe 
cardiac 
disease 
are 
excluded from the study; see 
Section 5.2. 
Treatment duration is limited to 
4 weeks. 
Monitoring 
of 
coagulation 
indices during the study; see 
SoA and Appendix 5. 
Dose-dependent 
increase 
in 
sodium 
retention 
(via 
renal 
mechanism), resulting in fluid 
retention, increased BP (new 
HTN or worsening of pre-existing 
HTN) and/or exacerbation of 
CHF. 
No notable changes in individual  
or mean sodium levels over time 
were detected in Study 2019-
4679. There were no notable 
changes 
in 
mean 
BP 
measurements over time. One 
subject 
(Treatment 
D) 
experienced 
increased 
BP, 
assessed as mild and unrelated to 
the IMP. 
As listed under [1] above. 
Patients 
with 
uncontrolled, 
severe 
cardiac 
disease 
are 
excluded from the study; see 
Section 5.2. 
Monitoring 
of 
BP 
and 
electrolyte levels during the 
study; see SoA and Appendix 5. 
Risk of hypersensitivity reactions 
to celecoxib or to any of the 
components/excipients, including 
No systemic hypersensitivity 
reactions occurred in Study 
2019-4679. 
As listed under [1] above. 
Patients with known sensitivity 
to celecoxib, or any other 
NSAID, 
or 
menthol 
are 


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Known Risks Associated with 
Oral Celecoxib (Celebrex CPM 
2022) 
Clinical Experience with G001 
(Phase 1 Study 2019-4679) 
Risk Mitigation Strategy in 
the Current Clinical Study 
potentially fatal anaphylactoid 
reactions and angioedema. 
excluded from the study; see 
Section 5.2. 
Serious GI toxicity (sometimes 
fatal), such as peptic / duodenal 
ulceration, 
inflammation, 
perforation, 
obstruction, 
and 
gastrointestinal bleeding. The risk 
is increased 10-fold in patients 
with a prior history of peptic 
/duodenal ulcer disease and/or GI 
bleeding. 
No cases of GI ulceration, 
inflammation, 
perforation, 
obstruction, or bleeding, and no 
other severe GI events occurred 
in  Study 2019-4679. 
As listed under [1] above. 
Patients 
with 
documented 
gastroduodenal ulcer or GI 
bleeding within the last 6 
months or presence of other GI 
disorder that could put the 
patient at increased risk, and 
alcohol abuse within the past 
year are excluded from the 
study; see Section 5.2. 
Treatment duration is limited to 
4 weeks. 
(GI bleeding:) Monitoring of 
coagulation indices during the 
study; see SoA and Appendix 5. 
Persistent 
urinary 
symptoms 
(bladder pain, dysuria, urinary 
frequency), hematuria or cystitis 
One 
subject 
(Treatment 
C) 
experienced 
urine 
analysis 
abnormal (including bacteria and 
leukocytes in urine), assessed as 
mild and unrelated to the IMP. 
As listed under [1] above. 
Safety 
laboratory 
testing 
includes urinalysis during the 
study; see SoA and Appendix 5. 
Anemia 
and 
other 
blood 
dyscrasias 
(neutropenia, 
leukopenia, 
thrombocytopenia, 
agranulocytosis) 
One subject each receiving 
Treatment 
C, 
E 
and 
F 
experienced 
haematocrit 
decreased 
and 
haemoglobin 
decreased, 
and 
1 
subject 
receiving 
Treatment 
F 
experienced red blood cell count 
decreased; all assessed as mild, 
and unrelated to the IMP.  
Mild reductions >10% in mean 
leukocytes, and neutrophils were 
detected with Treatments C, D, 
and F. AEs of white blood cell 
count decreased and neutrophil 
count decreased occurred in one 
subject receiving Treatment A 
(also 
present 
pre-treatment; 
assessed as mild and possibly 
related to the IMP), and 2 
subjects receiving Treatment D 
(assessed as mild, and unlikely 
related to the IMP). 
As listed under [1] above. 
Patients with hemoglobin levels 
<10 g/dL are excluded from the 
study; see Section 5.2. 
Hematology testing during the 
study; see SoA and Appendix 5. 


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Known Risks Associated with 
Oral Celecoxib (Celebrex CPM 
2022) 
Clinical Experience with G001 
(Phase 1 Study 2019-4679) 
Risk Mitigation Strategy in 
the Current Clinical Study 
Severe 
hepatic 
reactions, 
including liver 
necrosis 
and 
hepatic 
failure 
(with 
fatal 
outcomes 
or 
requiring 
liver 
transplant), fulminant hepatitis 
(with fatal outcome), cholestatic 
hepatitis (with fatal outcome) and 
jaundice [rare cases] 
Abnormal liver function tests: 
borderline elevations of one or 
more liver enzyme tests (AST, 
ALT, ALP) may occur in up to 
15% of patients 
Mild increases >10% in mean 
transaminases (ALT and AST) 
were observed with Treatment D 
at some of the assessments 
timepoints. Elevated ALT (up to 
140 IU/L) and AST (up to 341 
IU/L) occurred in 1 subject 
receiving 
Treatment 
C; 
the 
events were assessed as mild, 
and unrelated to the IMP.  
As listed under [1] above. 
Patients with severe hepatic 
disease, 
and 
patients 
with 
screening AST, ALT, or GGT 
levels ≥ 2 times the ULN are 
excluded from the study; see 
Section 5.2. 
Safety 
laboratory 
testing 
includes liver function tests 
during the study; see SoA and 
Appendix 5. 
As a standard precautionary 
measure, this protocol includes 
liver chemistry stopping criteria 
and reporting requirements; see 
Section 7.1.1. 
Severe renal impairment: acute 
interstitial nephritis, hematuria, 
low 
grade 
proteinuria 
and 
occasionally nephrotic syndrome 
and acute glomerulonephritis; 
renal insufficiency in patients 
with pre-renal conditions 
(Fluid and electrolyte balance: see 
above) 
There were no AEs or laboratory 
findings indicative of renal 
impairment in Study 2019-4679. 
As listed under [1] above. 
Patients 
with 
severe 
renal 
disease 
and 
patients 
with 
screening serum creatinine ≥ 1.5 
times the are excluded from the 
study; see Section 5.2. 
Serious skin reactions, some of 
them fatal, including exfoliative 
dermatitis, 
Stevens-Johnson 
syndrome, and toxic epidermal 
necrolysis [rare cases] 
No 
severe 
skin 
reactions 
occurred in Study 2019-4679. 
As listed under [1] above. 
Study assessments include skin 
irritation tests during the study; 
see SoA and Appendix 4. 
Respiratory: pneumonitis (some 
serious), ASA-induced asthma 
No respiratory AEs occurred in 
Study 2019-4679. 
As listed under [1] above. 
Patients with severe systemic 
disease are excluded from the 
study; see Section 5.2. 
Impaired fertility 
Not evaluated in Study 2019-
4679. 
As listed under [1] above. 
Patients 
who 
are 
currently 
pregnant or planning to be 
become pregnant are excluded 
from the study; see Section 5.2. 
Risk 
in 
pregnancy 
/ 
fetal 
exposure: Risk of premature 
closure of the ductus arteriosus 
and 
uterine 
inertia/prolonged 
Not evaluated in Study 2019-
4679. Pregnant subjects were 
As listed under [1] above. 
Patients 
who 
are 
currently 
pregnant or planning to be 


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Known Risks Associated with 
Oral Celecoxib (Celebrex CPM 
2022) 
Clinical Experience with G001 
(Phase 1 Study 2019-4679) 
Risk Mitigation Strategy in 
the Current Clinical Study 
parturition. Use of NSAIDS at 
approximately 
20 
weeks 
of 
gestation or later may cause fetal 
renal dysfunction leading to 
oligohydramnios and neonatal 
renal impairment or failure. 
excluded, and no pregnancy 
occurred during the study. 
become pregnant are excluded 
from the study; see Section 5.2. 
Potential for serious adverse 
reactions in nursing infants 
Not evaluated in Study 2019-
4679. 
Breastfeeding 
subjects 
were excluded from the study. 
As listed under [1] above. 
Patients who are breast-feeding 
are excluded from the study; see 
Section 5.2. 
Abbreviations: AE=adverse event; ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASA=acetylsalicylic acid; 
AST=aspartate aminotransferase; BP=blood pressure; CHF=congestive heart failure; CV=cardiovascular; GGT=gamma-
glutamyl transferase; GI=gastrointestinal; HTN=hypertension; NSAID=nonsteroidal anti-inflammatory drug; NYHA=New 
York Heart Association; SAE=serious adverse event; ULN=upper limit of normal 
2.5.2. 
Benefit Assessment 
The potential benefits of participating in the current study for individual participants may include 
the following: 
• Potential benefit of receiving study treatment during the 4-week study duration that may have 
clinical utility  
• Contributing to the process of developing new therapies in an area of unmet need  
• Medical evaluations/assessments associated with study procedures (e.g., physical exam, ECG, 
safety laboratory evaluations, etc.) 
2.5.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to patients participating in this study, the 
potential risks identified in association with G001 are justified by the anticipated benefits that may 
be afforded to patients with OA of the knee. 


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Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
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3. 
Objectives and Endpoints  
The objective of this study is to evaluate the efficacy, safety, and local tolerability of G001 
compared to vehicle in patients with symptomatic OA of the knee. 
Specific objectives and corresponding endpoints for the study are outlined in Table 5. 
Table 5 Study Objectives and Endpoints 
Objectives 
Corresponding Endpoints  
Primary Efficacy 
 
• 
To evaluate the efficacy of 
G001 compared to vehicle in 
patients with symptomatic OA 
of the knee, as measured by the 
WOMAC Pain Subscale Score 
• 
Change from Baseline in WOMAC Pain Subscale Score at 
Week 4/EOT 
Secondary Efficacy 
 
• 
To further evaluate the efficacy 
of G001 compared to vehicle in 
patients with symptomatic OA 
of the knee, as measured by the 
WOMAC Physical Function 
Subscale,  Stiffness Subscale, 
and Total scores; 11-point pain 
NRS scores, PGA and IGA of 
disease activity and overall 
treatment benefit, and rescue 
medication use 
• 
Mean worst daytime and mean worst nighttime pain severity 
scores (11-point pain NRS, from patient diary) at Week 
4/EOT and Week 5/FV2, including mean changes from 
Baseline  
• 
Percentages of patients achieving ≥20%, ≥30%, and ≥50% 
reduction from Baseline in worst daytime pain severity scores 
(11-point pain NRS, from patient diary) at Week 4/EOT 
• 
Percentages of patients achieving ≥20%, ≥30%, and ≥50% 
reduction from Baseline in worst nighttime pain severity 
scores (11-point pain NRS, from patient diary) at Week 
4/EOT 
• 
Change from Baseline to Week 4/EOT in WOMAC Physical 
Function Subscale score  
• 
Change from Baseline to Week 4/EOT in WOMAC Total 
score  
• 
Change from Baseline to Week 4/EOT in WOMAC Stiffness 
Subscale score 
• 
Change from Baseline to Week 2 in WOMAC Total and 
Subscale scores 
• 
Change from Week 4/EOT to Week 5/FV2 in WOMAC Total 
and Subscale scores 
• 
Change from Baseline in PGA of disease activity over time 
• 
Change from Baseline in IGA of disease activity over time 
• 
PGA and IGA of overall treatment benefit at Week 2 and 
Week 4/EOT 
• 
Incidence of rescue medication use, number of doses, and 
percentage of days with any rescue medication use during the 
last week of study treatment, and overall during the study 
treatment period (between the first and last study drug dose 
dates). 


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Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
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Safety 
 
• 
To evaluate the overall safety 
of G001 in patients with 
symptomatic OA of the knee, 
as determined by AE reporting, 
vital signs and ECG 
measurements, and physical 
examinations  
• 
Frequency and severity of AEs, study drug-related AEs, 
SAEs, and AEs leading to study drug discontinuation 
• 
Changes in safety laboratory test results, vital signs 
measurements, 12-lead ECG, and physical examination 
findings 
• 
To evaluate the local 
tolerability of G001 in patients 
with symptomatic OA of the 
knee, as determined by AE 
reporting, and skin irritation 
test scores 
• 
Frequency and severity of application site AEs 
• 
Skin irritation test scores at Week 2, Week 4/EOT, and Week 
6/EOS  
 


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4. 
Study Design 
4.1. 
Overall Design 
Study 2020-G001-P2 is a Phase 2 multicenter, double-blind, randomized, parallel-group, vehicle-
controlled study to evaluate the efficacy, safety, and local tolerability of G001 compared to vehicle 
in patients with symptomatic OA of the knee.  
A total of 210 patients with primary OA of the knee and moderate OA pain are planned to be 
enrolled at approximately 10 centres located in Canada (Quebec and Ontario). Each patient’s 
participation will be approximately 7 weeks (~1 week screening, 4 weeks of treatment, and 2 
weeks of post-treatment follow-up). Additional pre-screening time (after informed consent was 
obtained) may be required for washout periods and radiological examination. The overall study 
duration (from first patient first visit [FPFV] to last patient last visit [LPLV]) is expected to be 
about 6 months. 
Following screening, prior NSAID and/or acetaminophen use will be discontinued to allow for 
washout (3 to 7 days) and symptom flare. Acetaminophen may be used as rescue medication only, 
except within 12 hours prior to the Baseline/Flare Visit #1 (FV1). Patients will be instructed to 
rate their worst daytime and nighttime pain in their Screening Diary, as well as to document any 
rescue medication (acetaminophen) used for breakthrough pain.  
Eligible patients with adequate OA pain in the index knee at the Baseline/FV1 visit will be 
randomly assigned to one of two treatment groups (Group 1: G001 4.0%; Group 2: Vehicle) in a 
1:1 allocation ratio. 
Patients will be instructed to apply 4 grams of the IMP (test or reference product) to the index knee 
(i.e., knee selected for study treatment) four times daily for four weeks. Patients will also be 
instructed to rate their worst daytime and nighttime pain in their Treatment Diary, as well as to 
document the date and time of each IMP application, and any rescue medication (acetaminophen) 
use. No rescue medication use is allowed within 12 hours prior to an efficacy assessment. 
Patients will return to the clinic twice during the treatment period for efficacy and safety 
assessments: at Week 2 (after 14 ± 1 day of study treatment), and at Week 4/End-of-Treatment 
(EOT; after 28 ± 2 days of study treatment). During these visits, patients will undergo the following 
efficacy assessments: WOMAC Index, Patient Global Assessment (PGA), Investigator Global 
Assessment (IGA), and review of patient diary. In addition, the Investigator (or qualified designee) 
will contact the patient by phone after one week of treatment (Week 1, study Day 8 ± 1), and after 
three weeks of treatment (Week 3, study Day 22 ± 1), to verify compliance with the study drug 
application and daily diary completion requirements, and to follow up on how the IMP is tolerated. 
Safety assessments will include recording of AEs and concomitant medications, safety laboratory 
tests (complete blood count [CBC], blood chemistry, coagulation tests, and urinalysis), 12-lead 
ECG, physical examination and vital signs measurements, and skin irritation testing.   
Patients will return to the clinic 3 to 7 days after the last IMP application for a second Flare Visit 
(Week 5/FV2), and within approximately 2 weeks after the last IMP application (Week 6; study 
Day 43 ± 3) for an EOS evaluation. Daily diary completion will continue (as described above) 
until the Week 5/FV2 visit.  


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Protocol 2020-G001-P2 V4.0 (December 7, 2022) 
 
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Patients who discontinue study treatment prematurely will be asked to return to the clinic for  EOT 
assessments at the time of withdrawal, and the EOS evaluations 14 ± 2 days after the last study 
drug application, unless the patient withdraws consent from any further study participation. 
4.2. 
Scientific Rationale for Study Design 
The design of this study was developed in accordance with the current Osteoarthritis Research 
Society International (OARSI) recommendations for design, conduct, and reporting of clinical 
trials for knee OA (McAlindon et al. 2015), and taking into consideration the current ACR 
guidelines for the management of OA (Kolasinski et al. 2020).  
Parallel-group, randomized, placebo-controlled trials are considered gold standard study designs, 
including in OA research (McAlindon et al. 2015). The current study will evaluate the efficacy, 
safety, and tolerability of G001 compared to the vehicle formulation. To mitigate selection bias, 
eligible patients will be randomized using an interactive web response system (IWRS) to one of 
two treatment groups in a 1:1 allocation ratio. A separate blinding protocol will be in place to 
ensure that patients and clinic staff involved in assessing the study outcomes remain unaware of 
the treatment allocation.  
A major goal of early phase efficacy studies is to enroll a well-defined, homogenous population, 
most likely to benefit from the study treatment (McAlindon et al. 2015). Therefore, the study will 
enroll adult patients at least 40 years of age, with an established diagnosis of OA of the knee 
according to standard diagnostic (ACR) criteria and a disease duration of at least 6 months. In 
addition, as recommended for studies of symptom-modifying drugs, the study population will have 
sufficiently advanced OA, with radiologic evidence of mild or moderate disease (grade 2 or 3) 
according to internationally recognized and utilized Kellgren and Lawrence Radiographic Grading 
(Kellgren and Lawrence, 1957; Petersson et al. 1997). The exclusion criteria have been defined to 
minimize interference of comorbidities with the pain and functional assessments planned in this 
study, as well as to mitigate the known risks associated with oral formulations of celecoxib.  
As recommended for studies of symptomatic response (McAlindon et al. 2015), the screening pain 
threshold has been selected to allow for detection of change between Screening and Baseline/FV1, 
as well as to optimize the chances of detecting a minimally clinically important difference (MCID) 
in the primary endpoint measure during the treatment period. The index joint (target joint for study 
treatment) will be selected based on symptom severity. To minimize the risk of pain inflation 
during the Screening period, research staff will be trained not to disclose information about the 
minimal pain thresholds to prospective study patients under any circumstances.  
Given that patient-reported outcome responses may differ between patients with unilateral and 
bilateral knee OA (Riddle and Stratford, 2013; Kahn et al. 2014; Cotofana et al. 2015), and that 
WOMAC scores are most strongly associated with pain intensity in patients with unilateral 
(compared to bilateral) pain (Riddle and Stratford, 2013), the pain threshold in the contralateral 
knee will be limited to ≤2 on the 11-point pain Numerical Rating Scale (NRS) to minimize 
interference with the assessments in the index knee.  
Symptomatic outcomes will be assessed based on WOMAC (5-point Likert format), 11-point pain 
NRS, and global assessment measures (PGA, IGA) of disease activity and treatment benefit, with 
the WOMAC Pain Subscale selected as primary endpoint measure. The WOMAC is a validated, 
and widely utilized patient-reported outcome measure of pain, stiffness, and function in patients 


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with OA of the knee or hip (Bellamy et al. 1988; Bellamy 1997; Bellamy 2002); see Section 4.3. 
Given that concomitant or rescue pain medication may improve patient-reported outcome 
assessments independent of a treatment effect, several measures will be included to control for 
these adverse influences: (1) washout periods for prior oral, intramuscular, or intra-articular 
corticosteroids; (2) discontinuation of NSAID and acetaminophen treatment at Screening (to 
prompt a flare during the Screening period); (3) prohibition of other analgesic use during the study; 
(4) standardized use of rescue medication (acetaminophen), including maximum individual dose 
and daily limits; (5) restrictions in concomitant analgesic use will continue through Week 5/FV2 
(3 to 7 days after the last IMP application), to detect changes in pain scores and in rescue 
medication use during the week after study drug discontinuation. The purpose of the Week 5/FV2 
visit is to capture any worsening in symptomatic outcomes after discontinuation of study treatment.  
4.3. 
Justification for the Primary Efficacy Measure 
The primary efficacy endpoint is the change from Baseline in WOMAC Pain Subscale Score at 
Week 4/EOT. The WOMAC 3.1 Index in 5-point Likert format will be used in this study; see 
Appendix 3. 
The WOMAC is one of the most widely utilized self-report measures of lower extremity symptoms 
and function (Bellamy et al. 1988; Bellamy 1997; Bellamy 2002). Its purpose is to assess pain, 
stiffness, and physical function in patients with hip and/or knee OA. The WOMAC has been used 
for almost 30 years in many different contexts and patient populations, and there are abundant data 
regarding its utility and measurement properties. 
The WOMAC consists of 24 items divided into 3 subscales: Pain (5 items), Stiffness (2 items), 
and Physical Function (17 items). Scoring instructions are provided in the WOMAC 3.1 User 
Guide XI. The WOMAC Pain Subscale score is derived by summing the five pain scores on the 
WOMAC OA Index (pain during walking, using stairs, in bed, sitting or lying, and standing), each 
measured on a 5-point Likert scale (0=none, 1=mild,  2=moderate, 3=severe, and 4=extreme). The 
maximum WOMAC Pain Subscale rating is 20 and higher scores indicate worse pain; refer to 
Section 8.2.1 and Appendix 3 for details.  
The WOMAC Total score is the sum of the items for all three subscales, with higher scores 
indicative of worse pain, stiffness, and functional limitations. The maximum WOMAC Total score 
is 96. 
It has been well documented that the WOMAC is a valid and reliable measure, responsive to 
change in patients with knee OA (Bellamy et al. 1988; Davies et al. 1999; Roos et al 1999; 
Bischoff-Ferrari et al. 2005; Salaffi et al. 2005).  
4.3.1.1. 
Clinically Important Differences 
In a study of patients with hip and knee OA undergoing comprehensive inpatient rehabilitation, 
the MCIDs for WOMAC global and subscale scores ranged from 0.51-1.33 (1.10 for the Pain 
Subscale) for worsening and 0.67-0.75 for improvement (0.75 for the Pain Subscale), on a 0-10 
scale (Angst et al. 2001). In a study of outpatients with knee or hip OA, the MCIDs on pain VAS 
(0-100 mm) ranged from -7.9 mm to -32.6 mm (Tubach et al. 2005). Based on these two studies, 
investigators used three definitions of MCID to calculate the frequency of clinically important 
improvement in function over 30 months in Multicenter Osteoarthritis Study (MOST) participants 


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(White et al. 2010). The three definitions were: MCID 26% (26% improvement from Baseline), 
MCID 17% (17% improvement from Baseline), and MCID tertiles (low, medium, and high, based 
on pre-specified criteria). In that study, 24-39% of participants reached MCID based on these 
criteria (White et al. 2010), suggesting that a clinically important improvement is frequent in 
individuals with or at high risk for knee OA. MCID values must be viewed cautiously because of 
limitations in methodology for calculating these values and should not be considered absolute 
thresholds. 
On the basis of the Osteoarthritis Research Society International–Outcome Measures in 
Rheumatology (OMERACT-OARSI) responder criteria, the authors of a recent systematic review 
and network meta-analysis (Bannuru et al. 2015) of pharmacologic interventions in knee OA 
prespecified an absolute change of 20 points on a scale of 0 to 100 as clinically significant 
improvement (Pham et al. 2004). 
4.4. 
Justification for Dose 
The current Phase 2 study will evaluate the efficacy, safety, and local tolerability of G001 
(Celecoxib Gel 4% for topical administration) in adult patients with symptomatic OA of the knee. 
As detailed in Section 2.3.2, first-in-human evaluation of the safety, tolerability, and PK of two 
dose strengths of Celecoxib Gel (1.5% and 4%) applied under single- and multiple dose conditions 
were completed in adult healthy volunteers as part of the double-blind, randomized, parallel-group, 
single- and multiple-dose Study 2019-4679. The results of this study indicate that systemic 
exposure to celecoxib is very low following application of multiple daily doses of Celecoxib Gel 
even under maximum dose conditions (4% dose strength administered to both knees and both 
hands four times daily for seven days), and that both dose strengths are well tolerated under single- 
and multiple-dose application.  
The 4% concentration represents the high end of the concentration range for the product. The range 
was selected empirically taking into consideration the oral dose and the concentrations in topical 
formulations of other NSAIDs widely used in the treatment of acute musculoskeletal pain, as well 
as the physical properties of the drug product.  
Evidence from RCTs as well as systematic reviews and meta-analyses support the comparable 
efficacy of the recommended oral doses of celecoxib (200 mg daily) and diclofenac (150 mg daily) 
in patients with OA (McKenna et al. 2001; Bannuru et al. 2015; Puljak et al. 2017), as well as  
between oral and topical NSAIDs (Tugwell et al. 2004; Simon et al. 2009; Puljak et al. 2017). The 
celecoxib doses administered to the index knee with the application of the 4% formulation of 
Celecoxib Gel (G001) is 160 mg per individual dose, and 840 mg per day. In comparison, the 
individual and daily doses of diclofenac applied through the administration of marketed topical 
diclofenac products are approximately 32 mg and 128 mg, respectively, for diclofenac sodium 
topical solution (Pennsaid Topical Solution 1.5%), and 40 mg and 160 mg, respectively for 
diclofenac sodium gel (Voltaren Gel 1%). Overall, this data indicate that, compared to 
the approved diclofenac formulations, the celecoxib doses expected to be delivered locally (on a 
mg basis) will be about  3 to 6.6 times higher with G001.  
The considerably lower systemic exposure to celecoxib (based on Cmax and AUC24) following 
multiple (7-day) applications of G001 compared to the systemic exposure to diclofenac following 
an identical 7-day dosing regimen of diclofenac sodium gel 1% (Kienzler et al. 2010) indicate 


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that higher doses of G001 can be applied locally (for a potentially better local effect) without the 
enhanced risks of higher systemic exposure. 
4.5. 
Justification for the Reference Product / Control Group 
The reference product in this study will be the Vehicle formulation, containing all excipients of 
the G001 (including L-menthol 1.5%), but without celecoxib. L-menthol is added to the 
formulation as a solubilizer and permeation enhancer. Menthol is a widely used penetration 
enhancer in topical and transdermal formulations due to its high efficiency and relative safety 
(Joshi et al. 2017; Nagai et al. 2019). Menthol is also well known for its ability to elicit cold 
sensations. The subjective cooling effect has been reported to last up to ~80 minutes in some 
subjects (mean around an hour) (Yosipovitch et al. 1996; Lasanen et al. 2016). 
Due to the characteristic cooling effect and odor of menthol in the test formulation, a vehicle 
formulation with the same amount of menthol (as opposed to a placebo with no menthol) was 
selected as control treatment to maintain the blind of the treatment allocations.   
4.6. 
End of Study Definition 
The end of the study is defined as the date of the last scheduled study assessment (as shown in the 
SoA; Section 1.3) for the last patient in the trial.  
A patient is considered to have completed the study if he/she has completed all phases of the study, 
including the last study visit (Week 6/EOS visit) as  shown in the SoA (Section 1.3). 
 


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5. 
Study Population 
A total of 210 patients with primary OA of the knee and moderate OA pain are planned to be 
enrolled in the study.  
Prospective study patients must meet all inclusion criteria (see Section 5.1) and none of the 
exclusion criteria (see Section 5.2) to qualify for enrolment. Prospective approval of protocol 
deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, 
will not be permitted. 
5.1. 
Inclusion Criteria 
Patients must meet all of the following criteria to qualify for the study: 
1. Male or female age ≥40 years  
2. Documented diagnosis of OA of the knee, meeting ACR criteria for classification of idiopathic 
(primary) OA (see Appendix 1) for at least 6 months prior to Screening  
3. Radiologic evidence of OA of the knee of grade 2 (mild) or grade 3 (moderate) according to 
Kellgren and Lawrence Radiographic Grading (see Appendix 2) 
4. Worst daily pain (within 24 hours prior to Screening and Baseline) in the index knee between 
4 and 8 on the 11-point pain NRS  
5. On stable analgesic therapy (i.e. at least 3 days per week for at least 30 days prior to Screening) 
with an oral or topical NSAID and/or acetaminophen 
6. In reasonably good general health (apart from OA), as assessed by the Investigator 
7. Females of childbearing potential: adequate birth control and negative pregnancy test at 
Screening and Baseline.  
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached 
a postmenopausal state (≥ 24 continuous months of amenorrhea with no identified cause other 
than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, 
fallopian tubes, and/or uterus) or another cause as determined by the Investigator (e.g., 
Müllerian agenesis). 
Adequate birth control is defined as: stable dose of an oral contraceptive for at least 2 months 
prior to the first study drug administration, intrauterine device, bilateral tubal ligation, barrier 
method of contraception in conjunction with spermicidal jelly, or abstinence. 
8. Negative urine drug screen (including for cannabinoids) at Screening and Baseline 
9. Subject is willing to participate in the study, comply with the study requirements and 
voluntarily provide written informed consent.   
Additional Inclusion Criteria Assessed at Baseline/Flare Visit #1 (FV1): 
Following Screening, prior NSAID and acetaminophen use will be discontinued to allow for 
washout (3 to 7 days) and symptom flare. Acetaminophen may be used as rescue medication only, 
with the following exception: no rescue medication is allowed within 12 hours prior to the 
Baseline/FV1 visit. 


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10. Development of a flare of pain following washout of stable analgesic (NSAID and/or 
acetaminophen) therapy, defined as follows: 
a. An increase of ≥2 points (out of possible 20) from the Screening assessment in the 
WOMAC Pain Subscale score for the index knee; and 
b. A score of ≥2 points (out of possible 4) on at least one of the 5 items in the WOMAC 
Pain Subscale (for the index knee). 
5.2. 
Exclusion Criteria   
Patients who meet any of the following criteria will be excluded from the study: 
Exclusions Related to OA: 
1. Radiologic evidence of severe OA of the knee (Kellgren and Lawrence grade 4) (see Appendix 
2) 
2. Secondary OA of the index knee (such as septic arthritis, inflammatory joint disease, gout, 
articular fracture, major dysplasia, congenital abnormality, hemochromatosis) 
3. Any other arthritis, included but not limited to RA, psoriatic arthritis, etc. 
4. History of pseudo-gout or inflammatory flare-ups 
5. History of severe neurological conditions (such as multiple sclerosis, sciatica, fibromyalgia, 
etc.) 
6. Any other chronic pain conditions (e.g., back pain) or disabling conditions affecting the joints 
7. Non-ambulatory or requires the use of crutches or a walker 
8. Started using a cane within 30 days prior to Screening 
9. Worst daily pain (within 24 hours prior to Baseline/FV1) in the contralateral knee assessed as 
>2 on the 11-point pain NRS scale. 
Study Drug-Related Exclusions & Other Medical Conditions 
10. Skin disorder present at the study drug application site 
11. Presence of contraindications, warnings, or precautions (listed in the Canadian Product 
Monograph for oral celecoxib) that may put the subject at risk, as assessed by the Investigator 
12. Known sensitivity to celecoxib, any NSAID, or menthol 
13. History of aspirin-sensitive asthma 
14. History of any of the following: 
a. Known coronary artery disease or cerebral artery disease 
b. Coronary artery bypass surgery (CABG) within 1 year prior to Screening 
c. Any other severe or uncontrolled cardiovascular disease, as assessed by the Investigator 
d. Systolic blood pressure (SBP) >149 mmHg and/or diastolic blood pressure (DBP) >94 
mmHg at Screening 


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15. Severe, uncontrolled hepatic, renal, or other systemic disease, as assessed by the Investigator 
16. Any malignancy within the previous 5 years, except for superficial skin cancer not on the index 
knee, cured with local therapy  
17. Documented gastroduodenal ulcer or gastrointestinal (GI) bleeding within the last 6 months or 
presence of other GI disorder that could put the patient at increased risk or interfere with the 
interpretation of the safety results of the study 
18. Uncontrolled diabetes or diabetic neuropathy 
19. Psychiatric or psychological conditions that in the opinion of the Investigator may affect the 
subject’s pain assessments (such as depression, anxiety, pain catastrophizing, poor sleep 
quality) 
20. Any of the following abnormal Screening laboratory test results:  
a. serum creatinine ≥ 1.5 times the upper limit of normal (ULN) or Estimated Glomerular 
Filtration Rate (eGFR) < 60 mL/min/1.73 m2 (Appendix 7); 
b. AST, ALT, or gamma-glutamyl transferase (GGT) ≥ 2 times the ULN;  
c. hemoglobin < 10 g/dL 
21. Positive serology for human immunodeficiency virus (HIV) antibody, hepatitis B surface 
antigen (HBsAg), or hepatitis C virus (HCV) antibody at Screening 
22. Documented alcohol or other substance abuse within 1 year 
23. Body Mass Index (BMI) above 40 kg/m2 
24. Patients who are currently pregnant or planning to be become pregnant or are breast-feeding. 
Prohibited Prior, Current, or Planned Treatments: 
25. Any history of major surgery to the index knee, minor knee surgery, or injury to the index knee 
within 1 year prior to Screening 
26. Knee arthroscopy (index knee) within 3 months prior to Screening  
27. Planned or candidate for knee replacement or knee reconstruction surgery 
28. Treatment with or need for any of the following: (1) oral or intramuscular corticosteroids 
within the past 90 days; (2) intra-articular corticosteroid injection into the index knee within 
the past 90 days, or into any other joint within the past 30 days; (3) current use of topical 
corticosteroids on the index knee 
29. Received intra-articular viscosupplementation/hyaluronate, joint lavage, or other invasive 
therapies to the index knee in the past 90 days 
30. Prior stable therapy (defined as >3 days per week prior to the Screening) with an opioid 
analgesic, or anticipated need for opioid analgesic use during the study  
31. Use of sedative hypnotic medication, antidepressants with known analgesic effect, 
antipsychotics, antiepileptics, and anti-Parkinson drugs within the past 14 days 


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Note: "Known analgesic effect" is defined as any documented evidence of a significant effect 
on pain outcomes, and is not equivalent to an approved indication or proven efficacy. 
32. Regular use of medication for headaches (≥10 days within 30 days prior to Screening) 
33. Use of another investigational drug within the previous 30 days or five half-lives of the 
investigational product, whichever is longer 
34. Use of any oral or topical NSAID (apart from the IMP) is prohibited during the study 
35. Receipt of a coronavirus 2019 (COVID-19) vaccine within 7 days prior to Screening, or 
anticipated during the study (between Screening and Week 5). 
Patients who received their first dose of the vaccine may be enrolled as long as their second 
dose is scheduled later than the planned Week 5 study visit. The dates of the first and second 
COVID-19 vaccine dose (actual or planned) should be documented in the patient’s study file. 
Additional Exclusion Criterion Assessed at Baseline/FV1: 
36. Non-compliance with the daily diary requirement during the 7-day Screening period (defined 
as <3 days of daily or nightly pain assessments or <3 days of rescue medication entries). 
5.3. 
Lifestyle Considerations 
Patients should abstain from the following during their study participation: 
• Smoking / use of tobacco products  
• Alcohol and/or recreational drug consumption 
• Changes from their routine exercise level (between Screening and the Week 6/EOS visit) 
There are no meal or dietary restrictions for study participants. 
5.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomly assigned to study treatment. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details 
(date, eligibility criteria failed, or other reason), and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failures) will not be 
rescreened.  


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6. 
Study Treatment and Concomitant Therapy 
Study intervention is defined as any investigational medicinal product (IMP) or non-
investigational medicinal product (NIMP) intended to be administered to a study participant 
according to the study protocol. 
G001 (Celecoxib 4% gel for topical administration) and Vehicle gel (placebo) are IMPs in this 
study. All IMPs are manufactured by Egis Pharmaceuticals PLC, Hungary for Buzzz 
Pharmaceuticals Limited, Ireland, and will be provided by Bay Area Research Logistics (BARL), 
Canada to the study sites. G001 and Vehicle may also be referred to as ‘study treatment’ or ‘study 
drug’ in this protocol. 
Rescue medication (acetaminophen) used to manage breakthrough pain is considered NIMP in this 
study and will be supplied locally by the study site (i.e., will not supplied by the Sponsor). 
6.1. 
Overview of the Study Interventions  
 
 
 
Study interventions administered during the study are detailed in Table 6. 
 
 
Table 6 Overview of Study Interventions 
Study Arm Name 
Group 1:  
G001 
Group 2:  
Vehicle  
Groups 1 and 2 
Intervention Name 
G001 (Celecoxib Gel 
4.0%) [1] 
Vehicle (Gel) [1] 
Acetaminophen (Rescue 
medication) 
Type  
Drug 
Drug 
Drug 
Dose Formulation 
Gel for topical 
administration 
Gel for topical 
administration 
Tablet 
Unit Dose Strength(s) 
G001 (Celecoxib Gel 
4.0%), containing 
celecoxib 40 mg/g [1] 
Vehicle Gel, containing 
no celecoxib [1] 
500 mg 
Dosage Level(s) 
4 grams of the IMP 
applied to the target knee 
4 times daily for 4 weeks 
4 grams of the IMP 
applied to the target knee 
4 times daily for 4 weeks 
Maximum 500 mg per 
dose and 2,000 mg/day 
to manage breakthrough 
pain [2] 
Route of 
Administration 
Topical 
Topical 
Oral 
Use 
Experimental (Test) 
Placebo (Reference) 
Rescue medication 
IMP / NIMP 
IMP 
IMP 
NIMP 
Sourcing 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided locally by the 
study site 
Packaging and 
Labeling 
The IMP will be 
provided in 100 gram 
tubes, labeled as per local 
The IMP will be 
provided in 100 gram 
tubes, labeled as per local 
Commercially available 
packaging 


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requirements [3], 
packaged according to 
the randomization 
scheme [4], and 
distributed by BARL  
requirements [3], 
packaged according to 
the randomization 
scheme [4], and 
distributed by BARL  
Abbreviations: BARL=Bay Area Research Logistics, Hamilton, ON, Canada; IMP=Investigational Medicinal 
Product; EOT=End-of-Treatment; FV1=Flare Visit #1; FV2=Flare Visit #2; NIMP=Non-investigational Medicinal 
Product 
[1] Both IMP formulations (G001 and Vehicle) contain menthol 1.5% (added to G001 as solubilizer). The reference 
product in this study (Vehicle formulation) contains all excipients of G001, but without celecoxib. 
[2] Rescue medication use is discouraged, but acetaminophen may be used, as needed, at a dose not exceeding 500 
mg per dose and 2,000 mg/day to manage breakthrough pain. No rescue medication use is permitted within 2 hours 
after each IMP application, and within 12 hours prior to each efficacy assessment (i.e., at the Screening, Baseline/FV1, 
Week 2, Week 4/EOT, and Week 5/FV2 visits). 
[3] The product name, strength, and lot/batch number will be included on each original drug container. 
[4] The IMP will be packaged in kit form: 3 x 100g tubes per kit and 12 dosing cards.  Each patient will be given 1 kit 
for each two-week period between visits. 
 
6.2. 
Study Drug Storage, Handling, Administration, and Accountability 
6.2.1. 
Study Drug Storage and Handling  
The Sponsor will supply a sufficient quantity of the study drugs to allow for completion of this 
study. The IMP will be provided in 100 gram tubes, packaged in kit form: 3 x 100 gram tubes per 
kit and 12 dosing cards.  Each patient will be given 1 kit for each two-week treatment period. 
Designated clinical staff will be responsible for monitoring the receipt, storage, and accounting of 
study drugs according to Good Clinical Practice (GCP). 
The IMP is to be transported and stored at room temperature between 15°C and 30°C. Spiking 
above 40ºC is not permitted. The Investigator or designee must confirm appropriate temperature 
conditions have been maintained during transit for all study drug received. All study drugs must 
be stored in a secure, environmentally controlled, and monitored (manual or automated) area under 
appropriate storage conditions with access limited to authorized/designated unblinded site staff. 
Any discrepancies/deviations from the above requirements are to be reported and resolved before 
use of the study drug. 
Further details will be provided in the Pharmacy Plan. 
6.2.2. 
Study Drug Dosage and Administration  
Only participants enrolled in the study may receive study treatment and only authorized site staff 
may supply or apply study drug. Application of the IMP will occur in accordance with the study-
specific Blinding Protocol; see Section 6.3.2.  
The first dose will be applied at the clinic, in the presence of a qualified unblinded treatment 
administrator; subsequent applications will be completed by the patient at the clinic (on Day 
15/Week 2 Visit) or at their home (all other applications). Patients will be dispensed a two-week 
supply of study drug (three tubes of 100 grams) on Day 1 (Baseline/FV1) and on Day 15 (Week 2 


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Visit), and will be asked to return all unused study drug supplies at the next study visit (Day 
15/Week 2 Visit, and Day 29/Week 4/EOT Visit, respectively). 
Four grams of the study drug (G001 gel or Vehicle gel) will be applied to the target knee four 
times daily for four weeks as follows:  
• 1st dose between 6 a.m. and 7 a.m.  
• 2nd dose: between 11 a.m. and  12 p.m. (~5 hours after the first dose) 
• 3rd dose: between 4 p.m. and 5 p.m. (~5 hours after the second dose) 
• 4th dose: between 10 p.m. and 11 p.m. (~6 hours after the third dose and shortly after the daily 
pain assessment) 
Note: the first study drug application (Day 1) may occur between 6 a.m. and 8 a.m. Subsequent 
application times on Day 1 may be modified accordingly, to maintain the ∼5-hour interval between 
consecutive applications. 
Accurate dosing will be ensured by using a dosing card; see Figure 2. The dosing card should be 
used for each application of study drug.  
Figure 2 Dosing Card for Study Drug 
 
Patients will be instructed to: 
• measure the gel by filling both shaded areas on the dosing card (see Figure 2); then  
• using the dosing card, apply the measured amount to the index knee (laterally, medially, and 
anteriorly: immediately proximal, and ≥4 inches or 10 cm distal to the knee; total application 
area of ~400 cm2), and massage it in over at least 1 minute to ensure adequate application over 
the affected joint; 
• replace the cap of the tube tightly after use;  
• wait ≥10 minutes before dressing; 
• avoid exercise for ≥1 hour before and after application; 
• forgo showering/bathing for ≥1 hour after application; 
• avoid contact with eyes and mouth;  


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• wash hands and the dosing card after use; 
• store the study drug at room temperature between 15°C and 30°C. 
Study treatment will continue for 4 weeks (28 ± 2 days). 
6.2.3. 
Study Drug Accountability  
The Investigator is responsible for study drug accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records) according to GCP. 
The study site will acknowledge receipt of IMPs supplied by the Sponsor by returning the 
appropriate documentation form to confirm the shipment condition and content. Any damaged 
shipments will be replaced. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by the study 
site should be recorded on a drug inventory log. 
Unused IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure (SOP) or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed to by the 
Sponsor. The site must obtain written authorization from the Sponsor before any Sponsor-supplied 
IMP is destroyed, and IMP destruction must be documented on the appropriate form. 
 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization  
To avoid bias in the assignment of patients to study treatment, increase the likelihood that known 
and unknown subject attributes (e.g., demographic and baseline characteristics) are evenly 
balanced across treatment groups, and to enhance the validity of statistical comparisons across 
treatments, treatment allocation in this study will occur through randomization.  
Eligible patients with adequate OA pain in the index knee at Baseline/FV1 will be randomly 
assigned to one of two treatment groups (Group 1: G001; Group 2: Vehicle) in a 1:1 allocation 
ratio. Randomization will occur centrally, based on a computer-generated randomization schedule, 
and using an IWRS.  
Patients discontinuing the trial after randomization will not be replaced. 
6.3.2. 
Blinding  
The Investigator and other study site personnel involved in patient assessments (safety and 
efficacy), as well as patients will remain blinded to treatment assignment throughout the course of 
the study. Because a full matching in physical appearance could not be achieved between the 
experimental and reference formulations (G001 and Vehicle), a separate Blinding Protocol will be 
in place to ensure that patients and clinic staff involved in assessing the study outcomes remain 
unaware of the treatment allocation. 


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To maintain the blind, a third party  (such as a designated pharmacist or research nurse), who is 
not otherwise involved in the patient assessments, will be responsible for the following at the study 
site:  
1) Dispensation of all IMP;  
2) Demonstration of the IMP application to each patient prior to their first dose;  
3) Oversight of any IMP applications occurring at the clinic; 
4) Ensuring that all IMP applications occurring at the clinic are completed individually, in a 
dedicated area not accessible/visible to other research staff or other patients, and in a consistent 
manner;  
5) Instructing study patients to avoid discussing any physical characteristics (color, transparency, 
consistency, smell, etc.) of the IMP with the Investigator, other research staff, or other study 
participants. 
The Sponsor and its agents will also be blinded to treatment assignment prior to unblinding of the 
treatment assignment at the study level, with the exception of select individuals who require access 
to patient treatment assignments to fulfil their roles during a clinical trial, including those involved 
in the creation and maintenance of the IWRS and drug dispensation.     
Further details are provided in the Blinding Protocol. 
6.3.3. 
Emergency Unblinding  
The Investigator will not be provided with the randomization codes. The randomization schedule 
will be maintained within the IWRS, which has the functionality to allow the Investigator to break 
the blind for an individual subject. 
Under normal circumstances, the blind should not be broken until all subjects have completed the 
trial and the database is locked. 
During the course of the study, the treatment code may only be broken in case of emergency. The 
Investigator may unblind the treatment assignment for a patient with an SAE if knowledge of 
treatment assignment will affect the immediate management of the patient. In such case, the 
Investigator will be able to break the treatment code solely for the patient experiencing the 
treatment-emergent SAE, within the IWRS. The Investigator is required to consult with the 
Medical Monitor prior to initiating emergency unblinding. If the SAE requires that an expedited 
regulatory report be submitted to one or more regulatory agencies (such as in the case of a 
suspected unexpected serious adverse reaction [SUSAR]), a copy of the report, identifying the 
patient’s treatment assignment, may be sent to investigators in accordance with local regulations.  
The Sponsor must be informed of any unblinding (accidental or for emergency reasons) as soon 
as possible. The date, time, and reason/circumstances for unblinding must be documented in the 
study file and in the appropriate section of the electronic Case Report Form (eCRF). 
Individual unblinding will result in the withdrawal of the patient from the study. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded study 
intervention records at the site(s) to verify that randomization/dispensing has been done accurately. 


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6.4. 
Study Drug Compliance 
As described in Section 6.2.2, the first dose of IMP will be applied at the clinic, in the presence of 
a qualified unblinded treatment administrator; subsequent applications will be made by the patient 
at the clinic (on Day 15/Week 2 Visit) or at their home (all other applications). Patients will be 
dispensed two-weeks’ supply of IMP (three tubes of 100 grams) on Day 1 (Baseline/FV1) and on 
Day 15 (Week 2 Visit), and will be asked to return all unused IMP supplies at the next study visit 
(Day 15/Week 2 Visit, and Day 29/Week 4 Visit, respectively).  
The date and time of each dose applied in the clinic will be recorded in the source documents by 
the qualified unblinded treatment administrator. The date and time of all other doses applied by 
the patient at home will be recorded on a daily basis in the Treatment Diary. The Investigator (or 
qualified designee) will contact the patient by phone after one week of treatment (Week 1, study 
Day 8 ± 1), and after three weeks of treatment (Week 3, study Day 22 ± 1), to verify compliance 
with the study drug application and daily diary completion requirements. Compliance with IMP 
applications occurring at home will be assessed at each visit by direct questioning, review of the 
Treatment Diary entries, and by weighing the unused study drug supplies (tubes) returned by the 
patient. Results of these compliance checks will be documented in the source documents and 
eCRF. Deviations from the prescribed dosage regimen should be recorded.  
A record of the quantity of IMP dispensed to and used by each patient must be maintained and 
reconciled with the IMP and compliance records. Study treatment interruptions, delays, and/or 
skipped doses (including dates) should also be recorded. 
Adequate treatment compliance is defined as >80% of the planned doses (i.e., ≥23 out of 28) 
applied during each week of study treatment.  
Inadequate compliance requiring permanent treatment discontinuation is defined as >3 days of 
consecutive study treatment missed. 
6.5. 
Dose Modifications, Interruptions, and Delays 
Patients will be treated according to a standardized dosing regimen consisting of four grams of the 
study drug (G001 or Vehicle gel) applied to the index knee four times daily (for a total daily dose 
of 16 grams) administered over four weeks.  
No dose modifications are planned for this study. However, in certain situations (e.g., moderate or 
severe local application site reactions; see description in Section 11.6.4), dosing may be interrupted 
until the event subsides or returns to tolerable levels. Patients should be instructed to contact the 
Investigator (or research staff) should they experience an AE that requires interruption of study 
treatment. Patients requiring treatment interruption lasting >3 consecutive days will have their 
study treatment permanently discontinued.   
6.6. 
Continued Access to Study Intervention after the End of the Study 
Currently, the Sponsor does not plan to provide G001 to patients who have completed the study. 
6.7. 
Treatment of Overdose 
The low systemic absorption of G001 renders overdose very unlikely. 


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However, undesirable effects similar to those observed following an overdose of celecoxib tablets 
can be expected if G001 is inadvertently ingested (1 unit of 100 grams of G001 contains the 
equivalent of 4 grams of celecoxib). 
Oral celecoxib (Celebrex) doses up to 2400 mg/day for up to 10 days in 12 patients did not result 
in serious toxicity. Symptoms following acute NSAID overdoses are usually limited to lethargy, 
drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive 
care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, 
and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic 
ingestion of NSAIDs and may occur following an overdose (Celebrex CPM 2022). 
In the event of accidental ingestion, patients should be managed by symptomatic and supportive 
care. There are no specific antidotes. Based on the high degree of plasma protein binding (>97%) 
hemodialysis, forced diuresis, alkalinization of urine, or hemoperfusion are unlikely to be useful 
in celecoxib overdose. Emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams/kg 
in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion 
with symptoms or following a large overdose (Celebrex CPM 2022). 
In the unlikely event of an overdose, apart from adequate patient management (as described 
above), the Investigator should: (1) contact the Medical Monitor immediately; (2) document the 
overdose, including the quantity of the excess dose; (3) consider withdrawal of the patient from 
the study. 
6.8. 
Concomitant Therapy 
Any medication (including over-the-counter or prescription medicines, recreational drugs, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded in the eCRF along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose, route of administration, and frequency 
6.8.1. 
Prohibited Medication and Interventions 
Patients taking any opioid analgesics > 3 days per week for the previous month before Screening 
will be excluded from the study. Patients on other opioid or other analgesic regimens may only be 
enrolled if their analgesic treatment may be safely discontinued by/at the Screening Visit. Prior 
NSAID and acetaminophen use will be discontinued at the Screening Visit to allow for washout 
and symptom flare. Acetaminophen may be used as rescue medication only (as described in 
Section 6.8.3). Any non-prescription or prescription analgesics (including NSAIDs, 
cyclooxygenase II-inhibitors, etc.) other than the IMP and the allowed amount of rescue 
medication (acetaminophen) are prohibited up to and including the Week 5/FV2 visit.  
Corticosteroids should not be taken during the trial or within the following timelines prior to 
Screening: (1) oral or intramuscular corticosteroids within the past 90 days; (2) intra-articular 
corticosteroid injection into the index knee within the past 90 days, or into any other joint within 
the past 30 days; (3) use of topical corticosteroids on the index knee must be discontinued by/at 
the Screening Visit. 


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Use of sedative hypnotic medication, anti-depressants with known analgesic effect, antipsychotics, 
antiepileptics, and anti-Parkinson drugs is prohibited within 14 days prior to Screening and during 
the study. "Known analgesic effect" is defined as any documented evidence of a significant effect 
on pain outcomes, and is not equivalent to an approved indication or proven efficacy. 
Refer to Table 7 for further details on prohibited medication and treatments, including minimum 
washout/treatment-free periods.  
Table 7 Prohibited Medication and Treatments 
 
Prior Surgeries & Other Interventions 
Minimum Treatment-Free Interval  
Prior to the Screening Visit 
Any major surgery to the index knee 
Minor surgery (or injury) to the index knee 
Lifetime 
12 months 
Knee arthroscopy (index knee) 
3 months (90 days) 
Oral or intramuscular corticosteroids  
Intra-articular corticosteroid injection into the index knee  
Intra-articular corticosteroid injection into any other joint  
Topical corticosteroid use on the index knee 
3 months (90 days) 
3 months (90 days) 
1 month (30 days) 
0 days [1] 
Intra-articular viscosupplementation/hyaluronic acid, joint 
lavage, or other invasive therapies to the index knee 
3 months (90 days) 
 
Prohibited Medication/Class 
Minimum Washout Period Prior to 
the Screening Visit 
Any investigational drug/therapy 
1 month (30 days) 
Hypnotics and Sedatives [2],  Antipsychotics / Neuroleptics [3], 
Antidepressants with known analgesic effect [4], Antiepileptics 
[5], and Anti-Parkinson drugs [6] 
2 weeks (14 days)  
Opioid analgesics [7] 
[5] 
Any oral and topical NSAIDs (apart from the IMP), and any 
other non-opioid analgesic medication apart from protocol-
permitted rescue medication use 
0 days [8] 
Receipt of a COVID-19 vaccine 
7 days 
Abbreviations: IMP=Investigational Medicinal Product; NSAID=nonsteroidal anti-inflammatory drug 
[1] Topical corticosteroid use  
[2] Anatomical Therapeutic Chemical (ATC) Classification, Pharmacological Subgroup N05C 
[3] ATC Classification, Pharmacological Subgroup N05A 
[4] ATC Classification, Pharmacological Subgroup N06A. "Known analgesic effect" is defined as any documented evidence of 
a significant effect on pain outcomes, and is not equivalent to an approved indication or proven efficacy. 
[5] ATC Classification, Therapeutic Subgroup N03 
[6] ATC Classification, Therapeutic Subgroup N04 
[7] ATC Classification, Pharmacological Subgroup N02A. Prior use of opioid analgesics > 3 days per week for the previous 
month prior to the Screening visit is exclusionary, and any opioid analgesic use during the study is prohibited. 
[8] All analgesic medication use (apart from protocol-permitted rescue medication) must be discontinued at Screening.  
 
The use of non-pharmacological pain management modalities (Transcutaneous Electrical Nerve 
Stimulation, acupuncture, and other interventional adjunctive therapy, physiotherapy, packs, 
massages), naturopathic treatments and remedies will be prohibited up to and including the Week 
5/FV2 visit. 


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The potential effect of the available coronavirus 2019 (COVID-19) vaccines on the safety or 
efficacy of COX-inhibitors or on existing inflammatory conditions is currently unknown. 
However, there is published evidence suggesting that NSAIDs dampen the body's antibody and 
cytokine response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection 
and vaccine (Chen et al. 2021). Furthermore, in clinical trials of COVID-19 vaccines approved for 
use in Canada, after the first and second doses of the vaccines, the incidence of arthralgia (reported 
as an adverse effect) was up to 28% and up to 45.5%, respectively, and the frequency of antipyretic 
or pain medication use was up to 28%, and up to 57%, respectively (COVID-19 Vaccine Moderna 
Product Monograph [PM], 2021; Pfizer-BioNTech COVID-19 Vaccine PM, 2021; AstraZeneca 
COVID-19 Vaccine PM, 2021; Janssen COVID-19 Vaccine PM, 2021). A similar frequency of 
adverse pain effects and concomitant analgesic use would have a significant impact on the safety 
and efficacy assessments in the current study, and therefore the integrity of the study overall. Given 
the above considerations, receipt of a COVID-19 vaccine will be prohibited during the study.     
The Medical Monitor should be contacted if there are any questions regarding medications and 
interventions. 
6.8.2. 
Exceptions to Prohibited Medication and Interventions 
Low-dose acetyl salicylic acid (ASA, aspirin) at oral doses ≤81 mg per day may be continued for 
cardiovascular prophylaxis. 
6.8.3. 
Rescue/Breakthrough Pain Medicine 
Rescue medication use is discouraged, but acetaminophen may be used, as needed, at a dose not 
exceeding 500 mg per dose and 2,000 mg/day to manage breakthrough pain. No rescue medication 
use is permitted within 2 hours after each IMP application, and within 12 hours prior to each 
efficacy assessment (i.e., at the Screening, Baseline/FV1, Week 2, Week 4/EOT, and Week 5/FV2 
visits). Acetaminophen may only be used as rescue medication during the study.  
Patients will be given a study diary and instructed to enter any breakthrough pain medication 
(acetaminophen) use on a daily basis. The reason for taking rescue medication (such as for OA 
pain or another pain condition) will also be recorded in the daily diary and in the eCRF. 
Rescue medication (acetaminophen) used to manage breakthrough pain is considered NIMP in this 
study and will be supplied locally by the study site (i.e., will not supplied by the Sponsor). 


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7. 
Discontinuation of Study Drug and Patient Withdrawal 
7.1. 
Discontinuation of Study Drug 
In rare instances, it may be necessary for a patient to permanently discontinue study treatment. 
Reasons for permanent discontinuation of study treatment may include any of the following: 
• Interruption of study treatment for >3 consecutive days (e.g., due to an AE or other reason) 
• Any medical condition that prevents the patient from safely completing the study 
• Investigator or Sponsor determination that treatment discontinuation is in the best interest of 
the patient 
• Use of/requirement for prohibited medication 
• Patient non-compliance with the study treatment or assessments, as determined by the 
Investigator or the Sponsor 
• Pregnancy 
• Patient’s decision / withdrawal of consent 
If study treatment is permanently discontinued for reasons other than withdrawal of consent from 
all further study participation, the patient will remain in the study, and will be asked to complete 
the EOT assessments (within no later than 2 days after the last dose of IMP), and the EOS 
assessments (within 14 ± 3 days after the last IMP application). See the SoA (Section 1.3) for data 
to be collected at these visits. 
The primary reason for permanent study drug discontinuation must be recorded in the eCRF. In 
case the reason is patient decision / withdrawal of consent, the patient’s willingness, or refusal to 
undergo further assessments (safety with/without efficacy assessments) should be recorded in the 
eCRF.   
7.1.1. 
Liver Chemistry Stopping Criteria 
As a standard precautionary measure, in case of:  
(1) ALT or AST ≥3 × ULN and total bilirubin ≥2 × ULN (>35% direct bilirubin) or  
(2) ALT or AST ≥3 × ULN and INR >1.5,  
which may indicate severe liver injury (possible Hy’s Law), regardless of the causality assessment 
of the event, the Medical Monitor must be notified in an expedited manner, and permanent 
discontinuation of study treatment may be considered. 
7.2. 
Patient Withdrawal from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  In 
addition, the Investigator has the right to withdraw a patient from the study at any time.  
Reasons for patient withdrawal from the study may include, but are not limited to, the following: 
• Patient withdrawal of consent 


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• AE 
• Loss to follow-up 
• Patient non-compliance with the study treatment or assessments 
• Study termination or site closure 
At the time of premature discontinuation, if feasible, an EOT should be conducted, followed by an 
EOS visit, as shown in the SoA (Section 1.3).  
The patient will be permanently discontinued both from the study treatment and from the study at 
that time. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request (verbally or in writing) destruction 
of any samples taken and not tested, and the Investigator must document this in the site study 
records. 
7.3. 
Lost to Follow up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to continue in the study. 
• Before a patient is deemed lost to follow up, the Investigator or designee must make every 
effort to regain contact with the patient (where possible, three telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have withdrawn 
from the study.  
Discontinuation of specific sites or of the study as a whole is described in Section 10.4.1. 


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8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Section 1.3). Adherence to the 
study design requirements, including those specified in the SoA, is essential and required for study 
conduct. Protocol waivers or exemptions are not allowed. 
All Screening evaluations must be completed and reviewed to confirm that potential patients meet 
all eligibility criteria.  
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) and 
obtained before signing of the Informed Consent Form (ICF) may be utilized for Screening or 
Baseline purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Section 1.3). 
Immediate safety concerns should be discussed with the Medical Monitor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
intervention. 
8.1. 
Screening Assessments and Activities 
8.1.1. 
Informed Consent Form and Screening Logs 
Written informed consent for participation in the study must be obtained before performing any 
study-specific screening test or procedure. Signed ICFs for randomized patients and for patients 
who are not subsequently randomized (screening failures) must be maintained at the study site; 
refer to Section 10.1.2 for details. 
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before enrollment. The Investigator (or qualified designee) will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record reasons 
for screening failure, as applicable. 
8.1.2. 
Demographic Data, General Medical and Disease History and 
Prior/Concomitant Medications 
Demographic data include age, gender, and self-reported race and ethnicity. 
Medical history includes OA history (date of diagnosis, prior treatment), general medical history, 
surgical history, and reproductive status. Documented diagnosis of OA of the knee, meeting ACR 
criteria for classification of idiopathic (primary) OA (see Appendix 1) for at least 6 months prior 
to Screening is required for enrolment. 
Medication history includes pharmacological treatment (oral,  parenteral, or topical; prescription 
and non-prescription) in the past 90 days, with focus on medications used for the management of 
OA and prohibited medications; see Section 6.8.1. 
Concomitant medications include all medications (e.g., prescription and non-prescription drugs, 
herbal or homeopathic remedies, nutritional supplements) used by the patient at the time of the 
Screening Visit or any time during the study. 


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8.1.3. 
Weight and Height Measurements 
The patient’s body weight and height will be measured, and BMI calculated by dividing the 
patient's weight in kilograms by the square of his/her height in meters. 
8.1.4. 
Screening Serology 
At the Screening Visit only, patients will be tested for HIV antibody, HBsAg, or HCV antibody; 
see Appendix 5. Patients with positive serology test results (any of the three parameters) will be 
excluded from the study. 
8.1.5. 
Radiological Examination 
Patients will undergo conventional radiological (X-ray) examination of the index knee during 
Screening. Exemptions include patients who:  
(1) had an X-ray of the index knee completed within 3 months prior to the Screening visit, and  
(2) received no treatment since that may have altered the radiological findings, including OA 
grade. 
Review and interpretation of radiographic images will be the responsibility of the Investigator. 
Radiologic evidence of OA in the index knee of grade 2 (mild) or grade 3 (moderate) according to 
Kellgren and Lawrence Radiographic Grading (see Appendix 2) is required for enrolment. 
8.1.6. 
Worst Daily Pain Assessment (11-point Pain NRS) 
The pain NRS is an ordinal 11-point Likert scale, with scores ranging from 0 (no pain) to 10 (worst 
possible pain).  
Worst daily pain (24-hour recall) will be assessed for both knees at the Screening and 
Baseline/FV1 visits using the 11-point pain NRS. 
The worst daily pain score (within 24 hours prior to Screening and Baseline/FV1) in the index 
knee must be between 4 and 8 on the 11-point pain NRS for eligibility. 
The worst daily pain score (within 24 hours prior to Baseline/FV1) in the contralateral knee must 
be ≤2 on the 11-point pain NRS scale for continued eligibility. 
8.1.7. 
Screening Diary 
Patients will be given a Screening Diary and instructed to enter the following on a daily basis 
during the 7-day Screening period: 
• Between 6 a.m. and 7 a.m., patients should rate their worst pain intensity from the previous 
~8 hours (night-time pain) in the index knee on the 11-point pain NRS;  
• Between 10 p.m. and 11 p.m., patients should rate their worst pain intensity from the previous 
~16 hours (daytime pain) in the index knee on the 11-point pain NRS, and enter any 
breakthrough pain medication (acetaminophen) use during the day. 
Diary entries made during the Screening period will be reviewed at the Baseline/FV1 visit.  


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8.1.8. 
Other Screening Assessments 
Other assessments completed at the Screening Visit are as follows: 
• WOMAC Index (see Section 8.2.1); 
• PGA and IGA of disease activity (see Section 8.2.2); 
• Physical examination (see Section 8.3.1);  
• Vital signs measurements (see Section 8.3.2);  
• Standard 12-lead ECG (see Section 8.3.3);  
• Safety Laboratory Testing* (see Section 8.3.4 and Appendix 5) 
• Urine pregnancy test (see Section 8.3.5); 
• Urine drug screen (see Section 8.3.6); 
• AE recording (see Section 8.4 and Appendix 6) 
* Note: For confirmation of eligibility, a screening laboratory test may only be repeated in case of 
a strictly borderline value. The Screening period may be extended by up to 2 days solely to obtain 
the repeat laboratory result, as long as there are adequate daily diary entries (minimum of 3 days 
preceding the baseline visit), and the patient continues to meet all other enrolment criteria. 
8.2. 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
8.2.1. 
WOMAC OA Index 
In this study, patients will complete the WOMAC OA Index in person at the Screening, 
Baseline/FV1, Week 2, Week 4/EOT, and the Week 5/FV2 visit; see SoA (Section 1.3). The 
WOMAC 3.1 Index in 5-point Likert format will be used in this study; see Appendix 3. 
The WOMAC OA index is a self-administered questionnaire assessing three dimensions of pain, 
disability and joint stiffness in knee and hip OA using a battery of 24 questions (Bellamy et al. 
1988): 
• Pain subscale (5 items): during walking, using stairs, in bed, sitting or lying, and standing 
• Stiffness subscale (2 items): after first waking and later in the day 
• Physical Function subscale (17 items): stair use, rising from sitting, standing, bending, 
walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, 
lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy household duties, 
light household duties 
The Likert version of the WOMAC is rated on an ordinal scale of 0 to 4, where 0 means the lowest 
level of symptoms or physical disability: 
• 0=none 
• 1=mild 
• 2=moderate 


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• 3=severe 
• 4=extreme 
The WOMAC takes approximately 12 minutes to complete. 
For each subscale, the scores for individual items are summed, providing the following possible 
ranges: 0 to 20 for pain, 0 to 8 for stiffness, and 0 to 68 for physical function. The sum of the three 
subscales provide a maximum total score of 96 (McConnell et al. 2001). Higher scores on the 
WOMAC indicate worse pain, stiffness, and functional limitations. 
8.2.1.1. 
Standardization of Assessments 
Even though the WOMAC measure has been used for decades (Bellamy et al. 1992) and is one of 
the most commonly used outcome measures in knee OA research (Kersten et al. 2010; Collins et 
al. 2011), different versions of the WOMAC measure exist, and there is variation in how the 
WOMAC outcome score is collected (5-level Likert scale, 11-point NRS, or 100 mm VAS), 
calculated (for example, using the total or average of the items) (Copsey et al. 2019), and reported 
(Woolacott et al. 2012). A lack of clarity and consistency in the use and scoring of an instrument 
can hinder the interpretation of study results (Copsey et al. 2019). Therefore, to standardize the 
use of the WOMAC Index across the study, guidance for minimizing bias will be provided through 
applicable training for site staff.   
8.2.2. 
Global Assessments of Disease Activity 
Patient and Investigator Global Assessment (PGA and IGA) of disease activity evaluate OA in the 
in the index knee over the last 48 hours on a 5-point Likert scale, where: 
• 0=very good  
• 1=good  
• 2=fair  
• 3=poor and  
• 4=very poor 
8.2.3. 
Global Assessments of Treatment Benefit 
Patient and Investigator Global Assessment (PGA and IGA) of treatment benefit will be completed 
using a 5-point Likert scale (0=very good; 1=good; 2=fair; 3=poor; and 4=very poor) after two (2) 
and four (4) weeks of treatment; see SoA. 
8.2.4. 
Treatment Diary 
Randomized patients will be given a Treatment diary at the Baseline/FV1 visit (after 
randomization) and instructed to enter the following on a daily basis through the Week 4/EOT 
Visit: 
• Between 6 a.m. and 7 a.m. (before the first daily study drug application), patients should rate 
their worst pain intensity from previous ~8 hours (nighttime pain) in the index knee on the 11-
point pain NRS;  
• During the day: patients should enter the time of each study drug application; 


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• Between 10 p.m. and 11 p.m. (before the last daily study drug application), patients should rate 
their worse pain intensity from previous ~16 hours (daytime pain) in the index knee on the 11-
point pain NRS, and enter any AE experienced, and rescue medication used during the past 
day. 
Between Week 4/EOT Visit and the Week 5/FV2 Visit, patients will be asked to enter the 
following in their Treatment diary on a daily basis: 
• Between 6 a.m. and 7 a.m., patients should rate their worst pain intensity from previous ~8 
hours (nighttime pain) in the index knee on the 11-point pain NRS;  
• Between 10 p.m. and 11 p.m., patients should rate their worse pain intensity from previous ~16 
hours (daytime pain) in the index knee on the 11-point pain NRS, and enter any AE 
experienced, and rescue medication used during the past day. 
Treatment diary entries will be reviewed by the clinical staff over the phone during the Week 1 
and Week 3 safety and compliance follow-up call, and in person at the Week 2, Week 4/EOT, and 
Week 5/FV2 visits. Any compliance issues will be addressed with the patient. 
8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1. 
Physical Examinations 
The Investigator or qualified health care provider designee will perform a complete physical 
examination at Screening and Week 4/EOT, and a brief, symptom-driven examination at Week 
6/EOS.  
A complete physical examination will be performed with special attention to the cardiovascular, 
gastrointestinal (GI), and musculoskeletal systems, as well as skin and subcutaneous tissues. 
Investigators may use medical judgment to determine the need for evaluating the breast, genital, 
and anorectal areas at each applicable study visit. 
8.3.2. 
Vital Signs Measurements 
Vital signs measurements will include blood pressure (BP), heart rate (HR),  respiratory rate (RR), 
and body temperature.  
Vital signs should be taken before blood collection for laboratory tests. 
Blood pressure and pulse (HR) measurements will be assessed with the patient in a sitting position, 
after 3 minutes of rest, with a completely automated device. Manual techniques will be used only 
if an automated device is not available. Two consecutive BP readings (at least 1 minute apart) will 
be recorded, and the average of the two readings will be entered in the eCRF.  
8.3.3. 
Electrocardiograms 
A single standard 12-lead ECG recording will be obtained as outlined in the SoA (Section 1.3) 
using an ECG machine that measures PR, QRS, QT interval, and automatically calculates the heart 
rate and QTc interval.   


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8.3.4. 
Clinical Safety Laboratory Assessments 
Refer to Appendix 5 for the list of clinical safety laboratory tests (hematology, blood chemistry, 
and urinalysis) to be performed and to the SoA (Section 1.3) for the timing and frequency. All 
protocol-required laboratory tests, as defined in Appendix 5, must be conducted in accordance 
with the laboratory manual and the SoA (Section 1.3). 
The Investigator must review each laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must be 
filed with the source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered clinically 
significant unless judged by the Investigator to be more severe than expected for the patient's 
condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or Baseline level or are no longer 
considered clinically significant by the Investigator or Medical Monitor. If clinically significant 
values do not return to normal/Baseline level within a period of time judged reasonable by the 
Investigator, the etiology should be identified, and the Medical Monitor notified. 
8.3.5. 
Pregnancy Testing 
All women of childbearing potential will undergo repeat urine human chorionic gonadotropin 
(hCG) pregnancy tests during the study, as outlined in the SoA (Section 1.3) and in Appendix 5. 
If a urine pregnancy test is positive, it must be confirmed by a serum hCG pregnancy test.  
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a 
postmenopausal state (≥ 24 continuous months of amenorrhea with no identified cause other than 
menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian 
tubes, and/or uterus) or another cause as determined by the Investigator (e.g., Müllerian agenesis). 
Patients with a positive pregnancy test during Screening will be excluded from the study. Patients 
with a positive pregnancy test during the treatment or post-treatment follow-up period will be 
withdrawn from the study.  
8.3.6. 
Urine Drug Screen 
Urine drug screen will include amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiates, phencyclidine, and a panel of tricyclic antidepressants. 
8.3.7. 
Skin Irritation Test 
Skin irritation will be assessed by the Investigator using the Berger/Bowman Scoring Scale (Berger 
and Bowman, 1982; US FDA Guidance 2018b), comprised of the ‘Dermal Response’ and ‘Other 
Effects’ scoring system, as outlined in Appendix 4. To the extent feasible, the same scorer should 
complete all three skin irritation assessments (Week 2, Week 4/EOT, and Week 6/EOS) for a 
patient. 
‘Dermal Response’ is evaluated on an 8-point scale (0=No evidence of irritation; 1=Minimal 
erythema that is barely perceptible; 2=Definite erythema that is readily visible and minimal edema 


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or minimal papular response; 3=Erythema and papules; 4=Definite edema; 5=Erythema, edema, 
and papules; 6=Vesicular eruption; 7=Strong reaction spreading beyond the application site). 
‘Other Effects’ scores are reported as a number and letter combination: A (0)=Slightly glazed 
appearance; B (1)=Marked glazed appearance; C (2)=Glazing with peeling and cracking; F 
(3)=Glazing with fissures; G (3)=Film of dried serous exudates covering all or part of the 
application site; H (3)=Small petechial erosions and/or scabs. 
The sum of the ‘Dermal Response’ and the numeric equivalent of the ‘Other Effects’ provides the 
Numerical Total Score. Refer to Appendix 4 for details. 
8.4. 
Adverse Events, Serious Adverse Event, and Other Safety Reporting 
The definitions of AEs and SAEs,  method of recording, evaluating, and assessing causality of 
AEs and SAEs and the procedures for completing and transmitting SAE reports are provided in 
Appendix 6. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs and SAEs; see Section 8.4.3.  
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs occurring between the Screening Visit and the Week 6/EOS Visit, whether reported by 
the patient or noted by study personnel, will be recorded in the patient's medical record and on the 
Adverse Event eCRF.  
All SAEs will be recorded and reported to the to the Pharmacovigilance (PV) and Safety Manager 
immediately and under no circumstance later than within 24 hours after learning about the event, 
as described in Appendix 6. The Investigator will submit any updated SAE data to the to the PV 
and Safety Manager within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the patient’s study participation. However, if the Investigator learns of any SAE (fatal or non-fatal), 
at any time after a patient has been discharged from the study, and he/she considers the event to 
be reasonably related to the study drug or study participation, the Investigator must promptly notify 
the Sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
The Investigator should proactively follow each AE/SAE until the event has resolved to Baseline 
level or better, the event is assessed as stable by the Investigator, the patient is lost to follow-up 
(as defined in Section 7.3), or the patient withdraws consent (as described in Section 7.2).   


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Every effort should be made to follow all SAEs considered to be related to the study drug until a 
final outcome can be reported. Further information on follow-up procedures is provided in 
Appendix 6. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor (or designee) of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Research Ethics Boards (REB), and 
investigators. This will include preparation and expedited submission of safety reports for 
SUSARs according to local regulatory requirements. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., SUSAR, or summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/REB, if appropriate 
according to local requirements. 
8.4.5. 
Pregnancy 
In the unlikely event of a pregnancy occurring during the study, the Investigator will record 
pregnancy information on the appropriate Pregnancy Reporting Form and submit it to the PV and 
Safety Manager within 24 hours of learning of the pregnancy, as described in Appendix 6.  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and must be reported as such. 
The patient  will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on the patient  and the neonate, and the information will be 
forwarded to the Sponsor. 
Any female patient who becomes pregnant while participating in the study will discontinue study 
treatment and be withdrawn from the study. 
8.4.6. 
Disease-Related Events Not Qualifying as AEs  
Worsening of the underlying condition (OA) and lack of efficacy will not be reported as AEs in 
this study.   
8.4.7. 
Adverse Events of Special Interest 
Adverse events of special interest for G001 include: 
• Application site adverse reactions. 


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9. 
Statistical Considerations 
This is a double-blind, randomized, parallel-group, vehicle-controlled study to evaluate the 
efficacy, safety, and local tolerability of G001 compared to Vehicle in patients with symptomatic 
OA of the knee. 
Eligible patients will be randomly assigned to one of two treatment groups (G001 or Vehicle) in a 
1:1 allocation ratio.  
The primary outcome will be the change from Baseline in the WOMAC Pain Subscale rating at 
the Week 4/EOT visit. 
9.1. 
Sample Size Determination 
A total sample size of 174 evaluable patients (87 per group) achieves 80% power to detect a 
difference between treatment groups analysed using a t-test and a significance level (alpha) of 
0.05. The assumed difference in group means from Vehicle control under the alternative 
hypothesis is 1.5 points in the WOMAC Likert Pain Subscale (0-20 scale). The common SD is 
assumed to be 3.5. This sample size calculation was performed using PASS 2020 v20.0.1.  
The assumptions on change in WOMAC pain score were selected based on available literature on 
clinically relevant differences and efficacy of celecoxib oral formulation (see Sections 2.2.1 and 
4.3.1).   
Based on available literature, it is estimated that up to 20% of patients may withdraw from the 
study prior to the Week 4 efficacy assessment. Therefore, to control for possible dropouts, the 
sample size is increased to 210, or 105 per treatment arm. 
9.2. 
Analysis Sets 
Analyses will be performed based on the following datasets:  
• Modified Intent-to-Treat Population (mITT): The mITT will include all randomized patients 
who received at least one dose of study drug and provided both Baseline/FV1 and Week 4/EOT 
efficacy assessments. The mITT population will be the primary analysis population for the 
assessment of efficacy. 
• Per Protocol (PP) Population: The PP population will include all patients in the mITT 
population who completed the study without major protocol deviations that could impact the 
assessment of efficacy. The primary and secondary efficacy analyses will also be completed 
on the PP population. The list of major protocol deviations requiring exclusion from the PP 
Population will be finalized prior to the clinical database lock and unblinding. 
• Safety Population: The Safety population will include all randomized patients who received 
any amount of study drug. The Safety Population will be used for all safety analyses only. 
For all efficacy analyses (based on the mITT and the PP populations), patients will be grouped 
according to the treatment assigned at randomization. For all safety analyses, patients will be 
grouped according to the treatment actually received. 


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9.3. 
Statistical Analyses 
This section is a summary of the planned statistical analyses for the protocol. A Statistical Analysis 
Plan (SAP) will be prepared and finalized prior to DBL and will include a full technical and 
detailed description of the statistical analyses described in this section. 
9.3.1. 
General Considerations 
All data collected will be documented using summary tables, figures, and/or patient data listings 
presented by treatment group. For continuous variables, descriptive statistics (number (n), mean, 
median, standard deviation, minimum and maximum) will be presented. For categorical variables, 
frequencies and percentages will be presented.  
Patient disposition, study drug exposure, reasons for study drug discontinuation and withdrawals 
from the study will be summarized, as will demographic variables such as age, sex, race/ethnicity, 
and other relevant baseline characteristics. 
All major protocol deviations will be summarized and reported. 
Unless otherwise specified, the baseline value of any variable will be defined as the last available 
value prior to the first administration of study treatment.  
9.3.2. 
Primary Endpoint 
The primary outcome will be the change from Baseline in the WOMAC Pain Subscale rating at 
the Week 4/EOT visit. The WOMAC will be scored according to the WOMAC 3.1 User Guide 
XI. The maximum WOMAC Pain Subscale rating is 20, and higher scores indicate worse pain; 
refer to Section 8.2.1 and Appendix 3 for details. 
While every effort will be made to avoid partially completed assessments, missing data will be 
handled as instructed in the WOMAC 3.1 User Guide XI. If two or more pain questions are 
missing an answer, the pain subscale will not be scored and will be considered missing. If only 
one question was not answered, the average value for the subscale from the remaining answers 
will be assigned for the missing question. There will be no imputation for entirely missing pain 
subscales scores. 
The primary analysis will be performed using an analysis of covariance (ANCOVA) model, to 
compute the t-test for the difference between group means adjusted for Baseline WOMAC Pain 
Subscale score. The model will include treatment as the independent variable, change from 
Baseline at the Week 4/EOT visit as the outcome variable, and Baseline WOMAC Pain Subscale 
score as a covariate. Statistical significance will be assessed using a significance level of 0.05.   
The primary endpoint will be assessed in the mITT population as primary, with no imputation for 
missing data (apart from missing data handled as instructed in the WOMAC 3.1 User Guide XI, 
as described above), and in the PP population as supportive. Additional sensitivity analysis of the 
primary endpoint, including a completers analysis, where subjects who discontinued prior to Week 
4 are excluded, may be performed, and will be further described in the SAP. WOMAC Pain 
Subscale scores will also be displayed graphically. 


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9.3.3. 
Secondary Endpoints 
A complete list of secondary endpoints is provided in Section 3 (Table 5).  
Analysis of secondary endpoints will be considered supportive analysis. Hence, no p-value 
adjustment will be made for multiple endpoints or multiple comparisons in the secondary efficacy 
analysis. 
9.3.3.1. 
WOMAC Physical Function and Stiffness Subscale and Total Scores 
The analysis of secondary efficacy endpoints of WOMAC Physical Function Subscale, WOMAC 
Stiffness Subscale and WOMAC Total Score will be consistent with that described for the primary 
endpoint. Refer to Section 8.2.1 and Appendix 3 for additional details on these scales. 
Missing data will be handled as suggested in the WOMAC 3.1 User Guide XI, with further details 
described in the SAP. Scores will also be displayed graphically.  
9.3.3.2. 
Weekly Mean Worst Daily and Nightly Pain NRS Scores 
Baseline worst daytime and worst nighttime pain severity scores will be calculated as the mean 
worst daytime or worst nighttime pain NRS scores from the screening diary entries (3-7 days prior 
to Baseline/FV1). 
The mean worst daytime pain severity scores at Week 4/EOT will be calculated as the sum of the 
worst daytime pain 11-point NRS scores for the last 7 days of the treatment period (e.g., from Day 
22 through Day 29), divided by the number of worst daytime pain assessments during this 7-day 
period.  
The mean worst nighttime pain severity scores at Week 4/EOT will be calculated as the sum of the 
worst nighttime pain 11-point NRS scores for the last 7 days of the treatment period (e.g., from 
Day 22 through Day 29), divided by the number of worst nighttime pain assessments during this 
7-day period.  
The average worst daytime and nighttime pain severity scores at the Week 5/FV2 visit will be 
calculated as the sum of the worst daytime or nighttime pain scores for the post-treatment period 
(i.e., between the Week 4/EOT and Week 5/FV2 visits) and divided by the number of days of post-
treatment follow-up.  
Weekly mean worst daytime and nighttime pain NRS scores will be presented by treatment group. 
Changes from baseline in average worst daytime and in average worst nighttime pain severity 
scores at Week 4/EOT in the two treatment groups will be compared using a t-test. Percentages of 
patients achieving ≥20%, ≥30% and ≥50% reduction from Baseline in worst daytime pain and in 
worst nighttime pain severity scores (11-point pain NRS) at Week 4/EOT will also be presented 
by treatment group. 
NRS scores will also be displayed graphically.  
9.3.3.3. 
Global Assessments of Disease Activity and Overall Treatment Benefit 
For PGA and IGA of disease activity, patients will be classified according to the following three 
categories:  


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• "Improved" (defined as a reduction of 2 grades or more from Baseline for grades 2 through 4 
or a change in grade from 1 to 0);  
• "Worsened" (defined as an increase of 2 or more grades from Baseline for grades 0 through 2 
or a change in grade from 3 to 4); or  
• “No change” (remaining patients).  
The categorical responses will be presented by treatment and visit. A logistic regression model 
may be used to assess between group differences, including baseline disease activity as a covariate, 
with further details described in the SAP.   
In addition, at the Week 4/EOT visit, patients will provide an overall assessment of treatment 
benefit using the same 5-point Likert scale (0=very good; 1=good; 2=fair; 3=poor; and 4=very 
poor). The distribution of overall treatment benefit scores will be presented descriptively, by 
treatment group.  
9.3.3.4. 
Rescue Medication Use 
The number and percentage of subjects with any rescue medication (acetaminophen) use will be 
presented, along with number of rescue doses, total daily dose, and the percentage of days with 
any rescue medication use during the last week of study treatment, and overall during the study 
treatment period (between the first and last dose dates).  
9.3.4. 
Subgroup Analyses of Efficacy Endpoints 
Subgroup analyses of primary and select secondary endpoints may be performed based on prior 
OA treatment (pre-study NSAID or acetaminophen use only) depending on the number of patients 
in each category. 
9.3.5. 
Safety Analyses 
Adverse events (AEs) will be coded using the most recent version of Medical Dictionary for 
Regulatory Activities (MedDRA) and presented by System Organ Class (SOC) and Preferred 
Term for each treatment group.  Additional displays will highlight the Investigator-rated severity 
and relationship to study treatment as well as serious adverse events (SAEs), AEs leading to 
withdrawal of treatment, and application site AEs. 
Laboratory parameters (and changes from Baseline in these parameters) will be summarized. In 
addition, shift changes from Baseline in categories (normal, low, high, missing) will be presented 
by treatment group across the visits.  Clinically relevant laboratory abnormalities will be recorded 
as AEs. 
Vital signs measurements (and changes from Baseline in these measurements) will be summarized 
by mean values (with SD), medians, and range. Clinically relevant changes in vital signs will be 
recorded as AEs. 
Clinically relevant abnormal physical examination findings will be recorded as medical history at 
Baseline/FV1 (prior to the first dose in study treatment), and as AEs if detected after the first dose 
of study treatment.  


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9.3.6. 
Analysis of Skin Irritation 
Skin irritation will be assessed using the Berger/Bowman Scoring Scale (Berger and Bowman, 
1982; US FDA Guidance 2018b), as described in Section 8.3.7. The Total Skin Irritation Score 
will be calculated as the sum of the ‘Dermal Response’ and the numeric equivalent of the ‘Other 
Effects’; see Appendix 4. 
Descriptive statistics for the numerical Total Skin Irritation Scores as well as the Dermal Response 
and Other Effects sub-scores will be presented by treatment group and visit.  
If a patient was removed from treatment due to skin irritation, the patient’s skin irritation score at 
the time of treatment discontinuation will be imputed at subsequent assessment time-point(s) (last 
observation carried forward [LOCF]). If a patient was removed from treatment due to reasons other 
than skin irritation, missing data will not be imputed. 
9.4. 
Interim Analysis 
No interim analysis is planned.  


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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the World 
Medical Association Declaration of Helsinki (Fortaleza, Brazil, October 2013) and Council 
for International Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable International Council for Harmonisation (ICH) GCP Guidelines 
• All applicable laws and regulations. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants. A Clinical Trial Application (CTA) for the study will be submitted to Health Canada 
and the study drug will not be initiated unless an appropriate ‘No Objection Letter’ has been 
received. A CTA notification will be provided to Health Canada upon completion of the study or 
at study termination. 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., patient recruitment materials) must be submitted to an IRB/REB by the Investigator and 
reviewed and approved by the IRB/REB before the study is initiated. IRB/REB notifications and 
approvals should be filed in the study file, with a copy provided to the Sponsor.  
Any amendments to the protocol will require IRB/REB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate hazard 
to study participants.  
The Investigator will be responsible for the following: 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
set out by the ICH guidelines, the IRB/REB, and all other applicable local regulations 
• Providing written summaries of the status of the study to the IRB/REB annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/REB 
• In addition to the requirements for reporting all SAEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs or other significant safety findings to the 
IRB/REB as required by IRB/REB procedures. 
10.1.1. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. 


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10.1.2. 
Informed Consent Process 
Written informed consent for participation in the study must be obtained before performing any 
study-specific screening test or procedure. 
The Investigator or his/her representative will explain the nature of the study to the prospective 
study participant and answer all questions regarding the study. 
Patients must be informed that their participation in the study is voluntary. Patients will be required 
to sign the study ICF that meets the requirements of local regulations, ICH guidelines, and the 
reviewing IRB/REB. The authorized person obtaining the informed consent must also sign the 
ICF. Signed ICFs for randomized patients and for patients who are not subsequently randomized 
(screening failures) must be maintained at the study site and must be available for verification by 
study monitors at any time. A copy of the signed ICF must be provided to the patient. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained.  
In case the ICF is amended, patients must be re-consented to the most current version of the ICF 
during their participation in the study. 
10.1.3. 
Data Protection 
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
Patient medical information obtained by this study is confidential and may be disclosed to third 
parties only as permitted by the ICF signed by the patient, unless otherwise required by law. Patient 
must be informed that their personal study-related data will be used by the Sponsor in accordance 
with local data protection law. The level of disclosure must also be explained to the patient who 
will be required to give consent for their data to be used as described in the ICF.  
Data generated by this study must be available for inspection upon request by representatives of 
national and local health authorities, Sponsor monitors, representatives, and collaborators, and the 
IRB/REB for each study site, as appropriate. Patients must be informed that their medical records 
may be examined by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the Sponsor, by appropriate IRB/REB members, and by inspectors from regulatory authorities. 
10.1.4. 
Dissemination of Clinical Study Data  
The Sponsor is dedicated to openly providing information on the trial to healthcare professionals 
and to the public, in clinical trial registries (such as www.ClinTrials.gov). 
10.2. 
Data Collection and Management 
10.2.1. 
Data Quality Assurance 
A contract research organization (CRO; Veristat Inc., Canada) will be responsible for the data 
management of this study, including quality checking of the data. Data will be collected via 
electronic data capture (EDC) through use of eCRFs. Sites will be responsible for data entry into 


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the EDC system. In the event of discrepant data, the CRO will request data clarification from the 
sites, which the sites will resolve electronically in the EDC system.   
The CRO will produce eCRF Specifications for the study, including quality checking to be 
performed on the data. eCRFs and correction documentation will be maintained in the EDC 
system's audit trail.  System backups for data stored and records retention for the study data will 
be consistent with the CRO's SOPs. 
Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can impact 
patient safety and/or reliability of study results. These pre-defined parameters will be monitored 
during the study and important deviations from the QTLs and remedial actions taken will be 
summarized in the clinical study report (CSR). 
10.2.2. 
Electronic Case Report Forms  
All patient data relating to the study will be recorded on eCRF unless transmitted to the CRO 
electronically (e.g., laboratory data).  Secure portals are used to transfer data to Data Management 
by the Central Laboratory. 
IBM Clinical Development, a validated United States (U.S.) Food and Drug Administration 
(FDA) 21 Code of Federal Regulations (CFR) Part 11 compliant eCRF system will be used to 
capture data for the study. The eCRF will be designed to capture the data according to the protocol, 
Sponsor requirements and Clinical Data Interchange Standards Consortium (CDISC) Clinical Data 
Acquisition Standards Harmonization (CDASH) guidelines. 
All eCRFs should be completed by designated, trained site staff. Guidance on completion of 
eCRFs will be provided. The Investigator is responsible for verifying that data entries are accurate 
and correct by electronically signing the eCRF. 
At the end of the study, the Investigator will receive patient data for his or her site in a readable 
format that must be kept with the study records. Acknowledgement of receipt of the patient data 
will be required. 
10.2.3. 
Patient and Clinician-Reported Outcome Data  
Patient-reported outcome data not included in the daily diary, and clinician-reported outcome data  
are being collected through use of appropriate paper forms provided by the clinical CRO (Veristat) 
and transferred to the EDC by site staff.   
10.2.4. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. 
Source documents (paper or electronic) are files in which patient data are originally (for the first 
time) recorded and documented. They include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, patient-reported outcomes, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, photographic 
negatives, microfilm or magnetic media, X-rays, patient files, and records kept at pharmacies, and 


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laboratories involved in a clinical trial. Before study initiation, the types of source documents that 
are to be generated will be clearly defined in the Monitoring Plan. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The Investigator may need to request 
previous medical records or transfer records, as applicable. Also, current medical records must be 
available. 
The Investigator must maintain accurate documentation (source data) that supports the information 
entered in the eCRF. Source documents that are required to verify the validity and completeness 
of data entered into the eCRFs must not be obliterated or destroyed and must be retained per the 
requirements for retention of records described in Section 10.2.5. 
Study monitors will perform ongoing source data verification to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of patients are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH GCP, and 
all applicable regulatory requirements. 
10.2.5. 
Record Retention 
Records and documents pertaining to the conduct of this study and the distribution of IMP, 
including signed ICFs, eCRFs, laboratory test results, and medication inventory records, must be 
retained by the Investigator for 15 years after study completion. After that period of time, the 
documents may be destroyed. No records may be destroyed during the retention period without 
the written approval of the Sponsor. No records may be transferred to another location or party 
without written notification to the Sponsor.  
10.3. 
Study Documentation and Monitoring 
10.3.1. 
Study Documentation 
The Investigator must maintain files of essential documents as defined by the ICH GCP guidelines 
and local requirements to enable the conduct of the study to be fully documented, including, but 
not limited to, the protocol, protocol amendments, ICFs, and documentation of IRB/REB and 
governmental approval.  
The Investigator’s site file must be available at monitoring visits and during an audit or inspection. 
In addition, at the end of the study, the Investigator will receive the patient data, including an audit 
trail containing a complete record of all changes to data. 
10.3.2. 
Site Inspections and Monitoring 
Site visits will be conducted by the Sponsor or an authorized CRO representative for inspection of 
study data, patients' medical records, and eCRFs. The Investigator must permit regular study-
related monitoring and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based monitoring, as applicable), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 


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In addition, the Investigator must permit Sponsor-appointed Quality Assurance representatives, 
the reviewing IRB/REB, or regulatory agency representatives to audit the facilities and 
documentation at agreed times. An audit is the systematic and independent examination of trial 
related activities and documents to determine whether the evaluated trial related activities were 
conducted, and the data recorded, analyzed, and accurately reported according to the protocol, 
Sponsor/designee/CRO’s SOPs, GCP and applicable regulatory requirements. Auditors are 
independent of the clinical trial and its performance. 
10.3.3. 
Protocol Amendments 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will be 
submitted to the IRB/REB and to the appropriate regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/REB and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an immediate 
hazard to patients or changes that involve logistical or administrative aspects only (e.g., change in 
Medical Monitor or contact information). 
10.3.4. 
Protocol Deviations 
The Investigator should document and explain any protocol deviations occurring during the study. 
In addition, the Investigator should promptly report any deviations that might have an impact on 
patient safety and data integrity to the Sponsor and to the IRB/REB in accordance with established 
IRB/REB policies and procedures. The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of GCP guidelines and require reporting to health 
authorities.   
Prospective requests to deviate from the protocol, including requests to waive protocol eligibility 
criteria, will not be allowed. 
10.4. 
Other Operational Considerations 
10.4.1. 
Study and Site Start and Closure 
The study start date is the date of the FPFV. 
The study end date is the date of the LPLV. 
Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are not 
limited to: 


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For study termination: 
• Discontinuation of further study drug development 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/REB 
or local health authorities, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of patients by 
the Investigator 
• Total number of patients enrolled earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the REBs/IRBs, the regulatory authorities, and the CRO used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform all patients still in the study and should assure appropriate 
patient treatment and/or follow-up. 
 


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11. 
Appendices 
11.1. 
Appendix 1: ACR Criteria for the Diagnosis of Osteoarthritis 
 
Clinical and laboratory 
Clinical and radiographic 
Clinical † 
Knee pain 
Knee pain 
Knee pain 
+ at least 5 of 9: 
+ at least 1 of 3: 
+ at least 3 of 6: 
    - Age > 50 years 
    - Age > 50 years 
    - Age > 50 years 
    - Stiffness < 30 minutes 
    - Stiffness < 30 minutes 
    - Stiffness < 30 minutes 
    - Crepitus 
    - Crepitus 
    - Crepitus 
    - Bony Tenderness 
+ Osteophytes 
    - Bony Tenderness 
    - Bony enlargement 
 
    - Bony enlargement 
    - No palpable warmth 
 
    - No palpable warmth 
    - ESR <40 mm/hour 
 
 
    - RF <1:40 
 
 
    - SF OA 
 
 
92% sensitive 
91% sensitive 
95% sensitive 
75% specific 
86% specific 
69% specific 
* ESR = erythrocyte sedimentation rate (Westergren); RF = rheumatoid factor; SF OA = synovial fluid signs of OA (clear, 
viscous, or white blood cell count <2,000/mm3). 
† Alternative for the clinical category would be 4 of 6, which is 84% sensitive and 89% specific. 
 
Source: Altman et al. 1986 
 


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11.2. 
Appendix 2: Kellgren & Lawrence Grading for Knee Osteoarthritis 
 
The Kellgren & Lawrence system (Kellgren and Lawrence, 1957; Petersson et al. 1997) is a method of 
classifying the severity of knee osteoarthritis according to the following five grades: 
Grade 
Description 
Grade 0 
No radiographic features of OA are present 
Grade 1 
Doubtful joint space narrowing (JSN) and possible osteophytic lipping 
Grade 2 
Presence of definite osteophytes and possible JSN on anteroposterior weight-
bearing radiograph 
Grade 3 
Multiple osteophytes, definite JSN, sclerosis, possible bony deformity 
Grade 4 
Large osteophytes, marked JSN, severe sclerosis and definitely bony deformity 
 
 
 
 
 


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11.3. 
Appendix 3: WOMAC for Knee Osteoarthritis (Sample) 
 
Source: www.womac.org   


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11.4. 
Appendix 4: Skin Irritation Scale 
 
Skin irritation will be assessed using the Berger/Bowman Scoring Scale (Berger and Bowman, 
1982; US FDA Guidance 2018b), comprised of the Dermal Response (Table 8) and Other Effects 
(Table 9) scoring system: 
Table 8 Dermal Response Scoring System 
Skin Appearance 
Score 
No evidence of irritation 
0 
Minimal erythema that is barely perceptible 
1 
Definite erythema that is readily visible and minimal edema or minimal papular response 
2 
Erythema and papules 
3 
Definite edema 
4 
Erythema, edema, and papules 
5 
Vesicular eruption 
6 
Strong reaction spreading beyond the application site 
7 
 
Table 9 Other Effects Scoring System 
Score  
(Numeric Equivalent) 
Observation 
A (0) 
Slightly glazed appearance 
B (1) 
Marked glazed appearance 
C (2) 
Glazing with peeling and cracking 
F (3) 
Glazing with fissures 
G (3) 
Film of dried serous exudates covering all or part of the application site 
H (3) 
Small petechial erosions and/or scabs 
 
 
When an Other Effects score is observed, the score should be reported as both a: 
• 
Number and letter combination score; and  
• 
Numerical total (Dermal Response score + Other Effects numerical score). 
Table 10 lists some examples of the combination score and numerical total scores to be reported. 
 


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Table 10 Reporting Skin Irritation Scores 
Dermal Response 
Score 
Other Effects 
Score* 
Combination Score1 
Numerical Total2 
0 
– 
0 – 
0 
1 
C (2) 
1 C 
3 
4 
– 
4 – 
4 
7 
G (3) 
7 G 
10 
2 
A (0) 
2 A 
2 
1  Combination Score is expressed as the ‘Dermal Response’ numerical score followed by the ‘Other Effects’ 
letter score.  
2  Total numeric is the sum of the ‘Dermal Response’ and the numeric equivalent of the ‘Other Effects’ 
* A dash (‘-‘) means ‘no other effects’ or ‘not applicable’. 
 
 
 
 
 
 
 


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11.5. 
Appendix 5: Clinical Laboratory Tests 
The tests detailed in Table 11 will be performed by the central laboratory (Dynacare). 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5.1 
and Section 5.2 of the protocol, respectively. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 11 Protocol-Required Safety Laboratory Tests 
Laboratory Tests 
Parameters 
Hematology 
RBC Count 
Hemoglobin 
Hematocrit 
Platelet Count 
RBC Indices: 
MCV 
MCH 
MCHC 
WBC count with Differential: 
Neutrophils, Lymphocytes 
Monocytes, Eosinophils, Basophils 
Clinical 
Chemistry [1] 
BUN 
Potassium 
AST/SGOT 
total cholesterol 
Creatinine [2] 
Sodium 
ALT/SGPT 
HDL-C 
Total Protein 
Calcium 
ALP  
LDL-C 
 
Albumin 
Magnesium 
Total bilirubin 
Triglycerides 
 
LDH 
Glucose (nonfasting) 
GGT 
 
Coagulation 
aPTT, INR, Prothrombin Time 
Routine Urinalysis • 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, nitrites, leukocytes by dipstick 
• 
Microscopic examination (if the urine blood, protein, or leukocyte test is 
abnormal) 
Pregnancy testing  
Highly sensitive urine hCG pregnancy test (for women of childbearing potential) [3].  
Screening only 
Serology: HIV antibody, HBsAg, and HCV antibody 
[1] Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.1 [Liver 
Chemistry Stopping Criteria]. As a standard precautionary measure, all events of ALT or AST ≥3 × ULN and total 
bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT or AST ≥3 × ULN and INR >1.5, which may indicate severe 
liver injury (possible Hy’s Law), must be reported to Medical Monitor in an expedited manner. 
[2] Serum creatinine-based estimation of eGFR will be completed as described in Appendix 7. 
[3] Local urine testing will be used unless serum testing is required by local regulation or IRB/REB. If a urine 
pregnancy test is positive, it must be confirmed by a serum hCG pregnancy test. 
Abbreviations: ALP=alkaline phosphatase ALT=alanine aminotransferase; apTT=activated partial thromboplastin time; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; eGFR=Estimated Glomerular Filtration Rate; HBsAg=hepatitis B 
surface antigen; hCG=human chorionic gonadotropin; HCV=hepatitis C virus; HDL-C=high-density lipoprotein cholesterol; 
HIV=human immunodeficiency virus; INR=(prothrombin) International Normalized Ratio; LDH=lactate dehydrogenase; LDL-
C=low-density lipoprotein cholesterol; MCH=Mean Corpuscular Hemoglobin; MCHC=Mean Corpuscular Hemoglobin 
Concentration; MCV=Mean Corpuscular Volume; RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; 
SGPT=serum glutamic-pyruvic transaminase; ULN=upper limit of normal; WBC=white blood cell 
Investigators must document their review of each laboratory safety report. 
 


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11.6. 
Appendix 6: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
11.6.1. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study intervention. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including 
those that worsen from Baseline, considered clinically significant in the medical and 
scientific judgment of the Investigator (i.e., not related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming intent. 
Such overdoses should be reported regardless of sequelae. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 


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• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
11.6.2. 
Definition of SAE 
An SAE is defined as any adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from Baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday 
life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical 


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intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive treatment 
for allergic bronchospasm, blood dyscrasias, convulsions or development of 
intervention dependency or intervention abuse. 
 
11.6.3. 
Recording of AEs and SAEs and Reporting Period 
AE Recording 
• Investigators (or qualified designees) will seek information on AEs at each patient contact. 
All AEs occurring between the Screening Visit and the Week 6/EOS Visit, whether reported 
by the patient or noted by study personnel, will be recorded in the patient's medical record 
and on the Adverse Event eCRF. After the Week 6/EOS Visit, AE recording (and reporting 
as applicable) will be limited to the following: updates to AEs that were ongoing at the time 
of the Week 6/EOS Visit, new onset AEs that are assessed by the Investigator as possibly, 
probably, or certainly related to the study drug, or as an SAE.   
• For each AE recorded on the Adverse Event eCRF, the Investigator will provide an 
assessment of seriousness (see Section 11.6.2 for seriousness criteria), severity (see Section 
11.6.4), and causality (see Section 11.6.5). 
• The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE (or SAE). 
• Actions in terms of concomitant therapy given to treat the AE will be documented according 
to the following categories: 
o None 
o Non-drug therapy 
o Drug therapy 
o Drug therapy and non-drug therapy 
o Not available 
• Actions taken toward the IMP as a result of the AE will be documented according to the 
following categories: 
o None 
o Dose(s) skipped 
o Dosing interrupted 
o Drug withdrawn 
o Not applicable (e.g., for pre-treatment AEs/Baseline complaints) 


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o Unknown (this designation may only be used if the patient is lost to follow-up or 
withdrew consent from all further study participation and contacts.) 
SAE Recording 
• When an SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports, as applicable) 
related to the event. 
• The Investigator will then record all relevant SAE information on the SAE Report Form and 
the Adverse Event eCRF.  
• For each SAE, the Investigator will provide an assessment of seriousness (see Section 11.6.2 
for seriousness criteria), severity (see Section 11.6.4), and causality (see Section 11.6.5). 
However, completion of these assessments should not delay reporting of the SAE to the 
Pharmacovigilance (PV) and Safety Manager (see Section 11.6.6). 
• It is not acceptable for the Investigator to send photocopies of the patient’s medical records 
to the PV and Safety Manager in lieu of completion of the SAE Form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor, Medical Monitor, or PV and Safety Manager. In this case, all patient identifiers, 
with the exception of the study-specific patient ID number and key demographic data (as 
permitted by the local IRB/REB policies), will be redacted on the copies of the medical 
records before submission to the PV and Safety Manager. 
 
11.6.4. 
Assessment of AE/SAE Intensity 
Assessment of Intensity 
The Investigator will provide an assessment of intensity for each clinical and laboratory AE and 
SAE reported during the study according to the following categories:  
• Mild: An event that is either asymptomatic or associated with mild symptoms that are 
easily tolerated by the participant, causing minimal discomfort, and not interfering with 
everyday activities, and not requiring intervention. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
age-appropriate activities and/or requires minimal, local, or non-invasive intervention. 
• Severe: An event that prevents normal everyday activities, and requires intervention 
(such as pharmacological treatment, surgical intervention, hospitalization, etc.) 
Note: An AE that is assessed as severe should not be confused with an SAE. Severe is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.  
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE (Section 11.6.2), NOT when it is rated as severe. 
 


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11.6.5. 
Assessment of AE/SAE Causality 
Assessment of Causality 
• The Investigator is required to assess the relationship between the study drug and each 
occurrence of each AE/SAE according to the following categories:  
o Not related: Sufficient evidence exists to conclude that there is no causal 
relationship to study drug administration (i.e., no temporal relationship to study drug 
administration or proved other cause). 
o Unlikely related: Sufficient evidence to exclude a causal relationship is lacking; 
however, there is also no evidence or argument to suggest a causal relationship to 
study drug administration (e.g., a temporal relationship to study drug administration 
which makes a causal relationship improbable, and other drugs, chemicals or 
underlying disease[s] provide plausible explanations). 
o Possibly related: Limited evidence or argument exists to suggest a causal 
relationship (e.g., a reasonable time sequence to administration of the study drug but 
could also be explained by concurrent disease(s) or other drugs or chemicals. 
Information on drug withdrawal may be lacking or unclear). 
o Probably related: Sufficient evidence or argument exists to suggest a causal 
relationship (e.g., a reasonable time sequence to administration of the study drug, 
unlikely to be attributed to concurrent disease(s) or other drugs or chemicals. 
Clinically reasonable response on withdrawal [dechallenge].) 
o Certainly related: Clear evidence exists for a causal relationship (i.e., a clinical 
event, including laboratory test abnormality, occurring in a plausible time 
relationship to study drug administration, which cannot be explained by concurrent 
disease or other drugs or chemicals. The response to withdrawal of the drug 
[dechallenge] should be clinically plausible. The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory rechallenge 
procedure, if necessary). 
• Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
AE/SAE is considered to be related to study drug. The following guidance should be 
taken into consideration when determining the causality of an AE/SAE: 
o Temporal relationship of the event onset to the study drug administration; 
o Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors; 
o Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as 
applicable) 
o Known association of the event with the disease under study 
o Known association of the event with the study drug or with similar treatments 


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• For each AE/SAE, clinic/medical notes must indicate that the Investigator has reviewed 
the AE/SAE and has provided an assessment of causality. 
• There may be situations in which the Investigator has minimal information for a reliable 
assessment of causality to be included on the Initial SAE Report Form. Completion of 
the causality assessments should not delay the initial reporting of the SAE to the PV and 
Safety Manager (see Section 11.6.6). However, the Investigator’s assessment of 
causality must be submitted as soon as possible (no later within 24 hours) on a Follow-
up SAE Report From. 
• The Investigator may also change his/her causality assessment in light of follow-up 
information obtained and send an SAE Follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining requirements for 
expedited regulatory reporting of the SAE. 
 
11.6.6. 
Reporting of SAEs 
SAE Reporting via an Electronic SAE Data Collection Tool 
• The primary mechanism for reporting an SAE to the PV and Safety Manager will be the 
electronic SAE data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE Report Form 
(see next section) to report the event within 24 hours of learning about the event. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic SAE data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study patient or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or to the PV 
and Safety Manager by telephone, followed by the submission of a duly completed and 
signed SAE Report Form (no later than within 24 hours of the telephone notification). 
• Contacts for SAE reporting are as follows: 
o PV and Safety Manager 
o Email: pharmacovigilance@veristat.com 
o Telephone: 1-888-662-0657 
o Fax: 1-888-662-0647  
SAE Reporting via Paper SAE Report Form 
• Facsimile or e-mail transmission of the SAE Report Form is the preferred method to transmit 
this information to the PV and Safety Manager. 


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• In rare circumstances, notification by telephone is acceptable, followed immediately after 
(within 24 hours of the telephone notification) by the submission of a duly completed and 
signed SAE Report Form. 
• Contacts for SAE reporting are as follows: 
o PV and Safety Manager 
o Email: pharmacovigilance@veristat.com 
o Telephone: 1-888-662-0657 
o Fax: 1-888-662-0647 
 
11.6.7. 
AE and SAE Follow-up and Outcomes 
Follow-up of AEs and SAEs 
• The Investigator should follow each AE/SAE until the event has resolved to Baseline level 
or better, the event is assessed as stable by the Investigator, the patient is lost to follow-up, 
or the patient withdraws consent.   
• Every effort should be made to follow all SAEs considered to be related to the study drug 
until a final outcome can be reported. Follow-up in case of SAEs may include arrangements 
for the conduct of supplemental measurements and/or evaluations (e.g., additional laboratory 
tests or investigations, or consultation with other health care professionals) as medically 
indicated or as requested by Medical Monitor  (to elucidate the nature and/or causality of the 
event as fully as possible). The Investigator is required to submit any updated SAE data to 
the PV and Safety Manager within 24 hours of receipt of the follow-up information. 
• For each AE, the event outcome (with date) should be documented on the Adverse Event 
eCRF and in the patient's medical record (and on the Final SAE Report Form for each SAE), 
using one of the following categories: 
o Resolved 
o Resolved with sequelae 
o Resolving 
o Not resolved/Ongoing 
o Fatal 
o Unknown (this designation may only be used if the patient is lost to follow-up or 
withdrew consent from all further study participation and contacts.) 
 
 


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11.7. 
Appendix 7: Estimated Glomerular Filtration Rate 
 
Estimated Glomerular Filtration Rate (GFR) will be calculated either by the central laboratory, or 
manually, using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
(Levey et al. 2009; Levey et al. 2010): 
• For females:  
eGFR = 141 x min(SCr/0.7, 1)-0.329 x max(SCr/0.7, 1)-1.209 x 0.993Age x 1.018 x 1.159 [if Black] 
• For males:  
eGFR = 141 x min(SCr/0.9, 1)-0.411 x max(SCr/0.9, 1)-1.209 x 0.993Age x 1.159 [if Black] 
where  
- 
eGFR is expressed in mL/min/1.73 m2 
- 
SCr is serum creatinine in mg/dL  
- 
min is the minimum of SCr/0.7 or 1 (for females) or the minimum of SCr/0.9 or 1 (for males)  
- 
max is the maximum of SCr/0.7 or 1 (for females) or the maximum of SCr/0.9 or 1 (for males) 
- 
Age is expressed in years. 
 
 
 
 


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12. 
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STATISTICAL ANALYSIS PLAN 
STUDY SPONSOR: 
SPONSOR REPRESENTATIVE: 
PROTOCOL TITLE: 
PROTOCOL NUMBER: 
Buzzz Pharmaceuticals Limited 
15 Main Street  
Raheny, Dublin 5, Ireland 
Tel: +44-773-310-4786 
Dr. Deirdre O’Keeffe 
Head of IP and Portfolio Management 
Phase 2 Multicenter, Double-Blind, Randomized, 
Parallel-Group, Vehicle-Controlled Study to 
Evaluate the Efficacy, Safety, and Local 
Tolerability of G001 in Patients with Osteoarthritis 
(OA) of the Knee 
2020-G001-P2 (ClinicalTrials.gov ID: NCT05007808)
PROTOCOL VERSION AND DATE: 
Version 4.0 (December 7, 2022) 
NAME OF TEST DRUG: 
G001 (Celecoxib Gel 4% for Topical 
Administration) 
PHASE: 
Phase 2 
METHODOLOGY: 
Randomized, Double-Blind, Vehicle-Controlled, 2-
Arm 
ANALYSIS PLAN DATE: 
30 March 2023 
ANALYSIS PLAN VERSION: 
Version 1.0 
AUTHOR: 
Julius Kirui 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Buzzz 
Pharmaceuticals and any unauthorized use or disclosure of such information without the 
prior written authorization of Buzzz Pharmaceuticals is expressly prohibited. 


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APPROVAL SIGNATURE PAGE 
Protocol Title: 
Phase 2 Multicenter, Double-Blind, Randomized, Parallel-
Group, Vehicle-Controlled Study to Evaluate the Efficacy, 
Safety, and Local Tolerability of G001 in Patients with 
Osteoarthritis (OA) of the Knee
Sponsor: 
Buzzz Pharmaceuticals Limited
15 Main Street, Raheny,  
Dublin 5, Ireland 
Protocol Number: 
2020-G001-P2
Document Date / Version: 
30 March 2023 / Version 1.0 
Veristat, Inc. Author: 
134 Turnpike Road, Suite 200 
Southborough, MA 01772 
Approval Signature
Job Title
Sponsor Signatory: 
15 Main Street 
Raheny, Dublin 5, Ireland
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidance and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments. All changes to the 
planned analyses will be described in the clinical study report. 



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TABLE OF CONTENTS 
Section 
Page 
1.
Information From the Study Protocol ......................................................................... 10
1.1.
Introduction and Objectives ............................................................................. 10
1.1.1.
Introduction ........................................................................................... 10
1.1.2.
Study Objectives ................................................................................... 10
1.1.2.1. Efficacy Objectives ................................................................ 10
1.1.2.2. Safety Objectives: .................................................................. 11
1.1.3.
Purpose of this Document ..................................................................... 11
1.2.
Study Design ....................................................................................................... 11
1.2.1.
Synopsis of Study Design ..................................................................... 11
1.2.2.
Randomization Methodology ............................................................... 12
1.2.3.
Stopping Rules and Unblinding ............................................................ 12
1.2.3.1. Stopping Rules ....................................................................... 12
1.2.3.2. Blinding.................................................................................. 13
1.2.4.
Study Procedures .................................................................................. 14
1.2.5.
Efficacy and Safety Parameters ............................................................ 18
1.2.5.1. Efficacy Parameters ............................................................... 18
1.2.5.2. Safety Parameters ................................................................... 18
2.
Subject Population ......................................................................................................... 20
2.1.
Population Definitions ....................................................................................... 20
2.2.
Protocol Deviations ............................................................................................ 21
3.
General Statistical Methods .......................................................................................... 22
3.1.
Sample Size Justification ................................................................................... 22
3.2.
General Methods ................................................................................................ 22
3.3.
Computing Environment .................................................................................. 22
3.4.
Baseline Definitions ............................................................................................ 23
3.5.
Methods of Pooling Data ................................................................................... 23
3.6.
Adjustments for Covariates .............................................................................. 23
3.7.
Multiple Comparisons/Multiplicity .................................................................. 23
3.8.
Subpopulations ................................................................................................... 23
3.9.
Withdrawals, Dropouts, Loss to Follow-up ..................................................... 23
3.10. Missing, Unused, and Spurious Data ............................................................... 24


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3.10.1.
Efficacy Data ........................................................................................ 24
3.10.2.
Adverse Event Dates ............................................................................. 24
3.10.3.
Skin Irritation Scores ............................................................................ 25
3.10.4.
Prior and Concomitant Medication ....................................................... 25
3.11. Visit Windows..................................................................................................... 26
3.12. Interim Analyses ................................................................................................ 26
4.
Study Analyses ............................................................................................................... 27
4.1.
Subject Disposition............................................................................................. 27
4.2.
Demographics and Baseline Characteristics ................................................... 27
4.3.
Efficacy Evaluation ............................................................................................ 28
4.3.1.
Primary Efficacy Analysis .................................................................... 28
4.3.1.1. Sensitivity Analyses ............................................................... 29
4.3.1.2. Dose Response Plot................................................................ 29
4.3.1.3. Subgroup Analyses of the Primary Endpoint ......................... 30
4.3.2.
Secondary Efficacy Analyses ............................................................... 30
4.3.2.1. WOMAC Stiffness Subscale, Physical Function Subscale, and 
Total Scores ........................................................................... 30
4.3.2.2. Global Assessment of Disease Activity ................................. 35
4.3.2.3. Global Assessment of Overall Treatment Benefit ................. 37
4.3.2.4. Weekly Mean Worst Daytime and Nighttime Pain NRS Scores
 ............................................................................................... 37
4.3.2.5. Incidence of Rescue Medication Use ..................................... 40
4.4.
Safety Analyses ................................................................................................... 41
4.4.1.
Study Drug Exposure and Compliance ................................................. 41
4.4.2.
Adverse Events ..................................................................................... 44
4.4.2.1. Summary of Adverse Events ................................................. 44
4.4.3.
Laboratory Data .................................................................................... 45
4.4.4.
Vital Signs and Physical Examination .................................................. 46
4.4.5.
Electrocardiogram ................................................................................. 46
4.4.6.
Analysis of Skin Irritation .................................................................... 47
4.4.7.
Concomitant Medications ..................................................................... 47
5.
Changes to Planned Analyses ....................................................................................... 49
6.
References ....................................................................................................................... 50


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7.
Appendix ......................................................................................................................... 52
7.1.
Adverse Events Related to Application Site .................................................... 52
 


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TABLES INCLUDED IN THE TEXT 
 
Page 
Table 1
Schedule of Assessments ..................................................................................... 15
Table 2 
MedDRA Preferred Terms for Application Site Adverse Events ........................ 52

 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ACR 
American College of Rheumatology 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomic therapeutic class 
BMI 
Body mass index 
BL 
Baseline 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EOS 
End-of-study 
EOT 
End-of-treatment 
FPFV 
First patient first visit 
FV 
Flare visit 
HR 
Heart rate 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IGA 
Investigator Global Assessment 
IMP 
Investigational medicinal product 
IWRS 
Interactive Web Response System 
LOCF 
Last observation carried forward 
LPLV 
Last patient last visit 
LS 
Least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
NRS 
Numerical Rating Scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
OA 
PGA 
PP 
PP1 
PP2 
PT 
Osteoarthritis 
Patient Global Assessment 
Per Protocol 
Per Protocol 1 
Per Protocol 2 
Preferred term 


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Abbreviation 
Definition 
Rel Day 
SAP 
SD 
SI 
SOC 
TEAE 
ULN 
WHO 
WOMAC 
Relative study day 
Statistical analysis plan 
Standard deviation 
International System of Units 
System organ class 
Treatment-emergent adverse event 
Upper limit normal 
World Health Organization 
Western Ontario and McMaster Universities Osteoarthritis Index 
 
 


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1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction and Objectives 
1.1.1. 
Introduction 
Osteoarthritis (OA) is a degenerative joint disease that is highly prevalent, and a leading cause 
of disability around the globe (Cross et al. 2014; GBD 2016). Clinically, the knee is the most 
common site of OA (accounting for approximately 85% of the OA burden worldwide), followed 
by the hand and hip (Hunter and Bierma-Zeinstra, 2019). 
Osteoarthritis is a heterogeneous disease with a very complex pathology that involves 
mechanical, inflammatory, and metabolic factors, which ultimately lead to structural destruction 
and failure of the synovial joint. Pain is the most disabling symptom in OA, and a major driver 
of clinical decision making and health service use (Hunter and Bierma-Zeinstra, 2019). 
Of the pharmacological interventions for the management of OA pain, medications with the 
least systemic exposure (i.e., local therapy) are preferred. Strongly recommended medications 
for the treatment of knee OA include topical nonsteroidal anti-inflammatory drugs (NSAIDs) as 
first choice (to be considered prior to use of oral NSAIDs, particularly in patients with more 
limited disease), oral NSAIDs, and intra-articular glucocorticoid injections, whereas topical 
capsaicin, acetaminophen, duloxetine, and tramadol are conditionally recommended (Bannuru et 
al. 2019; Kolasinski et al. 2020). Topical NSAIDs have similar efficacy to that of oral NSAIDs; 
however, due to the low systemic absorption, topical NSAIDs have a much better safety profile 
(Rannou et al. 2016). Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] 
benzenesulfonamide), a cyclooxygenase (COX)-2 selective inhibitor, belongs to the 
pharmacological class of NSAIDs. Celecoxib has established analgesic, anti-inflammatory, and 
antipyretic properties (Celebrex CPM, 2019; Celebrex USPI, 2019). 
G001 is a novel gel formulation of celecoxib for topical administration being developed by 
Buzzz Pharmaceuticals Ltd., Ireland for the treatment of signs and symptoms of OA of the knee 
and hand. In a Phase 1 double-blind, randomized, parallel-group study (Study 2019-4679), 
G001 (dose strengths of 1.5% and 4%) was generally well tolerated when administered under 
single-dose (N=18) or multiple dose conditions (N=48) in adult healthy volunteers. The current 
Phase 2 study will provide the first evaluation of the efficacy, safety, and local tolerability of a 
4-week dosing regimen of G001 (dose strength 4%) in patients with OA. 
1.1.2. 
Study Objectives 
The objective of this study is to evaluate the efficacy, safety, and local tolerability of G001 
compared to vehicle in patients with symptomatic OA of the knee. 
1.1.2.1. 
Efficacy Objectives 
Primary Efficacy Objective: 


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To evaluate the efficacy of G001 compared to vehicle in patients with symptomatic OA of the 
knee, as measured by the Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) Pain Subscale Score.  
Secondary Efficacy Objective: 
To further evaluate the efficacy of G001 compared to vehicle in patients with symptomatic OA 
of the knee, as measured by the WOMAC Physical Function Subscale, Stiffness Subscale, and 
Total scores; 11-point pain numerical rating scale (NRS) scores, patient global assessment 
(PGA) and investigator global assessment (IGA) of disease activity and overall treatment 
benefit, and rescue medication use. 
1.1.2.2. 
Safety Objectives: 
The safety objectives of this study include: 
x To evaluate the overall safety of G001 in patients with symptomatic OA of the knee, as 
determined by adverse event (AE) reporting, vital signs, electrocardiogram (ECG) 
measurements, and physical examinations 
x To evaluate the local tolerability of G001 in patients with symptomatic OA of the knee, 
as determined by AE reporting, and skin irritation test scores 
1.1.3. 
Purpose of this Document 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objectives. Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided. The statistical analyses 
and summary tabulations described in this SAP will provide the basis for the results sections of 
the clinical study report (CSR) for this trial. 
This SAP will also outline any differences in the currently planned analytical objectives and 
methods relative to those outlined in the study protocol. 
1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
Study 2020-G001-P2 is a Phase 2 multicenter, double-blind, randomized, parallel-group, 
vehicle-controlled study. A total of 210 patients with primary OA of the knee and moderate OA 
pain are planned to be enrolled at approximately 10 centers located in Canada (Quebec and 
Ontario).  
Following screening, prior NSAID and/or acetaminophen use will be discontinued to allow for 
washout (3 to 7 days) and symptom flare. Eligible patients (patients who meet all of inclusion 
criteria and none of the exclusion criteria) with adequate OA (flare) pain (where adequate OA 
pain is defined in Inclusion Criterion 10 of the protocol) in the index knee at the Baseline/Flare 


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Visit #1 (BL/FV1) will be randomly assigned to one of two treatment groups (G001 4.0% or 
Vehicle) in a 1:1 allocation ratio.  
Patients will have a demonstration of the study drug application at the clinic and receive their 
first dose of the investigational medicinal product (IMP), either G001 or Vehicle (reference 
product), before being sent home. Patients will be instructed to apply 4 grams of the IMP to the 
index knee (i.e., knee selected for study treatment) four times daily for four weeks. Patients will 
also be instructed to rate their worst daytime and nighttime pain in their Treatment Diary, as 
well as to document the date and time of each IMP application, and any rescue medication 
(acetaminophen) use.  
Rescue medication use is discouraged, but acetaminophen may be used, as needed, at a dose not 
exceeding 500 mg per dose and 2,000 mg/day to manage breakthrough pain. No rescue 
medication is allowed within 2 hours after each IMP application, and within 12 hours prior to an 
efficacy assessment.  
Patients will return to the clinic twice during the treatment period for efficacy and safety 
assessments: at Week 2 and at Week 4/End-of-Treatment (EOT). Patients will return to the 
clinic 3 to 7 days after the last IMP application for a second Flare Visit (Week 5/FV2), and 
within approximately 2 weeks after the last IMP application (Week 6) for an end-of-study 
(EOS) evaluation. 
Each patient’s participation will be approximately 7 weeks (~1 week screening, 4 weeks of 
treatment, and 2 weeks of post-treatment follow-up). The overall study duration (from first 
patient first visit [FPFV] to last patient last visit [LPLV]) is expected to be about 6 months. 
1.2.2. 
Randomization Methodology 
Patients will be evaluated for eligibility at the Screening Visit, and at the BL/FV1 prior to 
randomization. Eligible patients with adequate OA pain in the index knee at BL/FV1 will be 
randomized. Randomization will occur centrally, based on a computer-generated randomization 
schedule, and using an Interactive Web Response System (IWRS) within the electronic data 
capture (EDC) system.  
A total of 210 patients will be randomized at a 1:1 ratio to receive either G001 or Vehicle in 
order to achieve a total sample size of 174 evaluable patients (87 per arm), where evaluable is 
defined as randomized patients who have received at least one dose of study drug and provided 
both BL/FV1 and Week 4/EOT efficacy assessments (i.e., the modified Intent-to-Treat [mITT]) 
Population, as defined in Section 2.1). This sample size has been adjusted for an up to 20% 
drop-out rate (prior to the Week 4 efficacy assessment), which was estimated based on available 
literature. Patients discontinuing the trial after randomization will not be replaced due to this 
enrollment overage.  
1.2.3. 
Stopping Rules and Unblinding 
1.2.3.1. 
Stopping Rules 
Reasons for permanent discontinuation of study treatment may include any of the following:  


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x Interruption of study treatment for >3 consecutive days (e.g., due to an AE or other 
reason) 
x Any medical condition that prevents the patient from safely completing the study 
x Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
x Use of/requirement for prohibited medication 
x Patient non-compliance with the study treatment or assessments, as determined by the 
Investigator or the Sponsor 
x Pregnancy 
x Patient’s decision / withdrawal of consent 
Permanent discontinuation of study treatment may be considered if any of the following set of 
laboratory abnormalities indicating potential severe liver injury (possible Hy’s Law) is met, 
regardless of the causality assessment of the event: 
x Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 侔3x upper limit 
normal (ULN) and total bilirubin 侔2x ULN (>35% direct bilirubin) 
x ALT or AST 侔3x ULN and international normalized ratio (INR) >1.5  
Patients have the right to voluntarily withdraw from the study at any time for any reason. In 
addition, the Investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient withdrawal from the study may include, but are not limited to, the 
following: 
x Patient withdrawal of consent 
x AE 
x Loss to follow-up (a patient is considered loss to follow-up if he or she repeatedly fails 
to return for scheduled visits and is unable to be contacted by the study site) 
x Patient non-compliance with the study treatment or assessments 
x Study termination or site closure 
1.2.3.2. 
Blinding 
The Investigator and other study site personnel involved in patient assessments (safety and 
efficacy), as well as patients will remain blinded to treatment assignment throughout the course 
of the study. 
Because G001 and Vehicle formulations are physically distinguishable, at each site, a third party 
(such as a designated pharmacist or research nurse), who is not otherwise involved in the patient 
assessments will be responsible for overseeing all activities that pose a potential risk of 
unblinding, including IMP dispensation, demonstration of the IMP application, and ensuring all 


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IMP applications and discussion only occur in a completely private setting not accessible/visible 
to other staff or patients.      
The Sponsor and its agents will also be blinded to treatment assignment prior to unblinding of 
the treatment assignment at the study level, with the exception of select individuals who require 
access to patient treatment assignments to fulfil their roles during a clinical trial, including those 
involved in the creation and maintenance of the IWRS and drug dispensation. 
1.2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1. 
 


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Table 1 
Schedule of Assessments 
Study Visit 
Screening 
Visit 
BL/FV1 
Visit 
Week 1 
Phone call 
Week 2 
Visit 
Week 3 
Phone call 
Week 4/EOT 
Visit 
Week 5/FV2 
Visit 
Week 6/EOS 
Visit 
Study Day 
Day -7 to -3
Day 1 
Day 8±1 
Day 15±1 
Day 22±1 
Day 29±2 
3-7 Days 
After EOT 
Day 43±3 
Written informed consent [a] 
X 
Demographic data [b] 
X 
Medical and medication history [c] 
X 
OA diagnosis (ACR criteria) [d] 
X 
Radiological examination [e] 
X 
WOMAC Index [f] 
X 
X 
X 
X 
X 
PGA of disease activity [g] 
X 
X 
X 
X 
X 
IGA of disease activity [g] 
X 
X 
X 
X 
X 
PGA of overall treatment benefit [g] 
X 
X 
IGA of overall treatment benefit [g] 
X 
X 
Worst daily pain 11-point NRS (24-hour recall), 
index knee [h] 
X 
X 
 
 
 
 
 
 
Worst daily pain 11-point NRS (24-hour recall), 
contralateral knee [i] 
X 
X 
 
 
 
 
 
 
Physical examination [j] 
X 
X 
X 
Height, weight, and BMI 
X 
Vital signs measurements [k] 
X 
X 
X 
X 
X 
Standard 12-lead ECG [l] 
X 
X 
Safety Laboratory Testing [m] 
X 
X 
X 
X 
X 
Urine pregnancy test [n] 
X 
X 
X 
X 
Urine drug screen 
X 
X 
X 
X 
X 
Review of Inclusion / Exclusion criteria 
X 
X 
Randomization 
X 
Study drug dispensing/reconciliation 
X 
X 
X 
Study drug application (4 times per day) [o] 
X 
X 
X 
X 
X 
Adverse event recording 
X 
X 
X [p] 
X 
X [p] 
X 
X 
X 
Concomitant medications & therapies 
X 
X 
X [p] 
X 
X [p] 
X 
X 
X 
Skin irritation assessment [q] 
X 
X 
X 


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Patient diary completion [r] 
Completed by the patient on a daily basis 
 
Review of the Patient Diary [s] 
 
X 
X [p] 
X 
X [p] 
X 
X 
 
Abbreviations: ACR=American College of Rheumatology; BL=Baseline; BMI=body mass index; BP=blood pressure; ECG=electrocardiogram; EOS=End-of- 
Study; EOT=End-of-Treatment; FV1=Flare Visit #1; FV2=Flare Visit #2; IGA=Investigator Global Assessment; NRS=Numerical Rating Scale; PGA=Patient 
Global Assessment; WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index 
[a] Written informed consent is required before performing any study-specific tests or procedures. 
[b] Demographics include age, gender, and self-reported race/ethnicity. 
[c] Medical history OA history (date of diagnosis, prior treatment), general medical history, surgical history, and reproductive status. Medication history includes 
pharmacological treatment (oral, parenteral, intra-articular, or topical) used in the past 90 days, with focus on medications used for the management of OA, and 
prohibited medications; see Section 6.8.1 of the protocol. 
[d] Documented diagnosis of OA of the knee, meeting ACR clinical criteria for classification of idiopathic (primary) OA (see Appendix 1 of the protocol) for at 
least 6 months prior to Screening is required for enrolment. 
[e] Patients will undergo conventional radiological (X-ray) examination of the index knee during Screening. Exemptions include patients who: (1) had an X-ray of 
the index knee completed within 3 months prior to the Screening visit, and (2) received no treatment since that may have altered the radiological findings, including 
OA grade. Radiologic evidence of OA of the knee of grade 2 (mild) or grade 3 (moderate) according to Kellgren and Lawrence Radiographic Grading (see Appendix 
2 of the protocol) is required for enrolment. 
[f] Patients will complete the 5-point Likert format of the WOMAC® 3.1 Index; see Appendix 3 of the protocol. To qualify for randomization, all participants 
need to develop a flare of pain following washout (3-7 days) of stable analgesic (NSAID and/or acetaminophen) therapy, defined as (1) an increase of 2 
points from Screening in the WOMAC Pain Subscale score for the index knee; and (2) a score of 2 points on at least one of the 5 items in the WOMAC Pain 
Subscale (for the index knee). 
[g] PGA/IGA of disease activity (or PGA/IGA of treatment benefit) evaluates OA in the in the index knee over the last 48 hours on a 5-point Likert scale, where 
0=very good; 1=good; 2=fair; 3=poor; and 4=very poor. 
[h] Worst daily pain (within 24 hours prior to Screening and Baseline/FV1) in the index knee needs to be between 4 and 8 on the 11-point pain NRS for enrolment. 
[i] Worst daily pain (within 24 hours prior to Baseline/FV1) in the contralateral knee needs to be 2 on the 11-point pain NRS scale for enrolment. 
[j] Complete physical examination at Screening and Week 4/EOT, and symptom-driven examination at Week 6/EOS. A complete physical examination will 
include a review of all body systems, with special attention to the cardiovascular, gastrointestinal, and musculoskeletal systems, as well as skin and subcutaneous 
tissues. 


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[k] Vital signs measurements will include sitting (after 3 minutes of rest) blood pressure (BP), heart rate (HR), respiratory rate (RR), and body temperature. Two 
consecutive BP readings (at least 1 minute apart) will be recorded, and the average of the two readings will be entered in the eCRF. 
[l] Standard 12-lead ECG, taken in a supine position, after resting for at least 5 minutes. 
[m] Includes: Haematology, Biochemistry, Coagulation tests, Urinalysis; see Appendix 5 of the protocol. 
[n] A confirmatory serum pregnancy test must be completed in case the urine test is positive. Patients with a positive pregnancy test during Screening will be 
excluded from the study. Patients with a positive pregnancy test during the treatment or post-treatment follow-up period will be withdrawn from the study. 
[o] The first dose will be applied at the clinic, in the presence of a qualified unblinded treatment administrator; subsequent applications will be completed by the 
patient at the clinic (on Day 15/Week 2 Visit) or at their home (all other applications). Accurate dosing will be ensured by using a dosing card (to be used for all 
study drug applications). Patients will be dispensed a two-week supply of study drug (three tubes of 100 grams) on Day 1 (Baseline/FV1) and on Day 15 (Week 2 
Visit), and will be asked to return all unused study drug supplies at the next study visit. 
[p] The Investigator (or qualified designee) will contact the patient by phone after one week of treatment (Week 1, study Day 8 ± 1), and after three weeks of 
treatment (Week 3, study Day 22 ± 1), to verify compliance with the study drug application and daily diary completion requirements, and to follow up on how the 
IMP is tolerated. 
[q] Skin irritation will be assessed by the Investigator using the Berger/Bowman Scoring Scale; see Appendix 4 of the protocol. To the extent feasible, the 
same scorer should complete all three skin irritation assessments (Week 2, Week 4/EOT, and Week 6/EOS) for a patient. 
[r] Patients will be given a study diary and instructed to enter the following on a daily basis, from the Screening visit through the Week 5/FV2 visit: (1) Each 
morning between 6 a.m. and 7 a.m. (before the first daily study drug application on treatment days), patients should rate their worst night-time pain in the index 
knee on the 11-point pain NRS; (2) Between 10 p.m. and 11 p.m. (before the last daily study drug application on each treatment day), patients should rate their 
worse daytime pain in the index knee on the 11-point pain NRS and enter any adverse event experienced, and breakthrough pain medication use during the day; 
(3) In addition, on treatment days, patients should enter the time of each study drug application. 
[s] Non-compliance with the daily diary requirement during the Screening period (defined as <3 days of daytime or nighttime pain assessments or <3 days of 
rescue medication entries) will result in exclusion from the study. 
 


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1.2.5. 
Efficacy and Safety Parameters 
1.2.5.1. 
Efficacy Parameters 
The primary efficacy endpoint is the change from Baseline in WOMAC (version 3.1; 5-point 
Likert format) Index Pain Subscale score at the Week 4/EOT visit.  
The secondary efficacy endpoints include the following: 
x Mean worst daytime and mean worst nighttime pain severity scores (11-point pain NRS, 
from patient diary) at Week 4/EOT and Week 5/FV2 
x Change from Baseline in mean worst daytime and mean worst nighttime pain severity scores 
(11-point pain NRS, from patient diary) at Week 4/EOT and Week 5/FV2 (refer to Section 
3.4 for the definition of Baseline) 
x Percentages of patients achieving 20%, 30%, and 50% reduction from Baseline in worst 
daytime pain severity scores (11-point pain NRS, from patient diary) at Week 4/EOT 
x Percentages of patients achieving 20%, 30%, and 50% reduction from Baseline in worst 
nighttime pain severity scores (11-point pain NRS, from patient diary) at Week 4/EOT 
x Change from Baseline to Week 4/EOT in WOMAC Physical Function Subscale score  
x Change from Baseline to Week 4/EOT in WOMAC Total score 
x Change from Baseline to Week 4/EOT in WOMAC Stiffness Subscale score 
x Change from Baseline to Week 2 in WOMAC Total and each of the Subscale scores 
x Change from Week 4/EOT to Week 5/FV2 in WOMAC Total and each of the Subscale 
scores 
x Change from Baseline in PGA of disease activity over time 
x Change from Baseline in IGA of disease activity over time 
x PGA and IGA of overall treatment benefit at Week 2 and Week 4/EOT 
x Incidence of rescue medication use, number of doses, and percentage of days with any 
rescue medication use during the last week of study treatment and overall, during the study 
treatment period (between first and last IMP dose dates) 
1.2.5.2. 
Safety Parameters 
Safety evaluations performed during the study will include physical examinations, measurement 
of vital signs, 12-lead ECGs, skin irritation, clinical laboratory evaluations including 


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hematology, serum chemistry, coagulation, and urinalysis. In addition, AEs and concomitant 
medications will be monitored throughout the study period. 
The safety endpoints include the following: 
x Frequency and severity of AEs, study drug-related AEs, serious adverse events (SAEs), and 
AEs leading to study drug discontinuation 
x Changes in safety laboratory test results, vital signs measurements, 12-lead ECG, and 
physical examination findings 
x Frequency and severity of application site AEs 
x Skin irritation test scores at Week 2, Week 4/EOT, and Week 6/EOS  


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2. 
SUBJECT POPULATION 
2.1. 
Population Definitions 
The following patient populations will be evaluated and used for presentation and analysis of 
the data: 
x Modified Intent-to-Treat (mITT) Population: All randomized patients who received at least 
one dose of IMP and provided both BL/FV1 and Week 4/EOT efficacy assessments. 
x Per Protocol 1 (PP1) Population: All patients in the mITT population who completed the 
study without major protocol deviations/factors that could impact the assessment of efficacy. 
Reasons for exclusion from the PP1 population include:  
 Any violation of the Inclusion criteria that may affect the efficacy evaluations 
o Inclusion criteria 2 to 5, 8, and 10 
 Any violation of the Inclusion/Exclusion criteria that may affect the efficacy 
evaluations 
o Exclusion criteria 1 to 9, 19, 22, 25 to 36 
 Use of rescue medication other than acetaminophen, or rescue medication 
(acetaminophen) use within 12 hours prior to the Baseline and/or the Week4/EOT 
primary efficacy endpoint (WOMAC Pain Scale) assessment  
 Use of prohibited medications (as listed in Table 7 of the study protocol) during the 
treatment period  
 Inadequate (<80%) compliance, defined as <23 days of treatment, or <92 doses 
applied 
 >12 consecutive IMP doses missed 
 48 hours between last IMP dose and the Week4/EOT primary efficacy endpoint 
(WOMAC Pain Scale) assessment 
x Per Protocol 2 (PP2) Population: All patients in the PP1 population who received at least 
65% of the target amount of IMP during the overall 4-week treatment period and during the 
last 2 weeks of study treatment. Details on the derivation of the target amount of IMP 
(overall and for the last 2 weeks of study treatment), and compliance based on the amount of 
IMP used are provided in Section 4.4.1.    
x Safety Population:  All patients who received any amount of IMP (G001or Vehicle).  
The mITT population is the primary population for the analysis of efficacy parameters. All 
primary and secondary efficacy analyses will also be completed using the PP1 and PP2 
populations. The Safety population is the primary population for the analysis of all safety 
endpoints and demographics/baseline characteristics. 
For all efficacy analyses (based on the mITT, PP1 and PP2 populations), patients will be 
grouped according to the treatment assigned at randomization. For all safety analyses (based on 
the Safety population), patients will be grouped according to the treatment actually received.  


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2.2. 
Protocol Deviations 
A major protocol deviation is defined as: 
x Any violation of the Inclusion or Exclusion criteria 
x Less than 80% treatment compliance by the number of IMP applications (<23 days of 
treatment, or <92 doses applied) 
x >12 consecutive IMP doses missed 
x Use of rescue medication (acetaminophen or a non-permitted rescue medication) within 
12 hours prior to the Baseline and/or the Week4/EOT primary efficacy endpoint 
(WOMAC Pain Scale) assessment 
x Use of prohibited medications (as listed in Table 7 of the study protocol) during the 
treatment period 
x Any other deviations that might significantly affect the interpretation of the primary 
endpoint or compromise the scientific value of the trial 
x Any other deviation that might significantly affect a patient’s safety, well-being, or 
rights  
Major protocol deviations will be summarized and reported. All protocol deviations will be 
presented in a data listing. A separate listing will be presented for all major protocol deviations. 
At the discretion of the Sponsor, a blinded review of key study data will be undertaken prior to 
clinical database lock and unblinding at the study level, to determine the exclusions from the Per 
Protocol (PP) populations. The Sponsor or designee will be responsible for producing the final 
protocol deviation file (formatted as a Microsoft Excel). This file will include a description of 
each protocol deviation that warrants exclusion from each PP population (PP1 and PP2), as 
defined in Section 2.1. This file will be finalized prior to hard database lock.  
Relevant Output 
Table 14.1.5   
Major Protocol Deviations Summary  (Safety Population) 
Listing 16.2.2.1   Inclusion/Exclusion Criteria (All Screened Patients) 
Listing 16.2.2.2  Major Protocol Deviations (All Screened Patients) 
Listing 16.2.2.3   Minor Protocol Deviations  (All Randomized Patients) 


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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
A total sample size of 174 evaluable patients (87 patients in G001 treatment group and 87 
patients in Vehicle control group) achieves 80% power to detect a statistically significant 
difference of 1.5 points in the mean WOMAC Likert Pain Subscale scores (range from 0 – 20) 
between the two treatment groups, assuming a common standard deviation (SD) of 3.5 in a two-
sided t-test with Type I error rate (alpha) of 0.05.  
The assumptions on change in WOMAC Pain Subscale score between the two treatment groups 
were based on available literature on clinically relevant differences and efficacy of celecoxib 
oral formulation (Williams et al. 2000; McKenna et al. 2001; Rother et al. 2007). 
Based on available literature, it is estimated that up to 20% of enrolled patients may withdraw 
from the study prior to the Week 4/EOT efficacy assessment. Therefore, to control for possible 
dropouts, the sample size is increased to 210 patients, or 105 patients per treatment arm.    
3.2. 
General Methods 
All data listings that contain an evaluation date will contain a relative study day (Rel Day). Pre-
treatment and on-treatment study days are numbered relative to the day of the first dose of study 
medication which is designated as Day 1. The preceding day is Day -1, the day before that is 
Day -2, etc.  
All output will be incorporated into RTF and Adobe Acrobat PDF files, sorted and labeled 
according to the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) recommendations, and formatted to the appropriate page 
size(s). 
Tabulations will be produced for appropriate demographic, baseline, compliance, exposure, 
efficacy, and safety parameters. For categorical variables, summary tabulations of the number 
and percentage of subjects within each category (with a category for missing data) of the 
parameter will be presented. For continuous variables, the number of subjects, mean, median, 
SD, minimum, and maximum values will be presented.  
Formal statistical hypothesis testing will be performed on the primary efficacy endpoint with all 
tests conducted at the 2-sided, 0.05 level of significance. Summary statistics will be presented, 
as well as confidence intervals (CIs) on selected parameters, as described in the sections below.  
Tabulations will be presented by treatment group (G001 or Vehicle) and overall.  
3.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.4, 
unless otherwise noted. Medical history and AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) Version 23.1. Concomitant medications will be coded using 
the World Health Organization (WHO) Drug Dictionary Global B3 September 2020. 


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3.4. 
Baseline Definitions 
For all analyses except change from baseline in worst daytime and nighttime pain severity NRS 
scores, baseline will be defined as the most recent measurement prior to the first application of 
study drug (IMP).  
The baseline for worst daytime and nighttime pain severity NRS scores is defined as the mean 
of the 3 – 7 day pain scores prior to the Baseline Visit, as collected in the Screening diary.  
3.5. 
Methods of Pooling Data 
For purposes of summary tabulations, data will be pooled across study sites and by treatment 
group for all analyses. No additional pooling of data is planned.  
3.6. 
Adjustments for Covariates 
The analysis for primary and secondary efficacy endpoints includes baseline value of these 
endpoints as a covariate in the model. A sensitivity analysis for the primary efficacy endpoint 
will include percent treatment compliance based on IMP amount used (computed based on the 
leftover IMP returned to clinic; see Section 4.4.1), as a covariate.  
3.7. 
Multiple Comparisons/Multiplicity 
Multiplicity is not of concern for this study with a single primary efficacy endpoint.  
There are multiple secondary efficacy endpoints as specified in Section 1.2.5.1. Analysis of 
these secondary endpoints will be considered supportive. Hence, no adjustment for multiple 
comparisons will be made among the secondary efficacy endpoints.  
3.8. 
Subpopulations 
Subgroup analyses of primary and select secondary efficacy endpoints may be performed based 
on prior OA treatment and depending on the number of patients in each category (Section 
4.3.1.3).  
3.9. 
Withdrawals, Dropouts, Loss to Follow-up 
If a patient withdraws from the study prematurely for any reason or repeatedly fails to return for 
visits (i.e., is lost to follow-up), the Investigator should determine the primary reason for a 
patient’s premature withdrawal from the study and record the reason in the respective patient’s 
study documents. At the time of premature discontinuation, if feasible, an EOT visit should be 
conducted (within no later than 2 days after the last dose of IMP), followed by an EOS visit (14 
± 2 days after last study drug application) as shown in the Schedule of Assessment (Table 1).  
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.  


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Due to planned enrollment overage to account for potential dropouts, subjects who are 
withdrawn or discontinue from the study will not be replaced. 
3.10. 
Missing, Unused, and Spurious Data 
All data recorded on the case report form (CRF) will be included in data listings that will 
accompany the CSR. 
3.10.1. 
Efficacy Data  
Missing WOMAC assessments will be handled as instructed in the WOMAC 3.1 User Guide XI 
and is summarized as follows:   
WOMAC Pain Subscale: 
x If exactly 1 pain response (out of 5) is missing, the missing response will be imputed 
with the mean of the 4 non-missing pain responses.  
x If more than 1 pain response (out of 5) is missing, the Pain Subscale score for that time 
point will be considered missing. 
WOMAC Stiffness Subscale: 
x If exactly 1 stiffness response (out of 2) is missing, the missing response will be imputed 
with the other stiffness response.  
x If both stiffness responses are missing, the Stiffness Subscale score will be considered 
missing.  
WOMAC Physical Function Subscale: 
x If no more than 3 physical function responses (out of 17) are missing, the missing 
responses will be imputed as the mean of the non-missing physical function responses.  
x If more than 3 physical function responses (out of 17) are missing, the Physical Function 
Subscale score will be considered missing.  
WOMAC assessments that are missing completely at a visit will not be imputed. If at least one 
of the WOMAC subscale score is missing completely, the WOMAC Total Score will be 
considered missing and will not be imputed.   
Furthermore, missing PGA/IGA of disease activity, PGA/IGA of overall treatment benefit, and 
worst daytime and nighttime pain severity scores (11-point pain NRS) will not be imputed.    
3.10.2. 
Adverse Event Dates 
When tabulating AE data, partial dates will be handled as follows to determine treatment-
emergence.  
x If the start date of an AE is partially or completely missing, the date will be compared as 
far as possible with the date of the first study drug application. The AE will be assumed 


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to be treatment-emergent if it cannot be definitively shown that the AE did not occur or 
worsen during the treatment period (worst case approach).  
The following general rule will be used: 
x If the start date is complete, an AE will only be excluded from being treatment-emergent 
if the start date and start time is before the date and time of the first study drug 
application.  
x If the start day is missing but the start month and year are complete, an AE will only be 
excluded from being treatment-emergent if the start month/year is before the month/year 
of the first study drug application or if the stop date is before the first study drug 
application.  
x If the start day and month are missing but the start year is complete, an AE will only be 
excluded from being treatment-emergent if the start year is before the year of first study 
drug application or if the stop date is before the first study drug application.  
x If the start date is completely missing, an AE will be considered treatment-emergent 
unless the stop date is before the first study drug application.  
3.10.3. 
Skin Irritation Scores 
Skin irritation will be assessed by the Investigator using the Berger/Bowman Scoring Scale 
(Berger and Bowman, 1982; US FDA Guidance 2018b), comprising the “Dermal Response” 
and “Other Effects” scoring system, as outlined in Protocol Appendix 4. 
If a patient was removed from treatment due to skin irritation, the patient’s skin irritation score 
at the time of treatment discontinuation will be used as the imputed value at subsequent 
assessment timepoint(s) (i.e., last observation carried forward [LOCF]). If a patient was 
removed from treatment due to reasons other than skin irritation, missing data will not be 
imputed. 
3.10.4. 
Prior and Concomitant Medication 
Medications with partial or missing dates will be assumed to be concomitant unless there is 
clear evidence (i.e., through comparisons of partial dates as noted below) to suggest that the 
medication ended prior to study drug application. 
Partially missing dates for concomitant medications will be imputed for determination of 
designation of prior vs. concomitant medication as follows: 
x If the start date is unknown (i.e., complete missing start date):  
o If there is a record indicating that medication is not ongoing at baseline (although 
end date is unknown), the medication will be considered prior.  
o If there is no end date or any evidence that medication is not ongoing, the 
medication will be considered both prior and concomitant.  
x If the month and the day of the start date are missing, the month and the day will be 
imputed to January 1 of the year specified.  


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x If the day of the start date is missing and there is no end date, the day will be imputed to 
the first day of the month specified.  
x If the month and the day of the end date are missing, the month and the day will be 
imputed to December 31 of the year specified, unless there is evidence that the 
medication is not ongoing in the study (although complete end date is unknown). In such 
circumstances the medication will be considered as prior.  
x If the day of the end date is missing, the day will be imputed to the last day of the month 
specified, unless there is evidence that the medication is not ongoing in the study 
(although complete end date is unknown). In such circumstances the medication will be 
considered as prior.  
3.11. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. All data will be 
tabulated per the evaluation visit as recorded on the CRF even if the assessment is outside of the 
visit window (refer to Table 1 for visit window). If the evaluation visit is missing in the database 
but there are data from an unscheduled or additional visit that is inside the visit window, the 
data from the unscheduled or additional visit will be used in data summaries. In data listings, the 
relative day of all dates will be presented. 
3.12. 
Interim Analyses 
No interim analyses are planned for this study. 


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4. 
STUDY ANALYSES 
4.1. 
Subject Disposition 
Patient disposition will be tabulated and include the number screened, the number randomized, 
the number treated with G001/Vehicle control, and overall. The number in each patient 
population for analysis, the number who completed the treatment, the number who withdrew 
prior to completing treatment, primary reason for withdrawal from the treatment, the number 
who completed the study, the number who withdrew prior to completing the study and the 
primary reason for withdrawal from the study will also be summarized. 
A by-patient data listing of study completion information including the reason for premature 
withdrawal from the study, if applicable, will be presented. 
Relevant Output 
Table 14.1.1   
Subject Disposition 
Listing 16.2.1.1   Subject Disposition (All Randomized Patients) 
Listing 16.2.1.2   Randomization Details (All Screened Patients) 
Listing 16.2.3.1  Study Populations (All Randomized Patients) 
 
4.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized and presented by treatment 
group and overall for the Safety population. Age, height, weight, and body mass index (BMI) 
will be summarized using descriptive statistics (number of patients, mean, SD, median, 
minimum, and maximum). The number and percentage of patients in each sex, ethnicity and 
race category will be presented. The number and percentage of patients falling into each of the 
following age groups will also be presented: <40 years, 40 – 64 years, 65 – 74 years, t 75 years.    
Worst daily pain in the past 24 hours (11-point NRS) for the Screening Visit and BL/FV1 will 
be tabulated and summarized by the following 7 categories: 0–3, 4, 5, 6, 7, 8, 9–10, and 
presented separately for the index knee and contralateral knee.    
General medical history and OA history of the knee will be tabulated by treatment group for the 
Safety population.  
Demographic, baseline characteristics, OA history (date of diagnosis, American College of 
Rheumatology [ACR] clinical criteria, radiological examination), OA treatment history, medical 
history, and worst daily pain assessment results (11-point pain NRS) at Screening Visit and 
BL/FV1 for each patient will be provided in data listings. 
Relevant Output 
Table 14.1.2   
Demographic and Baseline Characteristics (Safety Population)
Table 14.1.3   
Medical History (Safety Population)
Table 14.1.4.1   History of Osteoarthritis of the Knee  (Safety Population) 


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Table 14.1.4.2 
Osteoarthritis Treatment History (Safety Population) 
Listing 16.2.4.1   Demographics and Baseline Characteristics  (All Randomized Patients) 
Listing 16.2.4.2   Medical History (All Randomized Patients) 
Listing 16.2.4.3   History of Osteoarthritis of the Knee  (All Randomized Patients) 
Listing 16.2.4.4  Osteoarthritis Treatment History  (All Randomized Patients) 
Listing 16.2.4.5 Worst Daily Pain 11-Point NRS  (All Randomized Patients) 
4.3. 
Efficacy Evaluation 
Efficacy analyses will be conducted using the mITT population as primary analysis population, 
and repeated using the PP1 and PP2 populations (repeat analyses using the PP1 and PP2 
populations may be limited to the primary efficacy endpoint, and select secondary efficacy 
endpoints). The primary and secondary efficacy endpoints are described in Section 1.2.5.1.  
For all efficacy evaluations involving WOMAC ratings, the WOMAC 3.1 Index (5-point Likert 
format) will be used. The WOMAC OA index is a self-administered questionnaire consisting of 
24 questions divided into three subscales (Bellamy et al. 1988): 
x Pain Subscale: 5 questions  
x Stiffness Subscale: 2 questions 
x Physical Function Subscale: 17 questions 
The Likert version of the WOMAC is rated on an ordinal scale of 0 to 4, where 0 represents the 
lowest level of symptoms or physical disability: 0 = None; 1 = Mild; 2 = Moderate; 3 = Severe; 
4 = Extreme. For each subscale, the scores for individual items are summed, providing the 
following possible ranges: 0 to 20 for Pain Subscale, 0 to 8 for Stiffness Subscale, and 0 to 68 
for Physical Function Subscale. The sum of the three subscales is the WOMAC Total score and 
ranges from 0 to 96. Higher scores on the WOMAC indicates worse pain, stiffness, and physical 
function. Imputation rules for missing WOMAC data are specified in Section 3.10.1.  
Sensitivity analyses of the primary and select secondary efficacy endpoints are detailed in 
Section 4.3.1.1. 
4.3.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the change from Baseline in the WOMAC Pain Subscale score 
in 5-point Likert format at the Week 4/EOT visit. The primary efficacy analysis will be 
performed using an analysis of covariance (ANCOVA) model. The model will include treatment 
(G001 or Vehicle) as the independent variable, change from Baseline in the WOMAC Pain 
Subscale score at the Week 4/EOT visit as the outcome (dependent) variable, and Baseline 
WOMAC Pain Subscale score as a covariate. The overall difference of adjusted means between 
the treatment groups will be analyzed by a partial F test at a significance level of 0.05.  
The primary efficacy outcome comparison between the two treatment groups (G001 group and 
Vehicle control) will also be provided by comparing their Least Square (LS) means of change 
from Baseline WOMAC Pain Subscale scores. The LS means are interpreted as the mean 
change from Baseline WOMAC Pain Subscale score of the two treatment groups after adjusting 
for the covariate (Baseline WOMAC score) in the model. Summary tables will include LS 


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means, standard errors, and 95% CIs for each treatment group. The difference in LS means, as 
well as the associated 95% CI and the p-value from the t-test for the statistical test for the LS 
means difference, will be presented as well.     
Refer to Section 4.3.2.1 for additional analysis of the WOMAC Pain Subscale score actual 
values by visit, graphical representation and by patient listing. 
Relevant Output 
Table 14.2.1.1.1A   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Pain Subscale (mITT 
Population: Primary Efficacy Analysis) 
Table 14.2.1.1.1B   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Pain Subscale (Per Protocol 
Population 1: Supportive Primary Efficacy Analysis) 
Table 14.2.1.1.1C   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Pain Subscale (Per Protocol 
Population 2: Supportive Primary Efficacy Analysis) 
4.3.1.1. 
Sensitivity Analyses  
A sensitivity analysis will be performed to evaluate the effect of IMP compliance on the primary 
efficacy endpoint. This sensitivity analysis will use the same ANCOVA model as described in 
Section 4.3.1 but with one additional covariate: percent IMP amount-based compliance. Percent 
IMP compliance will be computed according to leftover IMP returned to clinic by randomized 
patients in the mITT population, as detailed in Section 4.4.1. The overall difference of adjusted 
means between the treatment groups will be analyzed by a partial F test at a significance level of 
0.05. 
In addition, sensitivity ‘completers’ analysis on the primary (and potentially key secondary) 
efficacy endpoint(s) may be completed on a subset of patients who completed the Week 4/EOT 
efficacy assessments after a minimum 25-day overall treatment period.   
Relevant Output 
Table 14.2.1.1.1A1  Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Pain Subscale (mITT 
Population: IMP Compliance Sensitivity Analyses for Primary Efficacy 
Analysis) 
Table 14.2.1.1.1A2  Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Pain Subscale (mITT 
Population: Completers Sensitivity Analyses for Primary Efficacy 
Analysis) 
4.3.1.2. 
Dose Response Plot 
To support primary efficacy analysis and the assessment of the effect of percent IMP amount-
based compliance on efficacy, a dose response plot will be provided to explore the variation in 


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the primary efficacy endpoint as a function of percent IMP compliance (based on amount of 
IMP used, and number of IMP applications) in the two treatment groups. This plot will be 
considered supportive and no formal statistical inferences or quantitative conclusion will be 
drawn.  
Relevant Output 
Figure 14.2.1.1.1 
Dose Response Scatter Plot of Change from Baseline to Week 4/EOT in 
Western Ontario and McMaster Universities (WOMAC) Pain Subscale 
Score (mITT Population: Supportive Plot for IMP Amount Base)  
Figure 14.2.1.1.2  
Dose Response Scatter Plot of Change from Baseline to Week 4/EOT in 
Western Ontario and McMaster Universities Pain Subscale Score (mITT 
Population: Supportive Plot for Number of IMP Applications) 
 
4.3.1.3. 
Subgroup Analyses of the Primary Endpoint 
Subgroup analyses of primary and select secondary efficacy endpoints may be performed based 
on prior OA treatment categories, including the following: 
x Patients with Pre-study NSAID use for OA (with or without acetaminophen) 
x Patients with Pre-study Acetaminophen use only (without an NSAID) for OA 
Subgroup analysis for each category will be invoked if the minimum number of patients 
comprise of at least 30% of the total number of patients in mITT population and will be 
performed as detailed in Section 4.3.1. 
Relevant Output 
Table 14.2.1.1.1A3  Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT, Pain Subscale (mITT 
Population, Subgroup Analysis, by prior OA Medication Use)  
4.3.2. 
Secondary Efficacy Analyses 
Analyses of secondary efficacy endpoints will be considered supportive. Hence, no p-value 
adjustment will be made for multiple endpoints or multiple comparisons in the secondary efficacy 
analysis.  
4.3.2.1. 
WOMAC Stiffness Subscale, Physical Function Subscale, and Total Scores 
WOMAC Stiffness Subscale score, Physical Function Subscale score, and Total score will be 
analyzed via ANCOVA model similar to the primary efficacy endpoint as described in Section 
4.3.1.  
The following secondary efficacy endpoints will be evaluated: 
x Change from Baseline to Week 4/EOT in WOMAC Stiffness Subscale score 


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x Change from Baseline to Week 4/EOT in WOMAC Physical Function Subscale score 
x Change from Baseline to Week 4/EOT in WOMAC Total score, defined as the sum of 
the 3 WOMAC subscale scores (Pain, Stiffness, and Physical Function) 
x Change from Baseline to Week 2 in WOMAC Pain Subscale score 
x Change from Baseline to Week 2 in WOMAC Stiffness Subscale score 
x Change from Baseline to Week 2 in WOMAC Physical Function Subscale score 
x Change from Baseline to Week 2 in WOMAC Total score, defined as the sum of the 3 
WOMAC subscale scores (Pain, Stiffness, and Physical Function) 
x Change from Week 4/EOT to Week 5/FV2 in WOMAC Pain Subscale score 
x Change from Week 4/EOT to Week 5/FV2 in WOMAC Stiffness Subscale score 
x Change from Week 4/EOT to Week 5/FV2 in WOMAC Physical Function Subscale 
score  
x Change from Week 4/EOT to Week 5/FV2 in WOMAC Total score, defined as the sum 
of the 3 WOMAC subscale scores (Pain, Stiffness, and Physical Function)  
Descriptive statistics of the actual value and change from Baseline at each timepoint will be 
presented by treatment group.  
Actual mean scores and SDs will also be displayed graphically by visit for each subscale and 
total score. 
A by-patient data listing will be provided for each WOMAC Subscale scores (Pain, Stiffness, 
and Physical Function).   
Relevant Output 
Table 14.2.1.1.2A   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 2: Pain Subscale (mITT Population: 
Secondary Efficacy Analysis) 
Table 14.2.1.1.2B   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 2: Pain Subscale (Per Protocol  
Population 1: Secondary Efficacy Analysis) 
Table 14.2.1.1.3A   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Week 4/EOT to Week 5/FV2: Pain Subscale (mITT 
Population: Secondary Efficacy Analysis) 
Table 14.2.1.1.3B   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Week 4/EOT to Week 5/FV2: Pain Subscale (Per 
Protocol Population 1: Secondary Efficacy Analysis) 
Table 14.2.1.2.1A   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Stiffness Subscale (mITT 
Population) 


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Table 14.2.1.2.1B   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Stiffness Subscale (Per 
Protocol Population 1: Secondary Efficacy Analysis) 
Table 14.2.1.2.2A   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 2: Stiffness Subscale (mITT 
Population: Secondary Efficacy Analysis) 
Table 14.2.1.2.2B   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 2: Stiffness Subscale (Per Protocol 
Population 1: Secondary Efficacy Analysis) 
Table 14.2.1.2.3A   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Week 4/EOT to Week 5/FV2: Stiffness Subscale (mITT 
Population: Secondary Efficacy Analysis) 
Table 14.2.1.2.3B   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Week 4/EOT to Week 5/FV2: Stiffness Subscale (Per 
Protocol Population 1: Secondary Efficacy Analysis) 
Table 14.2.1.3.1A   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Physical Function Subscale 
(mITT Population: Secondary Efficacy Analysis) 
Table 14.2.1.3.1B   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Physical Function Subscale 
(Per Protocol Population 1: Secondary Efficacy Analysis)) 
Table 14.2.1.3.2A   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 2: Physical Function Subscale (mITT 
Population Secondary Efficacy Analysis) 
Table 14.2.1.3.2B   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 2: Physical Function Subscale (Per 
Protocol Population 1: Secondary Efficacy Analysis) 
Table 14.2.1.3.3A   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Week 4/EOT to Week 5/FV2: Physical Function Subscale 
(mITT Population Secondary Efficacy Analysis) 
Table 14.2.1.3.3B   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Week 4/EOT to Week 5/FV2: Physical Function Subscale 
(Per Protocol Population 1: Secondary Efficacy Analysis) 
Table 14.2.1.4.1A   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Total Score (mITT Population 
Secondary Efficacy Analysis) 
Table 14.2.1.4.1B   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Total Score (Per Protocol 
Population 1: Secondary Efficacy Analysis) 
Table 14.2.1.4.1C   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Total Score (Per Protocol 
Population 2: Secondary Efficacy Analysis) 
Table 14.2.1.4.2A   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 2: Total Score (mITT Population: 
Secondary Efficacy Analysis) 


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Table 14.2.1.4.2B   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 2: Total Score (Per Protocol Population 
1: Secondary Efficacy Analysis) 
Table 14.2.1.4.3A   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Week 4/EOT to Week 5/FV2: Total Score (mITT 
Population: Secondary Efficacy Analysis) 
Table 14.2.1.4.3B   Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Week 4/EOT to Week 5/FV2: Total Score (Per Protocol 
Population 1: Secondary Efficacy Analysis) 
Table 14.2.2.1A   
Western Ontario and McMaster Universities (WOMAC) Actual Scores and 
Change from Baseline by Visit and Treatment: Pain Subscale (mITT 
Population) 
Table 14.2.2.1B   
Western Ontario and McMaster Universities (WOMAC) Actual Scores and 
Change from Baseline by Visit and Treatment: Pain Subscale (Per Protocol 
Population 1) 
Table 14.2.2.1C   
Western Ontario and McMaster Universities (WOMAC) Actual Scores and 
Change from Baseline by Visit and Treatment: Pain Subscale (Per Protocol 
Population 2) 
Table 14.2.2.2A   
Western Ontario and McMaster Universities (WOMAC) Actual Scores and 
Change from Baseline by Visit and Treatment: Stiffness Subscale (mITT 
Population) 
Table 14.2.2.2B   
Western Ontario and McMaster Universities (WOMAC) Actual Scores and 
Change from Baseline by Visit and Treatment: Stiffness Subscale (Per 
Protocol Population 1) 
Table 14.2.2.3A   
Western Ontario and McMaster Universities (WOMAC) Actual Scores and 
Change from Baseline by Visit and Treatment: Physical Function Subscale 
(mITT Population) 
Table 14.2.2.3B   
Western Ontario and McMaster Universities (WOMAC) Actual Scores and 
Change from Baseline by Visit and Treatment: Physical Function Subscale 
(Per Protocol Population 1) 
Table 14.2.2.4A   
Western Ontario and McMaster Universities (WOMAC) Actual Scores and 
Change from Baseline by Visit and Treatment: Total Score (mITT 
Population) 
Table 14.2.2.4B   
Western Ontario and McMaster Universities (WOMAC) Actual Scores and 
Change from Baseline by Visit and Treatment: Total Score (Per Protocol 
Population 1) 
Table 14.2.2.4C   
Western Ontario and McMaster Universities (WOMAC) Actual Scores and 
Change from Baseline by Visit and Treatment: Total Score (Per Protocol 
Population 2) 
Listing 16.2.6.1   
Western Ontario and McMaster Universities (WOMAC) 3.1 Osteoarthritis 
Index Likert Scores: Pain Subscale (All Randomized Patients) 
Listing 16.2.6.2   
Western Ontario and McMaster Universities (WOMAC) 3.1 Osteoarthritis 
Index Likert Scores: Stiffness (All Randomized Patients) 
Listing 16.2.6.3   
Western Ontario and McMaster Universities (WOMAC) 3.1 Osteoarthritis 
Index Likert Scores: Physical Function (All Randomized Patients) 


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Listing 16.2.6.4 
Western Ontario and McMaster Universities (WOMAC) 3.1 Osteoarthritis 
Index Likert Scores: Total Scores (All Randomized Patients) 
Figure 14.2.2.1A   Western Ontario and McMaster Universities (WOMAC) Mean Scores by 
Visit and Treatment: Pain Subscale (mITT Population: Primary Efficacy 
Analysis) 
Figure 14.2.2.1B   Western Ontario and McMaster Universities (WOMAC) Mean Scores by 
Visit and Treatment: Pain Subscale (Per Protocol Population 1) 
Figure 14.2.2.1C   Western Ontario and McMaster Universities (WOMAC) Mean Scores by 
Visit and Treatment: Pain Subscale (Per Protocol Population 2) 
Figure 14.2.2.2A   Western Ontario and McMaster Universities (WOMAC) Mean Scores by 
Visit and Treatment: Stiffness Subscale (mITT Population) 
Figure 14.2.2.2B   Western Ontario and McMaster Universities (WOMAC) Mean Scores by 
Visit and Treatment: Stiffness Subscale (Per Protocol Population 1) 
Figure 14.2.2.3A   Western Ontario and McMaster Universities (WOMAC) Mean Scores by 
Visit and Treatment: Physical Function Subscale (mITT Population) 
Figure 14.2.2.3B   Western Ontario and McMaster Universities (WOMAC) Mean Scores by 
Visit and Treatment: Physical Function Subscale (Per Protocol Population 
1) 
Figure 14.2.2.4A   Western Ontario and McMaster Universities (WOMAC) Mean Scores by 
Visit and Treatment: Total Score (mITT Population) 
Figure 14.2.2.4B   Western Ontario and McMaster Universities (WOMAC) Mean Scores by 
Visit and Treatment: Total Score (Per Protocol Population 1) 
Figure 14.2.2.4C   Western Ontario and McMaster Universities (WOMAC) Mean Scores by 
Visit and Treatment: Total Score (Per Protocol Population 2)  
In addition, a sensitivity analysis of change from Baseline to Week 4/EOT in WOMAC Total 
score may also be completed using the ‘completers’ analysis population (see Section 4.3.1.1). 
Relevant Output 
Table 14.2.1.4.1A1  Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Total Score (mITT Population: 
Completers Sensitivity Analyses) 
Subgroup analyses of change from Baseline to Week 4/EOT in WOMAC Total score based on 
prior OA treatment may be performed as detailed in Section 4.3.1.3. 
Relevant Output 
Table 14.2.1.4.1A2  Western Ontario and McMaster Universities (WOMAC) Analysis of 
Covariance from Baseline to Week 4/EOT: Total Score (mITT Population: 
Subgroup Analysis, by prior OA Medication Use)  


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4.3.2.2. 
Global Assessment of Disease Activity 
Two global assessment of disease activity scores will be recorded in this study: PGA and IGA. 
Both PGA and IGA of disease activity measure OA in the index knee over the last 48 hours on a 
5-point Likert scale: 0 = Very Good; 1 = Good; 2 = Fair; 3 = Poor; 4 = Very Poor.  
PGA and IGA of disease activity will be recorded at Screening visit, BL/FV1, Week 2, Week 
4/EOT, and Week 5/FV2. At each visit post-BL/FV1, the change from Baseline PGA/IGA of 
disease activity scores will be calculated and the response will be classified into 3 categories 
according to the following rules: 
x Improved – defined as either of the following: 
o For Baseline Grade t 2: a reduction of t 2 grades from Baseline 
o For Baseline Grade = 1: a change in grade from 1 to 0 
x Worsened – defined as either of the following: 
o For Baseline Grade  2: an increase of t 2 grades from Baseline  
o For Baseline Grade = 3: a change in grade from 3 to 4 
x No Change – defined as a change from Baseline PGA/IGA of disease activity that is 
neither Improved nor Worsened 
An ordinal logistic regression model will be used to analyze PGA of disease activity at the 
Week 2 timepoint. The model will include treatment (G001 or Vehicle) as the independent 
variable, change from Baseline of PGA of disease activity category (Improved, No Change, or 
Worsened) at the Week 2 Visit as the outcome (dependent) variable, and Baseline PGA of 
disease activity score as a covariate. The ordinal logistic regression model will assume a 
proportional odds structure and be implemented by PROC LOGISTIC in SAS. The ordering of 
the 3 categories will be defined as follows: 
Worsened < No Change < Improved 
If the final data does not support proportional odds assumption, as judged by the p-value of the 
Score Test being significant at a significance level of 0.05, a non-proportional odds model will 
be used by inserting UNEQUALSLOPES option in the PROC LOGISTIC model statement.   
A summary table of the point estimates, standard errors, and p-values for the slopes and 
intercepts of the model will be presented. Point estimates and Wald 95% CIs for the odds ratio 
will also be summarized. Furthermore, a summary table for the number and percentage of 
patients in each of the 3 PGA disease activity categories will be presented by treatment group 
and overall.  
The same analysis will be repeated for the change from Baseline of PGA of disease activity at 
Week 4/EOT and Week 5/FV2.  
The change from Baseline of IGA of disease activity at the Week 2, Week 4/EOT, and Week 
5/FV2 timepoint will be analyzed in similar fashion as the change from Baseline of PGA of 
disease activity as described above.  


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Descriptive statistics of the actual value and change from Baseline of PGA and IGA of disease 
activity at each timepoint will be presented by treatment group.  
A by-patient data listing will be provided for PGA and IGA of disease activity scores.  
Relevant Output  
Table 14.2.3.1A   
Patient Global Assessment of Disease Activity Ordinal Logistic Regression 
at Week 2 (mITT Population) 
Table 14.2.3.1B   
Patient Global Assessment of Disease Activity Ordinal Logistic Regression 
at Week 2 (Per Protocol Population 1) 
Table 14.2.3.2A   
Patient Global Assessment of Disease Activity Ordinal Logistic Regression 
at Week 4/EOT (mITT Population) 
Table 14.2.3.2B   
Patient Global Assessment of Disease Activity Ordinal Logistic Regression 
at Week 4/EOT (Per Protocol Population 1) 
Table 14.2.3.3A   
Patient Global Assessment of Disease Activity Ordinal Logistic Regression 
at Week 5/FV2 (mITT Population) 
Table 14.2.3.3B   
Patient Global Assessment of Disease Activity Ordinal Logistic Regression 
at Week 5/FV2 (Per Protocol Population 1) 
Table 14.2.4.1A   
Patient Global Assessment of Disease Activity Ordinal Scores by Visit and 
Treatment (mITT Population) 
Table 14.2.4.1B   
Patient Global Assessment of Disease Activity Ordinal Scores by Visit and 
Treatment (Per Protocol Population 1) 
Table 14.2.5.1A   
Investigator Global Assessment of Disease Activity Ordinal Logistic 
Regression at Week 2 (mITT Population) 
Table 14.2.5.1B   
Investigator Global Assessment of Disease Activity Ordinal Logistic 
Regression at Week 2 (Per Protocol Population 1) 
Table 14.2.5.2A   
Investigator Global Assessment of Disease Activity Ordinal Logistic 
Regression at Week 4/EOT (mITT Population) 
Table 14.2.5.2B   
Investigator Global Assessment of Disease Activity Ordinal Logistic 
Regression at Week 4/EOT (Per Protocol Population 1) 
Table 14.2.5.3A   
Investigator Global Assessment of Disease Activity Ordinal Logistic 
Regression at Week 5/FV2 (mITT Population) 
Table 14.2.5.3B   
Investigator Global Assessment of Disease Activity Ordinal Logistic 
Regression at Week 5/FV2 (Per Protocol Population 1) 
Table 14.2.6.1A   
Investigator Global Assessment of Disease Activity Ordinal Scores by Visit 
and Treatment (mITT Population) 
Table 14.2.6.1B   
Investigator Global Assessment of Disease Activity Ordinal Scores by Visit 
and Treatment (Per Protocol Population 1) 
Table 14.2.7.1A   
Investigator and Patient Global Assessments of Disease Activity Actual 
Scores and Change from Baseline by Visit and Treatment  (mITT 
Population) 
Table 14.2.7.1B   
Investigator and Patient Global Assessments of Disease Activity Actual 
Scores and Change from Baseline by Visit and Treatment (Per Protocol 
Population 1) 


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Listing 16.2.6.5   
Patient Global Assessment (All Randomized Patients) 
Listing 16.2.6.6   
Investigator Global Assessment (All Randomized Patients) 
4.3.2.3. 
Global Assessment of Overall Treatment Benefit 
The PGA and IGA of overall treatment benefit are secondary efficacy endpoints and similar to 
the PGA/IGA of disease activity, are each evaluated on a 5-point Likert scale: 0 = Very Good; 1 
= Good; 2 = Fair; 3 = Poor; 4 = Very Poor.  
The mean of the PGA or IGA of overall treatment benefit at Week 2 from the two treatment 
groups (G001 and Vehicle) will be compared using a t-test and a 2-sided p-value will be 
presented. A similar analysis will be performed for the mean of the PGA or IGA of overall 
treatment benefit at Week 4/EOT. No formal statistical conclusion will be drawn based on these 
tests.  
Descriptive statistics of the actual value of PGA and IGA of overall treatment benefit scores at 
Week 2 and at Week 4/EOT will be presented by treatment group.  
A by-patient data listing will be provided for PGA and IGA of overall treatment benefit scores. 
Relevant Output 
Table 14.2.8.1A   
Investigator and Patient Global Assessments of Overall Treatment Benefit 
Actual Scores by Visit and Treatment  (mITT Population) 
Table 14.2.8.1B   
Investigator and Patient Global Assessments of Overall Treatment Benefit 
Actual Scores by Visit and Treatment (Per Protocol Population 1) 
4.3.2.4. 
Weekly Mean Worst Daytime and Nighttime Pain NRS Scores 
The mean worst daytime pain NRS score at the specified visit is computed based on patient diary 
entries as follows:  
x 
Baseline mean worst daytime pain NRS scores = sum of worst daytime pain NRS scores 
reported divided by the number of worst daytime pain assessments reported from 1 day before 
the date of Baseline/FV1 Visit up to 7 days before the date of Baseline/FV1 Visit 
x 
Week 2 Visit mean worst daytime pain NRS scores = sum of worst daytime pain NRS 
scores reported divided by the number of worst daytime pain assessments reported 
during the 7-day period from 1 day before the date of Week 2 Visit to 7 days before 
the date of Week 2 Visit  
x Week 4 Visit mean worst daytime pain NRS scores = sum of worst daytime pain NRS 
scores reported divided by the number of worst daytime pain assessments reported 
during the 7-day period from 1 day before the date of Week 4 Visit to 7 days before 
the date of Week 4 Visit  
x Week 5 Visit mean worst daytime pain NRS scores = sum of worst daytime pain NRS 
scores reported divided by the number of worst daytime pain assessments reported 
from 1 day before the date of Week 5 Visit up to the later of 7 days prior to the date of 
Week 5 Visit or the date of Week 4  
 


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The mean worst nighttime pain NRS score at the specified visit is computed based on patient 
diary entries as follows:  
x Baseline mean worst nighttime pain NRS scores = sum of worst nighttime pain NRS scores 
reported divided by the number of worst nighttime pain assessments reported from the date 
of Baseline/FV1 Visit up to 6 days before the date of Baseline/FV1 Visit 
x Week 2 Visit mean worst nighttime pain NRS scores = sum of worst nighttime pain 
NRS scores reported divided by the number of worst nighttime pain assessments 
reported during the 7-day period from the date of Week 2 Visit to 6 days before the 
date of Week 2 Visit  
x Week 4 Visit mean worst nighttime pain NRS scores = sum of worst nighttime pain 
NRS scores reported divided by the number of worst nighttime pain assessments 
reported during the 7-day period from the date of Week 4 Visit to 6 days before the 
date of Week 4 Visit  
x Week 5 Visit mean worst nighttime pain NRS scores = sum of worst nighttime pain 
NRS scores reported divided by the number of worst nighttime pain assessments 
reported from the date of Week 5 Visit up to the later of 6 days prior to the date of 
Week 5 Visit or the date of Week 4 +1 
 
Weekly mean worst daytime and nighttime pain NRS scores will be presented by treatment 
group. Changes from baseline in mean worst daytime and in mean worst nighttime pain severity 
scores at Week 4/EOT in the two treatment groups will be compared using a t-test. Percentages 
of patients achieving 20%, 30% and 50% reduction from Baseline in worst daytime pain and 
in worst nighttime pain severity scores (11-point pain NRS) at Week 4/EOT will be 
descriptively summarized, including the 95% exact CI. Cochran-Mantel-Haenszel (CMH) test 
will be used to determine the difference between treatment groups. The p-value from the general 
association test of CMH will be presented.  
 
A by-patient data listing will be provided for worst daytime and nighttime pain NRS scores. 
NRS scores will also be displayed graphically. 
Relevant Output 
Listing 16.2.6.7 
Worst Daytime/Nighttime Pain 11-Point NRS Diary (All 
Randomized Patients)  
Table 14.2.9.1A 
Weekly Mean Worst Daytime Pain Severity Numerical Rating Scale (NRS) 
by Visit (mITT Population) 
Table 14.2.9.1B 
Weekly Mean Worst Daytime Pain Severity Numerical Rating Scale (NRS) 
by Visit (Per Protocol Population 1) 
Table 14.2.9.1C 
Weekly Mean Worst Daytime Pain Severity Numerical Rating Scale (NRS) 
by Visit (Per Protocol Population 2) 
Table 14.2.9.2A  
Weekly Mean Worst Nighttime Pain Severity Numerical Rating Scale 
(NRS) by Visit (mITT Population) 
Table 14.2.9.2B  
Weekly Mean Worst Nighttime Pain Severity Numerical Rating Scale 
(NRS) by Visit (Per Protocol Population 1) 


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Table 14.2.9.2C  
Weekly Mean Worst Nighttime Pain Severity Numerical Rating Scale 
(NRS) by Visit (Per Protocol Population 2) 
Table 14.2.9.3A 
Percent Reduction from Baseline to Week 4/EOT in Worst Daytime and 
Worst Nighttime Pain (mITT Population) 
Table 14.2.9.3B 
Percent Reduction from Baseline to Week 4/EOT in Worst Daytime and 
Worst Nighttime Pain (Per Protocol Population 1) 
Table 14.2.9.3C 
Percent Reduction from Baseline to Week 4/EOT in Worst Daytime and 
Worst Nighttime Pain (Per Protocol Population 2) 
Figure 14.2.9.1A 
Weekly Mean Worst Daytime Pain Severity Numerical Rating Scale (NRS) 
Actual Scores by Visit (mITT Population) 
Figure 14.2.9.1B 
Weekly Mean Worst Daytime Pain Severity Numerical Rating Scale (NRS) 
Actual Scores by Visit (Per Protocol Population 1) 
Figure 14.2.9.1C 
Weekly Mean Worst Daytime Pain Severity Numerical Rating Scale (NRS) 
Actual Scores by Visit (Per Protocol Population 2) 
Figure 14.2.9.2A 
Weekly Mean Worst Nighttime Pain Severity Numerical Rating Scale 
(NRS) Actual Scores by Visit (mITT Population) 
Figure 14.2.9.2B 
Weekly Mean Worst Nighttime Pain Severity Numerical Rating Scale 
(NRS) Actual Scores by Visit (Per Protocol Population 1) 
Figure 14.2.9.2C 
Weekly Mean Worst Nighttime Pain Severity Numerical Rating Scale 
(NRS) Actual Scores by Visit (Per Protocol Population 2) 
In addition, a sensitivity analysis may also be completed using the ‘completers’ analysis 
population as detailed in Section 4.3.1.1. 
Sensitivity Analysis outputs: 
Table 14.2.9.1A1  Weekly Mean Worst Daytime Pain Severity Numerical Rating Scale (NRS) 
by Visit (mITT Population:  Completers Sensitivity Analyses) 
Table 14.2.9.2A1  Weekly Mean Worst Nighttime Pain Severity Numerical Rating Scale 
(NRS) by Visit (mITT Population:  Completers Sensitivity Analyses) 
Table 14.2.9.3A1  Percent Reduction from Baseline to Week 4/EOT in Worst Daytime Pain 
(mITT Population:  Completers Sensitivity Analyses) 
Subgroup analyses based on prior OA treatment may be performed for the following secondary 
endpoints as detailed above. 
x Mean worst daytime and mean worst nighttime pain severity scores (11-point pain NRS, 
from patient diary) at Week 4/EOT, including mean changes from Baseline 
x Percentages of patients achieving 20%, 30%, and 50% reduction from Baseline in 
worst daytime pain severity scores (11-point pain NRS, from patient diary) at Week 
4/EOT 
x Percentages of patients achieving 20%, 30%, and 50% reduction from Baseline in 
worst nighttime pain severity scores (11-point pain NRS, from patient diary) at Week 
4/EOT 


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Relevant Outputs: 
Table 14.2.9.1A2 
Weekly Mean Worst Daytime Pain Severity Numerical Rating Scale (NRS) 
by Visit (mITT Population: Subgroup Analysis, by prior OA Medication 
Use)  
Table 14.2.9.2A2 
Weekly Mean Worst Nighttime Pain Severity Numerical Rating Scale 
(NRS) by Visit (mITT Population: Subgroup Analysis, by prior OA 
Medication Use) 
Table 14.2.9.3A2 
Percent Reduction from Baseline to Week 4/EOT in Worst Daytime and 
Worst Nighttime Pain (mITT Population: Subgroup Analysis, by prior OA 
Medication Use) 
4.3.2.5. 
Incidence of Rescue Medication Use 
The number and percentage of patients with at least 1 rescue medication (acetaminophen) use 
will be presented by treatment group for:  
x Patients with at least one rescue medication use during the study  
x Patients with at least one rescue medication use during treatment period (day 1 through 
week 4/EOT) 
x Patients with at least one rescue medication use within 12 hours prior to primary efficacy 
endpoint assessment (WOMAC Pain Scale) at week 4/EOT visit 
x Rescue medication doses (mg) within 12 hours prior to primary efficacy endpoint 
assessment (WOMAC Pain Scale) at week 4/EOT visit 
x Number of rescue medication doses during the study 
x Number of rescue medication doses during treatment period (day 1 through week 
4/EOT) 
x Average daily rescue medication dose (mg/day) during the study 
x Average daily rescue medication dose (mg/day) during treatment period (day 1 through 
week 4/EOT) 
x Percentage of days with any rescue medication use during the study  
x Percentage of days with any rescue medication use during treatment period (day 1 
through week 4/EOT) 
x The percentage of days with any rescue medication use during the last week (from 1 day 
before the date of Week 4/EOT Visit to 7 days before the date of Week 4/EOT Visit) of 
study treatment  


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Relevant Output 
Table 14.2.10.1A   Rescue Medication Use by Treatment  (mITT Population) 
Table 14.2.10.1B  
Rescue Medication Use by Treatment (Per Protocol Population 1)    
Listing 16.2.6.8   
Rescue Medication Diary (All Randomized Patients) 
4.4. 
Safety Analyses 
Safety analyses will be conducted using the Safety population. 
4.4.1. 
Study Drug Exposure and Compliance 
The first IMP dose will be applied at the clinic, in the presence of a qualified unblinded 
treatment administrator; subsequent applications will be completed by the patient at the clinic 
(on Day 15/Week 2 Visit) or at their home (all other applications). Accurate dosing will be 
ensured by using a dosing card (to be used for all study drug applications). Patients will be 
dispensed a two-week supply of study drug (three tubes of 100 grams) on Day 1 (Baseline/FV1) 
and on Day 15 (Week 2 Visit) and will be asked to return all unused study drug supplies at the 
next study visit. 
The following study drug exposure and compliance parameters will be summarized using 
descriptive statistics for Safety population and mITT population, respectively. 
x Number of missed IMP applications evaluated based on overall target number of IMP 
applications (the greater of overall duration of exposure up to 30 days OR 26 days 
multiplied by 4 IMP applications per day) will be calculated by subtracting the number 
of IMP applications from overall target number of IMP applications. The number and 
percentage of patients with at least one missed IMP application, 5 to 8 consecutive 
missed IMP applications, 9 to 12 consecutive missed IMP applications or >12 
consecutive missed IMP applications will be provided. 
x Overall treatment period duration of exposure (days) will be derived as date of last 
IMP application minus date of first IMP application + 1 (Data source: Patient diary). 
o Week 1 + 2 duration of exposure (days) will be derived as last date of IMP 
application before the date of Week 2 Visit minus date of first IMP application + 
1. 
o Week 3 + 4 (last 2 weeks of study treatment) duration of exposure (days) will 
be derived as date of last IMP application minus date of Week 2 Visit + 1.   
x Overall treatment period number of IMP applications (doses) will be derived by 
counting the number of times where IMP was applied regardless of days or frequency of 
applications (Data source: patient diary). 
o Week 3 + 4 (last 2 weeks of study treatment) number of IMP Applications 
(doses) will be derived by counting the number of times where IMP was applied 


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regardless of days or frequency of applications in week 3 and 4 (starting from 
date of week 2 visit to the date of last IMP application). 
x Overall treatment period target number of IMP applications will be derived as (the 
greater of overall duration of exposure up to 30 days OR 26 days) multiplied by 4 IMP 
applications per day (Data source: patient diary). 
o Week 3 + 4 (last 2 weeks of study treatment) target number of IMP 
applications will be derived as (the greater of Week 3 + 4 duration of exposure 
up to 16 days OR 13 days) multiplied by 4 IMP applications per day. 
x Overall treatment period percent compliance (%) based on the number of 
applications will be calculated as (overall number of IMP applications divided by 
Overall treatment period target number of IMP applications) x 100. 
o Week 3 + 4 (last 2 weeks of study treatment) percent compliance (%) based 
on the number of applications will be calculated as (Week 3 + 4 number of 


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IMP applications divided by Week 3 + 4 target number of IMP applications) x 
100. 
x Overall treatment period amount of IMP used (g) will be derived as the total amount 
of IMP dispensed (g) minus the total amount of IMP returned (g) (Data source: patient 
Investigational product dispensing logs). 
o Week 3 + 4 (last 2 weeks of study treatment) amount of IMP used (g) will be 
derived as the amount of IMP dispensed (g) on Week 2 Visit (last kit number) 
minus the amount of IMP returned (g) on the same kit number. 
x Overall treatment period target amount of IMP used (g) will be derived as the 
overall treatment period target number of IMP applications multiplied by 4 g (Note: 
Overall treatment period target number of IMP applications derived above). 
o Week 3 + 4 (last 2 weeks of study treatment) target amount of IMP used (g) 
will be derived as the Week 3 + 4 target number of IMP applications multiplied 
by 4 g (Note: Week 3 + 4 target number of IMP applications derived above). 
x Overall treatment period percent compliance (%) based on the amount of IMP 
used (g) will be calculated as the amount of IMP used (g) divided by the target amount 
of IMP used (g) x 100. 
o Week 3 + 4 (last 2 weeks of study treatment) percent compliance (%) based 
on the amount of IMP used (g) will be calculated as the week 3 + 4 amount of 
IMP used (g) divided by week 3 + 4 target amount of IMP used (g) x 100. 
x Number of Days of Exposure (Overall treatment period) will be calculated as the 
number of distinct days where a patient has applied IMP at least once (Data source: 
patient diary). 
x Average daily exposure (g/day) will be calculated as overall treatment period amount 
of IMP used (g) divided by number of days of exposure.  
x Average exposure per dose (g/dose) will be calculated as the overall treatment period 
amount of IMP used (g) divided by the overall treatment period number of IMP 
applications (doses). 
All exposure data, including date and time of each IMP application, will be presented in a by-
patient data listing.  
Relevant Output 
Table 14.3.5.1.1   
Treatment Compliance Based on Number of Applications (mITT 
Population) 
Table 14.3.5.1.2   
Treatment Compliance Based on Amount of IMP Used (mITT Population) 
Table 14.3.5.1.3 
Treatment Exposure (Safety Population) 
Listing 16.2.5.1.1   Study Drug Dispensation (All Randomized Patients) 
Listing 16.2.5.1.2  Study Drug Application Diary (Safety Population) 
Listing 16.2.5.1.3   Study Drug Administration Summary Parameters - Based on Number of 
IMP Applications (Safety Population) 
Listing 16.2.5.1.4   Study Drug Administration Summary Parameters - Based on IMP Weight 
(Safety Population) 


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4.4.2. 
Adverse Events 
All AEs will be coded using the MedDRA coding system (MedDRA version 23.1) and 
displayed in tables and data listings using system organ class (SOC) and preferred term (PT). 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as any AE with onset during or after the first application of 
IMP through the end of the study (Week 6/EOS visit), or any event that was present at baseline 
but worsened in severity during or after the first application of IMP. 
4.4.2.1. 
Summary of Adverse Events 
The following AE subsets will be summarized by the total number of events and the number and 
percentage of patients with:  
x At least 1 treatment-emergent AE (TEAE) 
x At least 1 treatment-related TEAE 
x At least 1 serious TEAE 
x At least 1 treatment-related serious TEAE 
x At least 1 TEAE, by maximum severity 
x At least 1 TEAE leading to study drug discontinuation 
x At least 1 TEAE leading to withdrawal from the study 
x At least 1 TEAE leading to death 
x At least 1 TEAE related to application site (See Section 7.1 Table 2 for a list of 
applicable MedDRA PTs)  
In addition to the overall summary, each of the above categories will also be summarized and 
tabulated for each treatment group by SOC and PT. In these tabulations, each subject will 
contribute only once to the count for a given AE (SOC or PT), regardless of the number of 
episodes. The total number of AE events will also be summarized.  
No formal hypothesis-testing analysis of AE incidence rates will be performed. 
All AEs occurring on-study will be listed in by-patient data listings. By-patient listings also will 
be provided for serious AEs, AEs leading to study drug discontinuation and withdrawal from the 
study, and AEs leading to death.  
Relevant Output 
Table 14.3.1.1   Treatment-Emergent Adverse Events Summary (Safety Population) 
Table 14.3.1.2   Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term (Safety Population) 
Table 14.3.1.3   Treatment-Related Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term (Safety Population) 


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Table 14.3.1.4   Serious Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.5   Serious Treatment-Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.6   Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, 
and Maximum Severity (Safety Population) 
Table 14.3.1.7   Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation 
by System Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.8   Treatment-Emergent Adverse Events Leading to Death by System Organ 
Class and Preferred Term (Safety Population) 
Table 14.3.1.9   Application Site Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term (Safety Population) 
Table 14.3.2.1   Listing of Serious Adverse Events 
Table 14.3.2.2   Listing of Adverse Events Leading to Treatment Withdrawal  
Table 14.3.2.3 
Listing of Adverse Events Leading to Withdrawal from the Study 
Table 14.3.2.4   Listing of Adverse Events Leading to Death 
Listing 16.2.7.1   Listing of Adverse Events 
4.4.3. 
Laboratory Data 
Clinical laboratory values will be expressed using the International System of Units (SI). 
The actual value and change from Baseline to each on-study evaluation will be summarized for 
each clinical laboratory parameter, including hematology, clinical chemistry, and coagulation. 
In the event of repeat values, the last non-missing value per study day/time will be used. 
Shift tables of change from Baseline in level categories (normal, low, high, missing) will be 
presented by treatment group across all visits.   
Urine drug screen results will be summarized and presented by treatment group, including the 
number and percentage of patients with at least one positive result. Urine drug screen will 
include amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, 
opiates, phencyclidine, and a panel of tricyclic antidepressants.  
All laboratory data will be provided in data listings, including urine pregnancy test results, urine 
drug screen results, and serology test results at screening. Data listings will also be presented for 
all abnormal laboratory values, with a flag indicating clinical significance.  
Relevant Output 
Table 14.3.5.2.1   Clinical Laboratory Data Summary of Actual Value and Change from 
Baseline: Hematology (Safety Population) 
Table 14.3.5.2.2   Clinical Laboratory Data Summary of Actual Value and Change from 
Baseline: Chemistry (Safety Population) 
Table 14.3.5.2.3   Clinical Laboratory Data Summary of Actual Value and Change from 
Baseline: Coagulation (Safety Population) 
Table 14.3.5.2.4   Urine Drug Screen Results by Visit (Safety Population) 


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Table 14.3.5.3.1   Clinical Laboratory Shifts from Baseline to Each On-Study Visit: 
Hematology (Safety Population) 
Table 14.3.5.3.2   Clinical Laboratory Shifts from Baseline to Each On-Study Visit: Chemistry 
(Safety Population) 
Table 14.3.5.3.3   Clinical Laboratory Shifts from Baseline to Each On-Study Visit: 
Coagulation (Safety Population) 
Listing 16.2.8.1   Clinical Laboratory Results: Hematology (Safety Population) 
Listing 16.2.8.2   Clinical Laboratory Results: Chemistry (Safety Population) 
Listing 16.2.8.3   Clinical Laboratory Results: Coagulation (Safety Population) 
Listing 16.2.8.4   Clinical Laboratory Results: Urinalysis (Safety Population) 
Listing 16.2.8.5   Clinical Laboratory Results: Serology (Safety Population) 
Listing 16.2.8.6   Urine Drug Screen (Safety Population) 
Listing 16.2.8.7   Pregnancy Test Results (Safety Population) 
Listing 16.2.8.8 
Listing of Abnormal Clinical Laboratory Parameters (Safety Population) 
 
4.4.4. 
Vital Signs and Physical Examination 
The actual value and change from Baseline to each on-study evaluation will be summarized for 
vital signs. Vital signs include oral temperature, pulse rate, respiratory rate, systolic blood 
pressure, and diastolic blood pressure. 
Physical examination results (normal; abnormal, not clinically significant; abnormal, clinically 
significant; not done) at each time point will be summarized.  
All vital sign measurements and physical examination findings will be presented for each 
patient in a data listing. 
Relevant Output 
Table 14.3.5.4   Summary of Actual Value and Change from Baseline for Vital Signs (Safety 
Population) 
Table 14.3.5.5   Physical Examination (Safety Population) 
Listing 16.2.9.1   Vital Signs (Safety Population) 
Listing 16.2.9.2   Physical Examinations (Safety Population) 
4.4.5. 
Electrocardiogram 
Descriptive statistics (including actual value and change from baseline) will be provided for 
heart rate (HR), PR interval, QRS interval, QT interval, and QTc interval at Screening Visit 
(baseline) and Week 4/EOT Visit. QTc intervals calculated and reported on the electronic CRF 
using methods other than the Bazett method will be calculated using the following formula: 
QTc = QT / ¥RR 


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Number and percentage of subjects with normal, abnormal, and clinically significant abnormal 
results at Screening Visit and Week 4/EOT Visit for overall ECG interpretation will be 
provided. 
Electrocardiogram data for each subject will be provided in a data listing. 
Relevant Output 
Table 14.3.5.6   Summary of Actual Value and Change from Baseline for Electrocardiogram 
Results (Safety Population) 
Table 14.3.5.7   Electrocardiogram Interpretation by Visit (Safety Population) 
Listing 16.2.9.3   12-Lead ECG (Safety Population) 
4.4.6. 
Analysis of Skin Irritation 
Skin irritation will be assessed by the Investigator using the Berger/Bowman Scoring Scale 
(Berger and Bowman, 1982; US FDA Guidance 2018b), which comprises the “Dermal 
Response” and “Other Effects” scoring system, as outlined in Protocol Appendix 4. The Dermal 
Response score ranges from 0 (no evidence of irritation) to 7 (strong reaction spreading beyond 
the application site). The Other Effect score is a combination of a letter and a number with 7 
possible ordinal categories: A(0), B(1), C(2), F(3), G(3), H(3).  
The Total Skin Irritation Score will be calculated as the sum of the “Dermal Response” score 
and the numeric equivalent of the “Other Effect”.  
Total Skin Irritation Score, Dermal Response score, and Other Effect score (in “letter (number)” 
format) will be summarized descriptively by treatment group and visit.  
Missing Dermal Response and Other Effect scores will be imputed using LOCF as described in 
Section 3.10.3.   
Relevant Output 
Table 14.3.5.8   
Skin Irritation Assessment Results by Visit (Safety Population) 
Listing 16.2.9.4   Skin Irritation Assessment 
4.4.7. 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug Dictionary (WHO Drug Global 
B3 September 2020). Results will be tabulated by anatomic therapeutic class (ATC) Level 3 and 
PT. In any tabulation, a patient contributes only once to the count for a given ATC class or PT.  
Concomitant medications will be tabulated by treatment group, where any medications that did 
not end prior to first IMP application will be included. Missing and partial dates for concomitant 
determination will be handled as described in Section  3.10.4.  
The use of concomitant medications will be included in a by-subject data listing. A concomitant 
medication that is used as a rescue medication will be flagged in the listing.  


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Relevant Output 
Table 14.3.5.9   Concomitant Medications (Safety Population) 
Listing 16.2.9.5   Prior and Concomitant Medications (All Randomized Patients) 
 
 


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5. 
CHANGES TO PLANNED ANALYSES 
The following are changes between the protocol-defined statistical analyses and those presented 
in this SAP: 
x 
Section 6.4 of the final study protocol version 4.0) defined inadequate compliance as 80% of 
the planned doses (i.e., <23 out of 28) applied during each week of study treatment. In addition, 
inadequate compliance requiring permanent treatment discontinuation was defined as >3 days of 
consecutive study treatment missed. In addition to these criteria, compliance based on the 
amount of IMP applied relative to the target amount of IMP is also addressed on this SAP; see 
Section 4.4.1. 
x Compared to the final study protocol, this SAP (Section  2.1) includes an expanded 
definition of the PP1 Population, and provisions for a second Per Protocol Population 
(i.e., PP2) that also includes criteria for minimum compliance based on the amount of 
IMP used by study patients.    
x The analysis method for the percentages of patients achieving 20%, 30% and 50% 
reduction from Baseline in worst daytime pain and in worst nighttime detailed in Section 
4.3.2.4 of this SAP was not specified in the final protocol. 


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6. 
REFERENCES 
Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical 
management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019 
Nov;27(11):1578-1589. doi: 10.1016/j.joca.2019.06.011. 
Bellamy N, Buchanan WW, Goldsmith CH, et al. Validation study of WOMAC: a health status 
instrument for measuring clinically important patient relevant outcomes to antirheumatic drug 
therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988 Dec;15(12):1833-
40. 
Berger RS and Bowman JP. A Reappraisal of the 21-Day Cumulative Irritation Test in Man. 
Journal of Toxicology: Cutaneous and Ocular Toxicology. 1982;1(2):109-115. DOI: 
10.3109/15569528209051516. 
CELEBREX (celecoxib) capsules - Canadian Product Monograph. Pfizer Canada ULC, 
Kirkland, Quebec. Date of Revision: March 19, 2019. 
CELEBREX(celecoxib) capsules, for oral use - U.S. Prescribing Information. New York, NY: 
G.D. Searle, LLC. Revised 5/2019. 
Cross M, Smith E, Hoy D, et al. The global burden of hip and knee osteoarthritis: estimates 
from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7):1323-1330. 
doi:10.1136/annrheumdis-2013-204763. 
GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and 
national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 
195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016 
[published correction appears in Lancet. 2017 Oct 28;390(10106):e38]. Lancet. 
2017;390(10100):1211-1259. doi:10.1016/S0140-6736(17)32154-2. 
Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019 Apr 27;393(10182):1745-1759. doi: 
10.1016/S0140-6736(19)30417-9. 
Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of 
Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the 
Hand, Hip, and Knee. Arthritis Rheumatol. 2020 Jan 6. doi: 10.1002/art.41142. 
McKenna F, Borenstein D, Wendt H, et al. Celecoxib versus diclofenac in the management of 
osteoarthritis of the knee: a placebo-controlled, randomised, double-blind comparison. 
Scandinavian Journal of Rheumatology 2001;30(1):11–8. 
Rannou F, Pelletier JP, Martel-Pelletier J. Efficacy and safety of topical NSAIDs in the 
management of osteoarthritis: Evidence from real-life setting trials and surveys. Semin Arthritis 
Rheum. 2016 Feb;45(4 Suppl):S18-21. doi: 10.1016/j.semarthrit.2015.11.007. 
Rother M, Lavins BJ, Kneer W, et al. Efficacy and safety of epicutaneous ketoprofen in 
Transfersome (IDEA-033) versus oral celecoxib and placebo in osteoarthritis of the knee: 
multicentre randomised controlled trial. Annals of the Rheumatic Diseases 2007;66(9):1178–83. 


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US Food and Drug Administration. Guidance for Industry (Draft): Assessing the Irritation and 
Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs. October 
2018b. Available at: https://www.fda.gov/media/117569/download 
Williams GW, Ettlinger RE, Ruderman EM, Hubbard RC, Lonien ME, Yu SS, et al. Treatment 
of osteoarthritis with a once-daily dosing regimen of celecoxib: a randomized, controlled trial. 
Journal of Clinical Rheumatology 2000;6(2):65–74. 


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7. 
APPENDIX 
7.1. 
Adverse Events Related to Application Site 
The PTs listed in Table 2 will be used to summarize all TEAEs related to study drug application 
site.  
Table 2  
MedDRA Preferred Terms for Application Site Adverse Events 
System Organ 
Class Code 
System Organ 
Class 
Preferred 
Term Code 
Preferred Term 
10018065 
General disorders 
and administration 
site conditions 
10003036 
Application site dermatitis 
10018065 
General disorders 
and administration 
site conditions 
10003050 
Application site oedema 
10018065 
General disorders 
and administration 
site conditions 
10065331 
Application site fissure 
10018065 
General disorders 
and administration 
site conditions 
10049043 
Application site papules 
10018065 
General disorders 
and administration 
site conditions 
10058730 
Application site photosensitivity 
reaction 
10018065 
General disorders 
and administration 
site conditions 
10066209 
Application site scab 
10018065 
General disorders 
and administration 
site conditions 
10052162 
Application site discharge 
10018065 
General disorders 
and administration 
site conditions 
10065577 
Application site erosion 
10018065 
General disorders 
and administration 
site conditions 
10003046 
Application site irritation 


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System Organ 
Class Code 
System Organ 
Class 
Preferred 
Term Code 
Preferred Term 
10018065 
General disorders 
and administration 
site conditions 
10064578 
Application site exfoliation 
10018065 
General disorders 
and administration 
site conditions 
10003054 
Application site rash 
10018065 
General disorders 
and administration 
site conditions 
10050104 
Application site urticaria 
10018065 
General disorders 
and administration 
site conditions 
10048943 
Application site dryness 
10018065 
General disorders 
and administration 
site conditions 
10003041 
Application site erythema 
10018065 
General disorders 
and administration 
site conditions 
10003053 
Application site pruritus 
10018065 
General disorders 
and administration 
site conditions 
10072694 
Application site haemorrhage 
10018065 
General disorders 
and administration 
site conditions 
10003055 
Application site reaction 
10018065 
General disorders 
and administration 
site conditions 
10048941 
Application site vesicles